National Institute for Health and Care Excellence
DIAGNOSTICS ASSESSMENT
PROGRAMME
Evidence overview
Type 1 diabetes: Integrated sensor-augmented pump
therapy systems for managing blood glucose levels
(the MiniMed Paradigm Veo system and the Vibe and
G4 PLATINUM CGM system)
This overview summarises the key issues for the Diagnostics Advisory
Committee’s consideration. This document is intended to be read in
conjunction with the final scope issued by NICE for the assessment and the
diagnostics assessment report. A glossary of terms can be found in Appendix
B and an overview of existing and draft NICE guidance recommendations for
continuous subcutaneous insulin infusion and continuous glucose monitoring
can be found in Appendix C.
1
Background
1.1
Introduction
The purpose of this assessment is to evaluate the clinical and cost
effectiveness of integrated sensor-augmented pump therapy systems, the
MiniMed Paradigm Veo system and the Vibe and G4 PLATINUM CGM
system, for managing blood glucose levels in people with type 1 diabetes.
Both of the interventions comprise an insulin pump with integrated continuous
glucose monitoring, which show interstitial glucose levels and produce alerts if
the glucose levels become too high or too low. In addition the MiniMed
Paradigm Veo System can automatically suspend insulin delivery if there is no
response to a low glucose warning.
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Overview – Type 1 diabetes: Integrated sensor-augmented pump therapy systems for
managing blood glucose levels
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Provisional recommendations on the use of these technologies will be
formulated by the Diagnostics Advisory Committee at the Committee meeting
on 25 March 2015.
1.2
Scope of the evaluation
Table 1 Scope of the evaluation
Decision question
Populations
Does the use of the MiniMed Paradigm Veo System and,
the Vibe and G4 PLATINUM CGM system for managing
blood glucose levels in type 1 diabetes represent a
clinically- and cost-effective use of NHS resources?
People with type 1 diabetes
If evidence permits, the following sub-populations may be
included:
 Women who are pregnant and those planning
pregnancy (not including gestational diabetes)
 People who need to self-monitor their blood glucose
level more than 10 times a day.
 People who are having difficulty managing their
condition. These difficulties include:
o not maintaining the recommended HbA1c
level of 69.4 millimoles/mole (8.5%) or
below
o nocturnal hypoglycaemia
o impaired awareness of hypoglycaemia.
o severe hypoglycaemia defined as having
low blood glucose levels that requires
assistance from another person to treat.
Interventions


Comparator

Healthcare setting
The MiniMed Paradigm Veo System
The Vibe and G4 PLATINUM CGM system
Capillary blood testing with continuous
subcutaneous insulin infusion
 Capillary blood testing with multiple daily insulin
injections
 Continuous glucose monitoring with continuous
subcutaneous insulin infusion (non-integrated)
 Continuous glucose monitoring with multiple daily
injections
Self-use supervised by primary or secondary care
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Outcomes
Clinical outcomes for consideration may include:
 Adverse events from testing, false results,
treatment and sequelae
 Mean blood glucose levels including fasting glucose
levels
 Postprandial glucose level
 Amount of insulin being administered
 Number of ketone tests
 Episodes of diabetic ketoacidosis
 Episodes of hyperglycaemia (mild and severe)
 Episodes of hypoglycaemia (mild and severe
including nocturnal)
 Frequency of hypoglycaemic episodes
 HbA1c levels
 Long term complications of diabetes and treatment
including retinopathy, neuropathy, cognitive
impairment and end stage renal disease.
 Morbidity and mortality
In pregnant women, additional type 1 diabetes-related
clinical outcomes may include:
 Premature birth
 Macrosomia (excessive birth weight)
 Respiratory distress syndrome in newborn
Patient-reported outcomes for consideration may include:
 Acceptability of testing and method of insulin
administration
 Anxiety about experiencing hypoglycaemia
 Health related quality of life
Costs will be considered from an NHS and Personal Social
Services perspective. Costs for consideration may include:
 Cost of consumables (glucose testing strips,
sensors, infusion sets, ketone testing strips)
 Cost of technology
 Cost of insulin
 Cost of staff and training of staff and users.
 Costs of NHS treatment for episodes of diabetic
ketoacidosis
 Costs of NHS treatment for severe hypoglycaemic
episodes
 Medical costs arising from ongoing care and
treatment diabetes and associated sequelae
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
Time horizon
Costs of managing clinical outcomes arising from
diabetes during pregnancy. This may include:
o Premature birth
o Macrosomia (excessive birth weight)
o Respiratory distress syndrome in newborn
The cost-effectiveness of interventions should be
expressed in terms of incremental cost per quality-adjusted
life year.
The time horizon for estimating clinical and cost
effectiveness should be sufficiently long to reflect any
differences in costs or outcomes between the technologies
being compared.
Further details including descriptions of the interventions, comparators, care
pathway and outcomes can be found in the final scope.
2
The evidence
This section summarises data from the diagnostics assessment report
compiled by the External Assessment Group.
2.1
Clinical Effectiveness
The External Assessment Group conducted a systematic review of the
evidence on the clinical effectiveness of the MiniMed Paradigm Veo system
and the Vibe and G4 PLATINUM CGM system for managing blood glucose
levels in people with type 1 diabetes. Details of the systematic review can be
found starting on page 25 of the diagnostics assessment report.
In total, 54 publications reporting the results of 19 studies met the inclusion
criteria. These studies included either the intervention or comparator
technologies in a treatment arm. Two studies reported data for the MiniMed
Paradigm Veo system, 8 studies reported data for an integrated sensoraugmented pump therapy system without a low glucose suspend function
(included as a proxy for the Vibe and G4 PLATINUM system), and the
remainder reported data for capillary blood testing with continuous
subcutaneous insulin and capillary blood testing with multiple daily insulin
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injections. No studies reported data for either continuous glucose monitoring
with continuous subcutaneous insulin infusion or continuous glucose
monitoring with multiple daily insulin injections. In total, 19 studies were
included. Of the 19 included studies:
 10 include adults only
 3 include children only
 3 include a mixed population (adults and children) but do not report data for
each group separately
 2 studies include a mixed population and report data for adults and children
separately
 1 study includes pregnant women only.
The study which includes pregnant women only reports data for capillary
blood testing with continuous subcutaneous insulin infusion and capillary
blood testing with multiple daily insulin injections. Therefore it was not
reported further in the analyses. There is substantial heterogeneity in the
populations included in these studies. Of the 19 included studies, 9 include
people who had not previously used an insulin pump, and only 4 studies
report including people who had previously experienced hypoglycaemia (the
group most likely to gain benefit from using the interventions).
All included studies were randomised controlled trials. The methodological
quality of each study was appraised using the Cochrane risk of bias tool.
Eleven of the 19 studies were rated as a high risk of bias, primarily because
the participants, clinicians and assessors were not blinded to the allocation of
interventions and HbA1c results were interpreted with knowledge of the
treatment allocation. Of the remaining 8 studies, 4 were rated as unclear risk
of bias and 4 were rated as low risk of bias.
The results of the studies were presented as a narrative synthesis and
combined into network meta-analyses where possible. Direct head-to-head
meta-analyses were performed using a fixed-effects model unless otherwise
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stated (see Table 4) and indirect meta-analyses were performed according to
the method devised by Bucher et al. (1997). Full details of the quality
assessment can be found in Appendix 2 of the diagnostics assessment report.
Clinical effectiveness in adults
Twelve studies report data for adults; 10 studies conducted solely in adults
and 2 studies reporting subgroup data for adults. The results for the MiniMed
Paradigm Veo system and the integrated sensor-augmented pump therapy
system without a low glucose suspend function are shown below. Full details
of the analysis can be found starting on page 34 of the diagnostics
assessment report.
MiniMed Paradigm Veo system
One study (ASPIRE in-home) compared the MiniMed Paradigm Veo system
with an integrated sensor-augmented pump therapy system at three months
follow-up in adults with type 1 diabetes. This study included people who had
experienced 2 or more nocturnal hypoglycaemic events during the study runin phase, but excluded people who had experienced more than 1 episode of
severe hypoglycaemia in the 6 months prior to study recruitment. The study
reports that hypoglycaemic events occurred less frequently in the MiniMed
Paradigm Veo system group (3.3 ± 2.0 weekly events per patient compared to
4.7 ± 2.7 weekly events per patient; p<0.001), and this effect was consistent
when the results were restricted to nocturnal hypoglycaemic events (1.5 ±1.0
weekly events per patient compared to 2.2 ± 1.3 weekly events per patient;
p<0.001). The study also reports that, for the MiniMed Paradigm Veo system,
the mean hypoglycaemic area under the curve (AUC [derived from the
magnitude and severity of the sensor measured glucose level]) was
significantly lower (less severe) for all hypoglycaemic events combined and
nocturnal hypoglycaemia (p<0.001). No statistically significant differences
were observed for change in HbA1c, meter blood glucose values, insulin use,
diabetic ketoacidosis, quality of life, device related serious adverse events and
death.
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Data from the ASPIRE in-home study were used in a network analysis
(including Peyrot et al. [2009], Lee et al. [2007] and DeVries et al. [2002]) to
compare the MiniMed Paradigm Veo system to the integrated sensor
augmented pump therapy system with no low glucose suspend, capillary
blood testing with continuous subcutaneous insulin infusion, and capillary
blood testing with multiple daily insulin injections. None of the 3 additional
studies included in the network analysis reported whether they included
people who had experienced hypoglycaemia. The network analysis included
change in HbA1c and diabetic ketoacidosis at 3 months follow up as
outcomes. No statistically significant differences were observed in any of the
comparisons. Full details of the network analysis can be found on page 37 of
the diagnostics assessment report.
Integrated sensor-augmented pump therapy system (no low glucose suspend)
Five studies included integrated sensor-augmented pump therapy in a
treatment arm. One study (Hirsch et al. 2008) compared an integrated sensoraugmented pump therapy system with capillary blood testing and continuous
subcutaneous insulin infusion. This study did not exclude people with
hypoglycaemia unawareness. The study reports no statistically significant
difference in change in HbA1c (%) between the groups at 6 months follow up
(-0.0364% [standard error 0.1412] p=0.80).
The remaining 4 studies (Hermanides et al. 2011 [Eurythmics], Lee et al.
2007, Peyrot et al. 2009 and Bergenstal et al. 2010 [STAR-3]) compared the
integrated sensor-augmented pump therapy system with capillary blood
testing combined with multiple daily insulin injections. 3 of these studies did
not state inclusion/exclusion criteria for hypoglycaemia. Bergenstal et al.
(2010) excluded people with hypoglycaemia unawareness. The studies report
multiple outcomes at various follow-up points and are reported in full starting
on page 39 of the diagnostics assessment report. The key results are
summarised below:
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3 months follow up (2 studies): 1 study (Lee et al. 2007) reports a statistically
significant difference in the change in HbA1c (%) in favour of the integrated
sensor-augmented pump therapy system (-0.97; p=0.02). This difference was
not statistically significant in Peyrot et al. (2009) (-0.69; p=0.071) It is not clear
why this was not statistically significant in Peyrot et al. (2009), but both studies
include relatively small numbers of participants; Lee et al. (2007) includes 16
people and Peyrot et al. (2009) includes 27 people. No statistically significant
differences were observed for hypoglycaemic events, diabetic ketoacidosis or
serious adverse events in either study.
6 months follow up (1 study): Hermanides et al. (2011) reports statistically
significant differences in favour of the integrated sensor augmented pump
therapy system for the following outcomes:
 change in HbA1c (%); -1.1 (95%Confidence Interval [95% CI] -1.47 to 0.73)
 number of people with HbA1c <7% (53 mmol/mol) (14/41 compared to
0/36; p<0.001)
 daily insulin use (difference of -11.0 units per day [95%CI -16.1 to -5.9;
p<0.001])
 quality of life measured by the SF-36 (difference of 7.9 [95%CI 0.5 to 15.3;
p=0.04]).
No statistically significant difference was seen for hypo- or hyperglycaemic
events.
12 months follow up (1 study, excludes people with hypoglycaemia
unawareness): Bergenstal et al. (2010) reports statistically significant
differences in favour of the integrated sensor-augmented pump therapy
system for the following outcomes:
 change in HbA1c (%) (-0.6 [95%CI -0.8 to -0.4; p<0.001])
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 number of people with HbA1c <7% (53 mmol/mol) (57/166 compared to
19/163; p<0.001)
 hyperglycaemic AUC (3.74 compared to 7.38; p<0.001)
 improved quality of life measured by the SF-36 (difference of 3 [95%CI 1.36
to 4.64])
 fear of hypoglycaemia measured by the hypoglycaemia fear survey
(difference of -6.5% [95%CI -9.76 to -3.27]).
No statistically significant differences were seen for hypoglycaemic AUC,
severe hypoglycaemia or diabetic ketoacidosis.
All 5 studies were incorporated into several network analyses which were
performed to calculate effect estimates for the integrated sensor-augmented
pump therapy system. Full details of these network analyses can be found
starting on page 42 of the diagnostics assessment report. The results of the
analyses (table 2) suggest that there is a statistically significant reduction in
HbA1c (%) (weighted mean difference -1.10 [95% CI -1.46 to -0.74]), and a
statistically significant difference in the proportion of people with HbA1c <7%
(53 mmol/mol) (relative risk 25.55 [95%CI 1.58 to 413.59]) in favour of the
integrated sensor-augmented pump therapy system when compared to
capillary blood testing with multiple daily insulin injections. Quality of life
(measured by the diabetes treatment satisfaction questionnaire) associated
with integrated sensor augmented pump therapy is also significantly improved
when compared to both capillary blood testing with continuous subcutaneous
insulin infusion (weighted mean difference 5.90 [95%CI 2.22 to 9.58]) and
capillary blood testing with multiple daily insulin injections (weighted mean
difference 8.60 [95%CI 6.28 to 10.92]).
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Table 2 Results of network analyses for the clinical effectiveness of the integrated sensor-augmented pump therapy
system in adults
Capillary blood testing with continuous
subcutaneous insulin infusion
Capillary blood testing with multiple daily
insulin injections
Proportion of people with severe hypoglycaemia at 3 months: relative risk (95% CI); 3 studies
0.33 (0.03 to 3.87)
0.19 (0.02 to 1.51)
Integrated sensor augmented
pump therapy system
Indirect comparison
Direct comparison
Change in HbA1c (%) at 6 months: weighted mean difference (95%CI); 3 studies
-1.10 (-1.46 to -0.74)
-0.05 (-0.31 to 0.21)
Integrated sensor augmented
pump therapy system
Comparative data in network
Comparative data in network
Proportion of people with HbA1c <7% (53 mmol/mol) at 6 months; relative risk (95%CI); 2 studies
25.55 (1.58 to 413.59)
1.45 (0.74 to 2.84)
Integrated sensor augmented
pump therapy system
Direct comparison
Direct comparison
Quality of life*at 6 months; weighted mean difference (95%CI); 2 studies
5.90 (2.22 to 9.58)
8.60 (6.28 to 10.92)
Integrated sensor augmented
pump therapy system
Indirect comparison
Direct comparison
Statistically significant differences are shown in bold; *measured by the Diabetes Treatment Satisfaction Questionnaire
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Clinical effectiveness in children
Six studies report data for children, including 1 study (Ly et al. 2013) which
reports data for the MiniMed Paradigm Veo system. Of the remaining 5
studies, 2 report data for an integrated sensor augmented pump therapy
system (used as a proxy for the Vibe and G4 PLATINUM CGM system), and 3
report data for capillary blood testing with continuous subcutaneous insulin
infusion and capillary blood testing with multiple daily insulin injections.
MiniMed Paradigm Veo System
One study (Ly et al. 2013) reports results for the MiniMed Paradigm Veo
system compared with capillary blood testing and continuous subcutaneous
insulin infusion at 6 months follow up in a mixed population aged 4 to 50
years. 70% of the participants are aged under 18 years, and the study was
included in the analysis as it is the only study to report data for the MiniMed
Paradigm Veo system. This study includes people with an impaired
awareness of hypoglycaemia.
The study reports a statistically significant difference in the rate of
hypoglycaemic events, with a lower rate of events in the MiniMed Paradigm
Veo group (Incidence rate ratio 3.6 [95%CI 1.7 to 7.5, p<0.001]). No
statistically significant differences were reported for change in HbA1c, the
number of people experiencing hypoglycaemic events or the hypoglycaemia
unawareness score. Ly et al. (2013) was used to compare the MiniMed
Paradigm Veo system with an integrated sensor augmented pump therapy
system and capillary blood testing with continuous subcutaneous insulin
infusion in a network analysis which also included Hirsch et al. (2008). The
network analysis included 1 outcome, change in HbA1c at 6 months, and
shows no statistically significant difference between the technologies. The
results of this analysis are shown in table 3. Full details of this analysis can be
found on page 48 of the diagnostics assessment report.
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Table 3 Results of network meta-analysis for the MiniMed Paradigm Veo
System in children
Integrated sensor
augmented insulin pump
therapy
Capillary blood
testing with
continuous
subcutaneous insulin
infusion
Change in HbA1c (%) at six months follow up: weighted mean difference
(95% CI); 2 studies
-0.04 (-0.26 to 0.18)
MiniMed Paradigm Veo 0.38 (-0.16 to 0.92)
system
Indirect comparison
Direct comparison
No statistically significant differences were observed in any of the
comparisons
Integrated sensor-augmented pump therapy system (no low glucose suspend)
One study (Hirsch et al. 2008) compared an integrated sensor-augmented
pump therapy system with capillary blood testing and continuous
subcutaneous insulin infusion. The study includes data for the change in
HbA1c (%) at 6 months and found no statistically significant difference
between the technologies.
One study (Bergenstal et al. 2010) compared an integrated sensor augmented
pump therapy system with capillary blood testing and multiple daily insulin
injections, and reports data for 12 months follow-up for multiple outcomes. No
statistically significant differences were observed for the following outcomes:
 proportion with HbA1c ≤7% (53 mmol/mol)
 the number of people experiencing severe hypoglycaemic events
 the rate of severe hypoglycaemic events hypoglycaemia AUC (<70mg/dL)
 number of patients with diabetic ketoacidosis
 quality of life (measured by the paediatric quality of life inventory and
hypoglycaemia fear survey).
There was a statistically significant change in HbA1c (%) (-0.5 [95%CI -0.8 to
-0.2, p<0.001]) and a significantly lower hyperglycaemic AUC (>250 mg/dL)
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(9.2 compared to 17.64; p<0.001) in favour of the integrated sensoraugmented insulin pump therapy
Additional clinical-effectiveness analyses for economic model
A full network analysis of 14 studies was performed to calculate estimates of
change in HbA1c and severe hypoglycaemic event rates in adults for each of
the interventions and for capillary blood testing with continuous subcutaneous
insulin infusion and capillary blood testing with multiple daily injections. This
analysis includes 10 studies which report data for adults only, 2 studies which
report subgroup data for adults and 2 studies which report data for a mixed
population.
The results of this analysis (table 4) suggest that there are statistically
significant changes in HbA1c in favour of both the MiniMed Paradigm Veo
system and the integrated sensor-augmented pump therapy system when
compared to capillary blood testing with multiple daily insulin injections. The
results also suggest that there is a statistically significant difference in the
severe hypoglycaemic event rate in favour of capillary blood testing with
continuous subcutaneous insulin infusion when compared to the integrated
sensor-augmented pump therapy system. As the analysis pools different
population and results from different lengths of follow up it is subject to
substantial bias arising from heterogeneity in the studies. Full details of this
analysis can be found starting on page 50 of the diagnostics assessment
report.
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Table 4 results of full network analysis to derive effect estimates for the economic model
Integrated sensor
Capillary blood testing with
Capillary blood testing with
augmented pump therapy
continuous subcutaneous insulin multiple daily insulin injections
system
infusion
Change in HbA1c (%) (all time points): weighted mean difference (95%CI)
-0.66 (-1.05 to -0.27)
-0.07 (-0.31 to 0.17)
MiniMed Paradigm Veo 0.04 (-0.07 to 0.15)
system
Comparative data in network
Indirect comparison
Indirect comparison
-0.70 (-1.05 to -0.30)*
N/A
-0.11 (-0.32 to 0.10)
Integrated sensor
augmented pump
Comparative data in network
Comparative data in network
therapy system
N/A
-0.46 (-1.18 to 0.27)*
Capillary blood testing N/A
with subcutaneous
Comparative data in network
insulin infusion
Change in severe hypoglycaemic event rate (all time points): relative risk (95%CI)
0.39 (0.02 to 8.40)
0.10 (0.01 to 1.93)
MiniMed Paradigm Veo 0.12 (0.01 to 2.14)
system
Comparative data in network
Indirect comparison
Indirect comparison
3.23 (1.10 to 9.49)
N/A
0.86 (0.51 to 1.46)
Integrated sensor
augmented pump
Comparative data in network
Comparative data in network
therapy system
N/A
0.67 (0.38 to 1.20)
Capillary blood testing N/A
with subcutaneous
Comparative data in network
insulin infusion
Statistically significant results shown in bold; N/A: comparison not applicable; * Random effects analysis
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2.2
Costs and cost effectiveness
The External Assessment Group conducted a search to identify existing
studies reporting the cost effectiveness of the MiniMed Paradigm Veo System
and the Vibe and G4 PLATINUM CGM system. The EAG also utilised the IMS
CORE Diabetes Model to assess the cost effectiveness of the technologies.
Systematic review of cost effectiveness evidence
Details of the methods used for the systematic review of the economic
evidence can be found starting on page 60 of the diagnostics assessment
report. Two studies were included and were appraised using the Drummond
et al. (1996) checklist (see pages 67 and 68 of the diagnostics assessment
report).
Kamble et al. (2012) report the results of a cost effectiveness analysis which
compared the Vibe and G4 PLATINUM CGM system with capillary blood
testing and multiple daily insulin injections from the perspective of a US health
care system. The study used the IMS CORE Diabetes Model with a time
horizon of 60 years and included a population with an average age of 41.3
years with inadequately controlled type 1 diabetes. The study reports that,
when all health effects included in the IMS CORE Diabetes Model are taken
into account, the Vibe and G4 PLATINUM CGM system is not cost effective
with ICERs of $229,675 and $168,104 per QALY gained assuming a sensor
life of 3 or 6 days respectively.
Ly et al. (2014) report the results of a cost effectiveness analysis which
compared the MiniMed Paradigm Veo G4 PLATINUM CGM system compared
with capillary blood testing and continuous subcutaneous insulin from the
perspective of an Australian healthcare system perspective. The study used a
de novo decision analytic model which included a population with type 1
diabetes and an impaired awareness of hypoglycaemia. The model had a time
horizon of 6 months and incorporated severe hypoglycaemic events only. The
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study reports that the MiniMed Paradigm Veo system is cost effective with an
ICER of AU$40,803 for people aged 12 years or over.
Economic analysis
The External Assessment Group used the IMS CORE Diabetes Model to
assess the cost effectiveness of the MiniMed Paradigm Veo system and the
Vibe and G4 PLATINUM CGM system in adults with type 1 diabetes who are
eligible to receive an insulin pump, in accordance with NICE Technology
Appraisal 151. The population included in the base case has a mean age of
41.6 years, has had diabetes for a mean duration of 27.1 years, and a mean
HbA1c of 7.26%.
Model structure
The structure of the IMS CORE Diabetes Model is described on pages 70-73
of the diagnostics assessment report. It is a simulation model designed to
predict the long term health outcomes and costs associated with the
management of both type 1 and type 2 diabetes. The model structure
comprises 17 inter-dependent Markov sub-models which represent the most
common diabetes-related complications. This includes stroke, peripheral
vascular disease, diabetic retinopathy, hypoglycaemia and ketoacidosis.
The model was adapted to reflect the NHS and Personal Social Services
perspective, the population and interventions included in the assessment, and
parameters were inflated to 2015 values where necessary. The model was
run as a cohort simulation with a time horizon of 80 years.
Model inputs
The model was populated with data derived from the clinical effectiveness
review, published literature and routine sources of cost and prevalence data.
Where published data was unavailable, the External Assessment Group used
expert opinion to derive estimates to populate the model. A discount rate of
3.5% was applied to both costs and effects. Further details on the model input
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parameters can be found starting on page 74 of the diagnostics assessment
report.
One of the comparators listed in the final scope, continuous glucose
monitoring with multiple daily insulin injections, was excluded from the
analysis as no data was found for this comparator in the clinical effectiveness
review. In addition, the clinical effectiveness of the comparator, non-integrated
continuous glucose monitoring and continuous subcutaneous insulin therapy,
is assumed to be equivalent to that of the Vibe and G4 PLATINUM CGM
system (as derived from data for an integrated sensor-augmented pump
therapy system with no low glucose suspend function) because no data were
found for this comparator.
The reduction in HbA1c baseline level and number of severe hypoglycaemic
events are included in the model as clinical effectiveness outcomes. A
baseline HbA1c value of 7.26% was applied and estimates of mean HbA1c
change from baseline were derived from the clinical effectiveness review
(table 5). The values show that HbA1c increases from baseline for capillary
blood testing with continuous subcutaneous insulin infusion and capillary
blood testing with multiple daily insulin injections, but decrease for the
MiniMed Paradigm Veo System, Vibe and G4 PLATINUM CGM system and
non-integrated continuous glucose monitoring with continuous subcutaneous
insulin infusion. In the IMS CORE Diabetes Model, the change in HbA1c level
is assumed to occur within the first 12 months, thereafter annual progression
occurs (that is, a 0.045% increase in [worsening of] HbA1c each year). The
value for annual progression was chosen to correspond with the assumptions
made in the economic model from the draft NICE clinical guideline on the
diagnosis and management of type 1 diabetes in adults, and is taken from the
Diabetes Control and Complications Trial.
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Table 5 HbA1c change values applied in the model
Technology
Mean change in HbA1c from baseline
(SE)
MiniMed Paradigm Veo System
Vibe and G4 PLATINUM CGM system
Capillary blood testing with continuous
subcutaneous insulin infusion
Capillary blood testing with multiple daily
insulin injections
Continuous glucose monitoring with
continuous subcutaneous insulin infusion
(non-integrated)
-0.02 (0.04)
-0.06 (0.05)
0.05 (0.12)
0.64 (0.19)
-0.06 (0.05)
Severe hypoglycaemic event rates for the interventions and the comparators
were estimated from the clinical effectiveness review (table 6). No baseline
event rates were required for this parameter as the model assumes that these
values are treatment specific.
Table 6 severe hypoglycaemic event rates applied in the model
Technology
Rate per 100 patient years of severe
hypoglycaemic episodes
MiniMed Paradigm Veo system
Vibe and G4 PLATINUM CGM system
Capillary blood testing with continuous
subcutaneous insulin infusion
Capillary blood testing with multiple
daily insulin injections
Continuous glucose monitoring with
continuous subcutaneous insulin
infusion (non-integrated)
1.9584
16.32
5.0215
19.584
16.32
Costs
Costs included in the model were associated with the primary prevention of
diabetes related complications, managing diabetes related complications,
treating diabetes (including the costs of the interventions) and related hospital
costs. NHS costs were taken from routinely available data and from related
NICE clinical guidelines. The costs of the MiniMed Paradigm Veo system and
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the Vibe and G4 PLATINUM CGM system are £2961.62 and £3195.48,
respectively. A total cost per year for the technologies was calculated
assuming a 4 year lifespan for the insulin pumps which takes into account the
need to replace consumables such as insulin cannulas and reservoirs,
glucose monitoring sensors and transmitters, and batteries. The total cost per
year for the MiniMed Paradigm Veo system is £4862.10 and for the Vibe and
G4 PLATINUM CGM system is £5298.65. The costs of comparator
technologies were taken from the draft NICE clinical guideline on the
diagnosis and management of type 1 diabetes in adults and from the
published literature. In the base case analysis, comparator technology costs
were weighted by UK market share.
Health related quality of life
The utility values applied to each health state were derived from the published
literature. A disutility of -0.012 was applied to a severe hypoglycaemic event,
which also incorporates the (dis)utility associated with fear of hypoglycaemia.
The full range of utility values included in the model can be found on page 85
of the diagnostics assessment report.
Base-case results
For the purposes of decision making, the incremental cost effectiveness ratios
(ICERs) per quality adjusted life year (QALY) gained or lost will be
considered. The following key assumptions were applied in the base case
analysis:
 The population has a mean age of 41.6 years, has had diabetes for a mean
duration of 27.1 years, and a mean HbA1c of 7.26%.
 The insulin pumps used in the integrated systems and as stand-alone
devices have a lifetime of 4 years.
 4 capillary blood tests are required each day for monitoring blood glucose
with either continuous glucose monitoring or capillary blood testing.
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 48 units of short-acting insulin are used per day for continuous
subcutaneous insulin infusion.
 48 units of insulin are used per day for multiple daily insulin injections, with
twice daily insulin detemir (long-acting) and 3 boluses of short-acting insulin
at meal times.
 3 HbA1c tests are required per year.
 Treatment effects (HbA1c) are estimated as the mean reduction from the
baseline value derived from the clinical effectiveness review. This reduction
occurs over the first year, then annual progression (0.045%) occurs.
 The clinical effectiveness of the Vibe and G4 PLATINUM CGM system and
the continuous glucose monitoring with continuous subcutaneous insulin
infusion (non-integrated) system are equivalent. The clinical effectiveness
data for these technologies are derived from the integrated sensoraugmented pump therapy system with no low glucose suspend function.
 The probability of death from a severe hypoglycaemia event is 0%.
A full list of the assumptions applied in the base case can be found starting on
page 92 of the diagnostics assessment report
The results of the probabilistic base case analysis are shown in table 7.
Results from the deterministic base case analysis are shown on page 95 of
the diagnostics assessment report. The results of the base case analysis
suggest that the integrated sensor-augmented pump therapy systems are not
cost effective when compared to capillary blood testing with multiple daily
insulin injections and capillary blood testing with continuous subcutaneous
insulin infusion. When the MiniMed Paradigm Veo System is compared to
continuous glucose monitoring with subcutaneous insulin infusion (nonintegrated), it is associated with an incremental QALY loss (-0.0192). This is
driven by the non-integrated system having the highest decrease in HbA1c
from baseline in the clinical effectiveness review (see table 5). This decrease
in HbA1c leads to a decrease in the number of lifetime diabetes related
complications which compensates for the higher number of hypoglycaemic
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events observed with the non-integrated system, despite the MiniMed
Paradigm Veo system having the lowest number of lifetime hypoglycaemic
events (0.622 severe hypoglycaemic events per person). In the comparison
with the non-integrated continuous glucose monitoring and continuous
subcutaneous insulin infusion, the cost-effectiveness of the Vibe and G4
PLATINUM system is driven by the cost of the comparator. The nonintegrated system becomes more expensive than the Vibe and G4 PLATINUM
CGM system when average non-integrated device costs are used (see page
109 of the diagnostics assessment report).
The cost-effectiveness plane for the base case probabilistic sensitivity
analysis shows a positive correlation between costs and QALYs, with the
treatments which include continuous glucose monitoring associated with both
increased cost and increased QALYs. The results of the probabilistic
sensitivity analysis were also plotted on a cost effectiveness acceptability
curve which shows that the probability of technologies which contain
continuous glucose monitoring being cost effective is 0% for all maximum
acceptable ICERs included in the analysis. This is because the cost of the
technologies is too large to be offset by the additional QALYs gained when
compared with capillary blood testing. The cost effectiveness plane and cost
effectiveness acceptability curve for the base case probabilistic sensitivity
analysis can be found on pages 97 and 98 of the diagnostics assessment
report.
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Table 7 results of probabilistic base case
Intervention
Comparator
QALY
Cost
12.0412
£138,357
Vibe and G4 PLATINUM CGM
system
12.0604
£147,150
MiniMed Paradigm Veo
system
MiniMed Paradigm Veo
system
12.0412
£138,357
Vibe and G4 PLATINUM CGM
system
12.0604
£147,150
MiniMed Paradigm Veo
system
12.0412
£138,357
Vibe and G4 PLATINUM CGM
system
12.0604
£147,150
QALY
Capillary blood
testing with multiple
daily insulin injections 11.4146
Capillary blood
testing with
continuous
subcutaneous insulin
infusion
11.9756
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
12.0604
Cost
£64,563
£90,436
£146,476
Incr.
QALY
Incr. Cost
ICER
0.6266
£73,794
£117,769
0.6458
£82,587
£127,883
0.0656
£47,921
£730,501
0.0849
£56,713
£668,789
-0.0192
-£8,119
£422,849*
0
£674
undefined
* ICER for this comparison is cost saved per QALY lost
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Two alternative base case scenarios were also run. These analyses are
described in more detail on pages 98 and 99 of the diagnostics assessment
report. The first scenario excludes multiple daily insulin injections and
assumes all insulin therapy is delivered by continuous subcutaneous insulin
infusion. This is intended to reflect the recommendation made in NICE
Technology Appraisal 151 which supports the use of continuous
subcutaneous insulin infusion as an option where multiple daily insulin
injections are not considered appropriate (see Appendix C). The results of this
full incremental analysis (table 8) show that when capillary blood testing with
multiple daily insulin injections is excluded from the analysis, the MiniMed
Paradigm Veo system and Vibe and G4 Platinum CGM system are extendedly
dominated and dominated respectively, by the non-integrated system. The
cost effectiveness acceptability curve for this analysis (see page 99 of the
diagnostics assessment report) shows that capillary blood testing with
continuous subcutaneous insulin infusion .is the strategy with the greatest
probability of being cost effective.
Table 8 results of scenario which excludes multiple daily injections
QALYs Cost
Capillary blood testing
with continuous
subcutaneous insulin
infusion
Incr.
QALY
Incr.
Cost
ICER
11.9756 £90,436
Extendedly
dominated by nonintegrated system
MiniMed Paradigm Veo
12.0412 £138,357
system
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
12.0604 £146,476 0.0849
Vibe and G4
PLATINUM CGM
system
12.0604 £147,150
£56,039
£660,376
dominated by nonintegrated system
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The second scenario excludes comparators which include capillary blood
testing and assumes all glucose monitoring is done using continuous glucose
monitoring. This is intended to show the impact of the low glucose suspend
function of the MiniMed Paradigm Veo system. The results of this full
incremental analysis (table 9) show that the MiniMed Paradigm Veo is the
least expensive strategy. The Vibe and G4 PLATINUM CGM system remains
dominated by the non-integrated system, largely because the technologies
are assumed to be equally effective but the Vibe and G4 PLATINUM CGM
system is more expensive. The cost effectiveness acceptability curve for this
analysis (see page 100 of the diagnostics assessment report) shows that the
MiniMed Paradigm Veo system is the strategy with the highest probability of
being cost effective at maximum acceptable ICERs of £20,000 and £30,000
per QALY gained.
Table 9 results of scenario which excludes capillary blood testing
QALYs Cost
Incr.
QALY
Incr.
Cost
ICER
0.0192
£8,119
£422,849
MiniMed Paradigm Veo
12.0412 £138,357
system
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
12.0604 £146,476
Vibe and G4
PLATINUM CGM
system
12.0604 £147,150
dominated by nonintegrated system
Scenario analyses
Several scenario analyses were performed to assess the impact of the
assumptions made in the base case analysis. The following assumptions were
assessed:
 Applying the baseline population characteristics from the draft NICE clinical
guideline on the diagnosis and management of type 1 diabetes in adults
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 Frequency of daily capillary blood tests
 Amount of insulin used per day
 No progression of HbA1c after 1 year
 No HbA1c change in year 1
 Rates of severe hypoglycaemic events
 Mortality of 4.9% for severe hypoglycaemia
 Method of estimating QALYs
 4 year time horizon
 Addition of a utility increment for fear of hypoglycaemia
 Average annual cost for non-integrated systems without market share
weighting.
The scenario analyses are reported in detail starting on page 100 of the
diagnostics assessment report. The ICERs changed substantially under the
following assumptions:
 No change in HbA1c in year 1
 Mortality rate of 4.9% for severe hypoglycaemia
 Utility increment of 0.0329 for fear of hypoglycaemia
The ICERs did not change substantially in the remaining scenarios modelled
including when a relative risk for severe hypoglycaemic events of 0.125 was
applied to the MiniMed Paradigm Veo system (see page 103 and page 283 of
the diagnostics assessment report for further details).
No change in HbA1c in year 1
The ICERs changed substantially when it is assumed that there is no change
in HbA1c in the first year. In this scenario the Vibe and G4 PLATINUM system
is dominated when compared to all 3 comparators included in the analysis,
the MiniMed Paradigm Veo system dominates in the comparison with the nonintegrated system. The ICERs for this scenario are shown in table 10. The
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ICERs for the full incremental analysis can be found on page 102 of the
diagnostics assessment report.
Table 10 no change in HbA1c in year 1 scenario analysis
Intervention
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
Comparator
Incr.
QALY
Incr.
Cost
ICER
£77,999
£3,196,686
£86,764
Dominated
0.0099
£48,360
£4,871,356
-0.0154
£57,126
Dominated
0.0254
-£8,093
Dominates
0
£672
undefined
0.0244
Capillary blood
testing with multiple
daily insulin injections -0.0009
Capillary blood
testing with
continuous
subcutaneous insulin
infusion
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
Mortality rate of 4.9% for severe hypoglycaemia
The ICERs change substantially when it is assumed that severe
hypoglycaemia has a mortality rate of 4.9%. In this scenario the Vibe and G4
PLATINUM CGM system is dominated when compared with capillary blood
testing with continuous subcutaneous insulin infusion and the MiniMed
Paradigm Veo system dominates in the comparison with the non-integrated
system. The ICERs for this scenario are shown in table 11. The ICERs for the
full incremental analysis can be found on page 104 of the diagnostics
assessment report.
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Table 11 mortality of 4.9% for severe hypoglycaemia scenario analysis
Intervention
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
Comparator
Incr.
QALY
Incr.
Cost
ICER
£75,878
£84,029
£80,948
£121,544
0.1290
£48,327
£374,626
-0.1079
£53,397
Dominated
0.2369
-£4,413
Dominates
0
£ 657
undefined
0.9029
Capillary blood
testing with multiple
daily insulin injections 0.6659
Capillary blood
testing with
continuous
subcutaneous insulin
infusion
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
Utility increment of 0.0329 for fear of hypoglycaemia
The ICERs also change substantially when a utility increment of 0.0329 is
applied to represent a reduction in fear of hypoglycaemia. This utility
increment was applied only to the MiniMed Paradigm Veo System and the
Vibe and G4 PLATINUM CGM system. The ICERs for this scenario are shown
in table 12. The ICERs for the full incremental analysis can be found on page
107 of the diagnostics assessment report.
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Table 12 fear of hypoglycaemia scenario analysis
Intervention
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
MiniMed Paradigm Veo
system
Vibe and G4 PLATINUM
CGM system
3
Comparator
Incr.
QALY
Incr.
Cost
ICER
£73,794
£61,100
£82,587
£67,238
0.6468
£47,921
£74,088
0.6468
£47,921
£74,089
0.5619
-£8,119
Dominates
0.5824
£674
£1,157
1.2077
Capillary blood
testing with multiple
daily insulin injections 1.2282
Capillary blood
testing with
continuous
subcutaneous insulin
infusion
Continuous glucose
monitoring with
continuous
subcutaneous insulin
infusion (nonintegrated)
Summary of key findings
The External Assessment Group concluded that the MiniMed Paradigm Veo
System appears to reduce hypoglycaemic events in adults compared with the
integrated sensor-augmented pump therapy system without low glucose
suspend, but no statistically significant impact on HbA1c was observed. In
addition, no statistically significant change in HbA1c is seen when the
MiniMed Paradigm Veo system is compared to both capillary blood testing
with continuous subcutaneous insulin infusion and capillary blood testing with
multiple daily insulin injections. Data from a pooled analysis suggest that the
MiniMed Paradigm Veo system significantly improves HbA1c, without a
statistically significant impact on severe hypoglycaemia, when compared to
capillary blood testing with multiple daily insulin injections. A reduction in
hypoglycaemic events without a statistically significant impact on HbA1c is
also observed for the MiniMed Paradigm Veo system in children. No evidence
was found for the Vibe and G4 PLATINUM CGM system.
The results of the base case cost-effectiveness analysis suggest that, in
adults, the integrated sensor-augmented pump therapy systems cannot be
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considered cost effective when compared with both capillary blood testing with
multiple daily insulin injections and capillary blood testing with continuous
subcutaneous insulin infusion. No data were available to estimate the cost
effectiveness of the integrated sensor-augmented pump therapy systems
compared to continuous glucose monitoring with multiple daily insulin
injections. The ICERs became more favourable when the integrated sensoraugmented pump therapy systems are compared to non-integrated
continuous glucose monitoring with continuous subcutaneous insulin infusion.
However, these conclusions are subject to a number of caveats which are
outlined below.
4
Issues for consideration
Clinical effectiveness
 No data are available for the Vibe and G4 PLATINUM CGM system. Data
from an alternative integrated sensor-augmented pump therapy system
with no low glucose suspend function was included as a proxy to show the
incremental effects of the low glucose suspend function of the MiniMed
Paradigm Veo system. All of these studies were conducted in the US and it
is uncertain how applicable these data are to both the Vibe and G4
PLATINUM CGM system and the NHS.
 The majority (11) of the 19 included studies were conducted outside
Europe, with only 8 studies including European populations, 3 of which
include patients from the UK. Of the 11 studies conducted outside Europe,
8 were in North America, 2 in Australia and 1 in Israel. It is not certain how
applicable these studies are to the NHS. It is possible that interactions with
healthcare providers will impact upon patient behaviour and consequently
on the effectiveness of continuous subcutaneous insulin infusion and
continuous glucose monitors.
 Many of the included studies have small sample sizes and consequently,
relatively rare adverse events such as diabetic ketoacidosis are not
observed. Many comparisons between the intervention and comparator
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technologies for rare events do not show a statistically significant
difference. However, it is not certain to what extent the non-significant
results are driven by the small sample sizes in the studies reducing the
probability of differences in rare outcomes reaching statistical significance.
 It is uncertain how applicable the populations included in the studies are to
the decision problem. It is likely that the integrated sensor-augmented
pump therapy systems will be of greatest benefit to people who have
difficulty achieving target HbA1c and who experience severe
hypoglycaemic events. The studies which report data for the MiniMed
Paradigm Veo system (ASPIRE in home and Ly et al. 2013) include people
with at least 6 months experience of continuous subcutaneous insulin
infusion who would be expected to have more stable HbA1c. Further, the
baseline HbA1c differs substantially between all the included studies (range
7.2 to 11.5%) suggesting that there is substantial clinical heterogeneity
between the populations, which could mask differences in treatment effects
in the pooled network-analysis. In addition many studies exclude people
with severe hypoglycaemia, reducing the likelihood of the true impact of the
technologies on severe hypoglycaemia being captured in the analysis.
 Limited studies were available to compare the technologies in specific
populations at specific time points. Several studies were excluded because
they did not specify the type of blood glucose monitoring or the method of
insulin therapy. Many of the studies include mixed populations which are
subject to substantial clinical heterogeneity due to differences in behaviour
between younger children, adolescents and adults. Direct data were only
available for the following comparisons:
 MiniMed Paradigm Veo system vs. integrated sensoraugmented pump therapy system (no low glucose suspend)
(adults)
 Integrated sensor-augmented pump therapy system (no low
glucose suspend) vs. capillary blood testing with continuous
subcutaneous insulin infusion (adults)
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 Integrated sensor-augmented pump therapy system (no low
glucose suspend) vs. capillary blood testing with multiple daily
insulin injection (adults)
 MiniMed Paradigm Veo system vs capillary blood testing with
continuous subcutaneous insulin infusion (children [70% aged
<18 years] )
 Integrated sensor-augmented pump therapy system (no low
glucose suspend) vs. capillary blood testing with continuous
subcutaneous insulin infusion (children)
 Integrated sensor-augmented pump therapy system (no low
glucose suspend) vs. capillary blood testing with multiple daily
insulin injection (children)
 Effect estimates derived from the clinical effectiveness analysis for children
are subject to substantial heterogeneity because of differences in the age
of participants included in the studies (2 to 21 years). There are likely to be
substantial differences in control of diabetes between younger children
whose treatment is supervised by parents, and teenagers who manage
their treatment independently and who are also undergoing endocrine
changes during puberty. Further, the only study for the MiniMed Paradigm
Veo system included in the analysis for children (Ly et al. 2013) included a
population aged between 4 to 50 years of which around 70% were aged
less than 18 years.
 There is substantial uncertainty in the comparisons made between
continuous subcutaneous insulin infusion and multiple daily insulin
injections. Continuous subcutaneous insulin infusion is typically
recommended for people in whom multiple daily injections are not suitable,
therefore there are likely to be substantial differences in baseline HbA1c in
studies which include continuous insulin infusion and in those which include
multiple daily insulin injections. Consequently the effect estimates for these
comparisons, which are calculated indirectly in the clinical effectiveness
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review, are likely to be highly uncertain and open to bias arising from
clinical heterogeneity.
 No data for 2 of the comparators included in the final scope (continuous
glucose monitoring with continuous subcutaneous insulin infusion [nonintegrated] and continuous glucose monitoring with multiple daily insulin
injections) were found in the systematic review. It is therefore not known
how the clinical effectiveness of interventions compare to either of these
comparator technologies as neither direct nor indirect effect estimates
could be calculated.
 No data were reported for any of the subgroups included in the final scope.
These subgroups include women who are pregnant and those planning
pregnancy, people who need to self-monitor their blood glucose level more
than 10 times a day and people who have difficulty managing their
condition, that is people who have difficulty maintaining the recommended
HbA1c level, people who experience nocturnal hypoglycaemia, impaired
awareness of hypoglycaemia and severe hypoglycaemia. Although 1 study
did include pregnant women it did not report data for either the MiniMed
Paradigm Veo system or the Vibe and G4 PLATINUM CGM system and
consequently it did not contribute to the analyses.
Cost effectiveness
 No data were available for non-integrated continuous glucose monitoring
with continuous subcutaneous insulin infusion in the clinical effectiveness
review. The cost effectiveness analysis therefore assumes that the clinical
effectiveness of the Vibe and G4 PLATINUM CGM system and the nonintegrated continuous glucose monitoring with continuous subcutaneous
insulin system is equivalent. This results in the comparison between the
Vibe and G4 PLATINUM system and the non-integrated continuous
glucose monitoring with continuous subcutaneous insulin system being
predominantly driven by cost and consequently there is substantial
uncertainty in the ICERs for the Vibe and G4 PLATINUM CGM system.
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 Continuous glucose monitoring with multiple daily insulin injections is not
included as a comparator in the cost effectiveness analysis because no
data were found for this technology in the clinical effectiveness review. It is
therefore not known how the cost effectiveness of the integrated sensoraugmented pump therapy systems compares with this comparator
technology.
 The cost effectiveness analysis is based on effect estimates for change in
HbA1c and rates of severe hypoglycaemia derived from the network
analysis of pooled studies. This analysis included mixed populations, and
outcome data from different follow-up times calculate direct and indirect
effect estimates. There is likely to be substantial heterogeneity in the
pooled studies and consequently, a greater risk of bias in the effect
estimates. This is of particular importance for HbA1c which drives longerterm complications and outcomes in the economic model. The relationship
between HbA1c as an intermediate outcome measure and the long-term
complications of type 1 diabetes is therefore a key consideration for
interpreting the life-time cost-effectiveness of the integrated sensoraugmented insulin pump-therapy systems, and may be influenced by
baseline HbA1c in the study populations, length of follow-up, and
heterogeneity in the effect estimates.
 The effect estimates used in the economic model suggest that HbA1c (%)
increases from baseline (0.05; SE 0.12) for capillary blood testing with
continuous subcutaneous infusion. This appears to be counterintuitive
because continuous subcutaneous insulin infusion is usually intended as
an aid to improving HbA1c and arises because of the substantial
uncertainty in the pooled effect estimates. In addition the Vibe and G4
PLATINUM CGM system and continuous glucose monitoring with
continuous subcutaneous insulin infusion have a rate of severe
hypoglycaemic episodes (16.32 per 100 patient years) which is
substantially greater than capillary blood testing with continuous
subcutaneous insulin infusion (5.0215 per 100 patient years). This
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relationship also appears to be counterintuitive as the addition of
continuous glucose monitoring is intended as an aid to reduce
hypoglycaemia and is again likely to have arisen because of the substantial
uncertainty in the pooled effect estimates. As a reduction in both HbA1c
and rates of severe hypoglycaemia are likely to be the key outcomes
associated with the use of the integrated sensor-augmented pump therapy
systems it is possible that the clinical effects have not been fully captured in
the ICERs.
 Severe hypoglycaemic event rates were not included in the probabilistic
analysis because the event rates are a fixed parameter in the IMS CORE
Diabetes Model. In order to estimate the effects of severe hypoglycaemia
on longer-term outcomes several scenario analyses were run using
different event rates. The results of the scenario analyses suggest that the
ICER is not sensitive to rates of severe hypoglycaemic events, however, it
is likely that the uncertainty around the base case ICERs is underestimated
as a result of this fixed parameter.
 It is not certain to what extent the effects associated with severe
hypoglycaemia have been captured in the analysis. In the base case, when
a disutility of -0.012 is applied for severe hypoglycaemia, the MiniMed
Paradigm Veo is extendedly dominated by non-integrated continuous
glucose monitoring with continuous subcutaneous insulin infusion and is
associated with QALY loss despite having a substantially lower rate of
hypoglycaemic events (1.9584 versus 16.32 per 100 patient years). This is
because the effect of reducing hypoglycaemia is outweighed by the greater
reduction in HbA1c associated with the non-integrated devices which leads
to fewer long-term adverse outcomes. When the mortality rate associated
with severe hypoglycaemia is increased from 0% to 4.9% the MiniMed
Paradigm Veo system dominates the non-integrated devices in a direct
comparison. The MiniMed Paradigm Veo system also dominates the nonintegrated devices in a direct comparison when a utility associated with fear
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of hypoglycaemia is included. The results of the scenario analyses suggest
that impact of severe hypoglycaemia is subject to substantial uncertainty.
 Diabetic ketoacidosis and minor hypoglycaemic events are not included in
the economic model because no reliable effect estimates were reported for
these outcomes in the clinical effectiveness review. As a result the impacts
of these outcomes are not captured in the ICERs.
 Children and pregnant women are not included in the cost effectiveness
analysis because The IMS CORE Diabetes Model does not include
background risk adjustment or risk factor progression equations which are
applicable to these populations. In addition, limited clinical effectiveness
data were available for children and no evidence was found for pregnant
women so it is not possible to determine reliable effect estimates for these
groups. There is uncertainty whether the results of the analysis for the adult
population are generalisable to children or pregnant women.
5
Equality considerations
NICE is committed to promoting equality of opportunity, eliminating unlawful
discrimination and fostering good relations between people with particular
protected characteristics and others.
Potential equality issues which need to be considered are:
 People with cognitive disorders and people whose vision or hearing does
not allow recognition of pump signals and alarms may have difficulty in
using the technologies.
 People with a disability may have difficulty in self-administering insulin
injections.
 Glucose levels should be more tightly controlled in pregnancy.
 Impaired awareness of hypoglycaemia is more common in older people.
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6
Implementation
NICE technology appraisal 151 recommends continuous subcutaneous insulin
infusion for people with diabetes who meet the clinical criteria stated in the
guidance. However, the UK-wide Insulin Pump Audit (2013) reported that
approximately half of the sites that deliver continuous subcutaneous insulin
infusion have to submit separate funding applications for each person who
requires continuous subcutaneous insulin infusion. The audit also reported
that 18% of clinical commissioning groups have a fixed quota for continuous
subcutaneous insulin infusion in adults.
Anecdotally, people with diabetes and patient organisations also report that it
is difficult to gain access to continuous glucose monitors because of a lack of
funding.
Other potential implementation issues include:
 Provision of training for healthcare professionals to increase capacity. Half
of diabetes nurse specialists delivering continuous subcutaneous insulin
infusion services have attended training; only 1 consultant per centre has
attended training (UK-wide Insulin Pump Audit, 2013).
 Less experience in continuous glucose monitoring than multiple daily
injections and continuous subcutaneous insulin infusion among healthcare
professionals.
 Training and educational tools are needed to teach users and their carers
how to manage glucose levels. Some users and their carers may find
interpreting the data challenging and becoming competent at managing
glucose levels can involve a lot of time and dedication.
 Lack of whole time equivalent diabetes specialist nurses with continuous
subcutaneous insulin infusion expertise.
 There may be difficulty in managing data because the IT software and
systems in the homes of people with diabetes may not be compatible with
those used by healthcare professionals in the NHS.
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 Users and their carers report that some sensors fail and that the supply of
sensors from manufacturers can be inconsistent. Both of these can cause
the user to run out of sensors.
7
Authors
Rebecca Albrow
Topic Lead
Sarah Byron
Technical Adviser
March 2015
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Appendix A: Sources of evidence considered in the
preparation of the overview
A.
The diagnostics assessment report for this assessment was prepared by
Kleijnen Systematic Reviews Ltd:
Riemsma R, Corro Ramos I, Birnie R et al. (2015) Type 1 diabetes: Integrated
sensor-augmented pump therapy systems for managing blood glucose levels
(The MiniMed Paradigm Veo System and Vibe and G4 PLATINUM CGM
system), a systematic review and economic evaluation.
B.
The following organisations accepted the invitation to participate in this
assessment as stakeholders. They were invited to attend the scoping
workshop and to comment on the diagnostics assessment report.
Manufacturer(s) of technologies included in the final scope:
 Medtronic Limited
 Dexcom
 Johnson & Johnson/Animas
Other commercial organisations:
 Cellnovo Ltd
 OmniPod
 Roche Diagnostics
Professional groups and patient/carer groups:
 Royal College of Physicians
 Royal College of Pathologists
 Dose Adjustment for Normal Eating (DAFNE)
 Diabetes Inpatient Specialist Nurse UK Group
 Juvenile Diabetes Research Foundation (JDRF)
 INPUT Patient Advocacy
 Diabetes UK
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Research groups:
 University of Southampton
 Institute of Metabolic Science, University of Cambridge
Associated guideline groups:
None
Others:
 Department of Health
 Healthcare Improvement Scotland
 NHS England
 Welsh Government
 BIVDA
 Advanced Therapeutics UK Limited
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Appendix B: Glossary of terms
Diabetic ketoacidosis
Occurs when the body is unable to use blood glucose because of inadequate
insulin. Instead, fat is broken down as an alternative source of fuel; a process
that leads to a build-up of a by-product called ketones.
Hyper- and hypoglycaemic area under the curve
The area under the curve value is derived from the product of the magnitude
and duration of the senor measured glucose level above or below a specified
cut-off. Higher area under the curve values indicate more frequent, severe or
prolonged glycaemic events.
Impaired awareness of hypoglycaemia
A situation where people with diabetes are frequently unable to notice when
they have low blood sugar.
Ketonaemia
The presence of an abnormally high concentration of ketone bodies in the
blood.
Ketonuria
The presence of abnormally high amounts of ketones and ketone bodies (a
by-product of the breakdown of cells) in the urine. Ketonuria is a sign seen in
badly controlled diabetes.
Nephropathy
Damage to or disease of a kidney.
Neuropathy
Disease or dysfunction of one or more peripheral nerves, typically causing
numbness or weakness
Retinopathy
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Diabetic retinopathy is a common complication of diabetes. It occurs when
high blood sugar levels damage the cells at the back of the eye (known as the
retina). If not treated it can lead to blindness.
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Appendix C: NICE guidance on continuous
subcutaneous insulin infusion and continuous
glucose monitoring
Existing guidance
Diabetes in pregnancy: management of diabetes and its complications from
preconception to the postnatal period (2015) NICE guidelines NG3
Continuous subcutaneous insulin infusion
1.3.16 Offer women with insulin‑treated diabetes continuous subcutaneous
insulin infusion (CSII; also known as insulin pump therapy) during pregnancy if
adequate blood glucose control is not obtained by multiple daily injections of
insulin without significant disabling hypoglycaemia [8]. [2008]
Continuous glucose monitoring
1.3.17 Do not offer continuous glucose monitoring routinely to pregnant
women with diabetes. [new 2015]
1.3.18 Consider continuous glucose monitoring for pregnant women on insulin
therapy:
 who have problematic severe hypoglycaemia (with or without impaired
awareness of hypoglycaemia) or
 who have unstable blood glucose levels (to minimise variability) or
 to gain information about variability in blood glucose levels. [new 2015]
1.3.19 Ensure that support is available for pregnant women who are using
continuous glucose monitoring from a member of the joint diabetes and
antenatal care team with expertise in its use. [new 2015]
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Continuous subcutaneous insulin infusion for the treatment of diabetes
mellitus (2008) NICE technology appraisal guidance TA151
1.1 Continuous subcutaneous insulin infusion (CSII or 'insulin pump') therapy
is recommended as a treatment option for adults and children 12 years and
older with type 1 diabetes mellitus provided that:
 attempts to achieve target haemoglobin A1c (HbA1c) levels with multiple
daily injections (MDIs) result in the person experiencing disabling
hypoglycaemia. For the purpose of this guidance, disabling hypoglycaemia
is defined as the repeated and unpredictable occurrence of hypoglycaemia
that results in persistent anxiety about recurrence and is associated with a
significant adverse effect on quality of life
or
 HbA1c levels have remained high (that is, at 8.5% [69 mmol/mol] or above)
on MDI therapy (including, if appropriate, the use of long-acting insulin
analogues) despite a high level of care.
1.2 CSII therapy is recommended as a treatment option for children younger
than 12 years with type 1 diabetes mellitus provided that:
 MDI therapy is considered to be impractical or inappropriate, and
 children on insulin pumps would be expected to undergo a trial of MDI
therapy between the ages of 12 and 18 years.
1.3 It is recommended that CSII therapy be initiated only by a trained
specialist team, which should normally comprise a physician with a specialist
interest in insulin pump therapy, a diabetes specialist nurse and a dietitian.
Specialist teams should provide structured education programmes and advice
on diet, lifestyle and exercise appropriate for people using CSII.
1.4 Following initiation in adults and children 12 years and older, CSII therapy
should only be continued if it results in a sustained improvement in glycaemic
control, evidenced by a fall in HbA1c levels, or a sustained decrease in the
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rate of hypoglycaemic episodes. Appropriate targets for such improvements
should be set by the responsible physician, in discussion with the person
receiving the treatment or their carer.
1.5 CSII therapy is not recommended for the treatment of people with type 2
diabetes mellitus.
Type 1 diabetes: Diagnosis and management of type 1 diabetes in children,
young people and adults (2004) NICE guideline CG15
Continuous subcutaneous insulin infusion
1.2.2.8 Continuous subcutaneous insulin infusion (or insulin pump therapy) is
recommended as an option for people with type 1 diabetes provided that:
 multiple-dose insulin therapy (including, where appropriate, the use of
insulin glargine) has failed;[2] and
 those receiving the treatment have the commitment and competence to use
the therapy effectively.
1.2.2.9 Continuous subcutaneous insulin infusion therapy should be initiated
only by a trained specialist team, which should normally comprise a physician
with a specialist interest in insulin pump therapy, a diabetes specialist nurse
and a dietitian.
1.2.2.10 All individuals beginning continuous subcutaneous insulin infusion
therapy should be provided with specific training in its use. Ongoing support
from a specialist team should be available, particularly in the period
immediately following the initiation of continuous subcutaneous insulin
infusion. It is recommended that specialist teams should agree a common
core of advice appropriate for continuous subcutaneous insulin infusion users.
1.2.2.11 Established users of continuous subcutaneous insulin infusion
therapy should have their insulin management reviewed by their specialist
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team so that a decision can be made about whether a trial or a switch to
multiple-dose insulin incorporating insulin glargine would be appropriate
1.9.3.13 Continuous subcutaneous insulin infusion (or insulin pump therapy) is
recommended as an option for people with type 1 diabetes provided that:
 multiple-dose insulin therapy (including, where appropriate, the use of
insulin glargine) has failed;[2] and
 those receiving the treatment have the commitment and competence to use
the therapy effectively.
Continuous glucose monitoring
1.2.6.14 Children and young people with type 1 diabetes who have persistent
problems with hypoglycaemia unawareness or repeated hypoglycaemia or
hyperglycaemia should be offered continuous glucose monitoring systems
1.9.1.6 Continuous glucose monitoring systems have a role in the assessment
of glucose profiles in adults with consistent glucose control problems on
insulin therapy, notably:
 repeated hyper- or hypoglycaemia at the same time of day
 hypoglycaemia unawareness, unresponsive to conventional insulin dose
adjustment
Draft recommendations
Type 1 diabetes in adults NICE clinical guideline (updates CG15) publication
expected August 2015
Continuous subcutaneous insulin infusion
1.7.6 For guidance on the use of continuous subcutaneous insulin infusion
(CSII or insulin pump) therapy for adults with type 1diabetes, see Continuous
subcutaneous insulin infusion for the treatment of diabetes mellitus (NICE
technology appraisal guidance 151). [new 2015]
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Continuous glucose monitoring
1.6.20 Do not offer real-time continuous glucose monitoring routinely to adults
with type 1 diabetes. [new 2015]
1.6.21 Consider real-time continuous glucose monitoring for adults with type 1
diabetes who are willing to commit to using it at least 70% of the time and to
calibrate it as needed, and who have any of the following that persist despite
optimised use of insulin therapy and conventional blood glucose monitoring:
 more than 1 episode a year of severe hypoglycaemia with no obviously
preventable precipitating cause
 complete loss of awareness of hypoglycaemia
 frequent (more than 2 episodes a week) asymptomatic hypoglycaemia that
is causing problems with daily activities
 extreme fear of hypoglycaemia. [new 2015]
1.6.22 For people who are having continuous glucose monitoring, use the
principles of flexible insulin therapy with either a multiple daily injection insulin
regimen or continuous subcutaneous insulin infusion (CSII or insulin pump)
therapy. [new 2015]
1.6.23 Continuous glucose monitoring should be provided by a centre with
expertise in its use, as part of strategies to optimise a person’s HbA1c levels
and reduce the frequency of hypoglycaemic episodes. [new 2015]
Research recommendations
2.2 In adults with type 1 diabetes who have chronically poor control of blood
glucose levels, what is the clinical and cost effectiveness of continuous
glucose monitoring technologies?
2.5 For adults with type 1 diabetes, what are the optimum technologies (such
as insulin pump therapy and/or continuous glucose monitoring, partially or
fully automated insulin delivery, and behavioural, psychological and
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educational interventions) and how are they best used, in terms of clinical and
cost effectiveness, for preventing and treating impaired awareness of
hypoglycaemia?
Diabetes in children and young people NICE clinical guideline publication
expected August 2015
Continuous subcutaneous insulin infusion
1.2.20 Offer children and young people with type 1 diabetes multiple daily
insulin injection regimens from diagnosis. If a multiple daily insulin injection
regimen is not appropriate for a child or young person with type 1 diabetes,
consider continuous subcutaneous insulin infusion (CSII or insulin pump)
therapy as recommended in Continuous subcutaneous insulin infusion for the
treatment of diabetes mellitus (NICE technology appraisal guidance 151).
[new 2015]
1.2.22 Provide all children and young people with type 1 diabetes who are
starting continuous subcutaneous insulin infusion therapy (CSII or insulin
pump) and their family members or carers (as appropriate) with specific
training in its use. Provide ongoing support from a specialist team, particularly
in the period immediately after starting continuous subcutaneous insulin
infusion. Specialist teams should agree a common core of advice for
continuous subcutaneous insulin infusion users. [2004, amended 2015]
Continuous glucose monitoring
1.2.63 Offer ongoing unblinded (‘real-time’) continuous glucose monitoring
with alarms to children and young people with type 1 diabetes who have:
 frequent severe hypoglycaemia or
 impaired awareness of hypoglycaemia associated with adverse
consequences (for example, seizures or anxiety). [new 2015]
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1.2.64 Consider ongoing unblinded (‘real-time’) continuous glucose monitoring
for:
 neonates, infants and pre-school children
 children and young people who undertake high levels of physical activity
(for example, sport at a regional, national or international level)
 children and young people who have comorbidities (for example, anorexia
nervosa) or who are receiving treatments (for example corticosteroids) that
can make blood glucose control difficult. [new 2015]
1.2.65 Consider intermittent (unblinded [‘real-time’] or blinded[‘retrospective’])
continuous glucose monitoring to help improve blood glucose control in
children and young people who continue to have hyperglycaemia despite
insulin adjustment and additional support. [new 2015]
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CONFIDENTIAL UNTIL PUBLISHED
Type 1 diabetes: Integrated sensor-augmented pump
therapy systems for managing blood glucose levels
(The MiniMed Paradigm Veo System and the Vibe and
G4 PLATINUM CGM system), a systematic review and
economic evaluation
A Diagnostic Assessment Report commissioned by the NIHR HTA Programme
on behalf of the National Institute for Health and Care Excellence
Kleijnen Systematic Reviews Ltd in collaboration with Erasmus
University Rotterdam and Maastricht University
1
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Diagnostic Assessment Report commissioned by the NIHR HTA Programme on behalf
of the National Institute for Health and Clinical Excellence
Title: Type 1 diabetes: Integrated sensor-augmented pump therapy systems for managing
blood glucose levels (The MiniMed Paradigm Veo System and the Vibe and G4 PLATINUM
CGM system), a systematic review and economic evaluation.
Produced by
Kleijnen Systematic Reviews Ltd. Assessment Group
Authors
Rob Riemsma, Review Manager, Kleijnen Systematic Reviews
Ltd, UK
Isaac Corro Ramos, Health Economics Researcher, Institute of
Health Policy and Management, Erasmus University
Rotterdam, the Netherlands
Richard Birnie, Systematic Reviewer, KSR Ltd, UK
Nasuh Büyükkaramikli, Health Economics Researcher, EUR
Nigel Armstrong, Health Economist, KSR Ltd, UK
Steve Ryder, Health Economist, KSR Ltd, UK
Steven Duffy, Information Specialist, KSR Ltd, UK
Gill Worthy, Statistician, KSR Ltd, UK
Maiwenn Al, Health Economics Researcher, EUR
Hans Severens, Professor of Evaluation in Healthcare, EUR
Jos Kleijnen, Director, KSR Ltd, UK, Professor of Systematic
Reviews in Health Care, Maastricht University, the
Netherlands
Correspondence to
Rob Riemsma
Kleijnen Systematic Reviews Ltd
Unit 6, Escrick Business Park
Riccall Road
Escrick
York YO19 6FD
Tel: 01904 727983
Email: [email protected]
Date completed
27 February 2015
PROSPERO
registration
CRD42014013764
Source of funding
This report was commissioned by the NIHR HTA Programme
as project number 14/69/01.
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Declared competing interests of the authors
None
Acknowledgements
The authors acknowledge the clinical advice and expert opinion provided by the following
specialist DAC members:
- Dr Karen Anthony, Consultant in Diabetes & Endocrinology, the Whittington Hospital NHS
Trust
- Mrs Joanne Buchanan, Diabetes Specialist Nurse, Portsmouth Hospital Trust
- Dr Andrew Day, Consultant Medical Biochemist, University Hospitals Bristol NHS
Foundation Trust.
In addition, the authors acknowledge the clinical advice and expert opinion provided by:
- Dr Nick Oliver, Consultant Diabetologist, Imperial College Healthcare NHS Trust
The views expressed in this report are those of the authors and not necessarily those of the
NIHR HTA Programme. Any errors are the responsibility of the authors.
This report should be referenced as follows:
Riemsma R, Corro Ramos I, Birnie R, Büyükkaramikli N, Armstrong N, Ryder S, Duffy S,
Worthy G, Al MJ, Severens JL, Kleijnen J. Type 1 diabetes: Integrated sensor-augmented
pump therapy systems for managing blood glucose levels (The MiniMed Paradigm Veo
System and the Vibe and G4 PLATINUM CGM system), a systematic review and economic
evaluation. Kleijnen Systematic Reviews Ltd, 2015.
Contributions of authors
Rob Riemsma, Richard Birnie and Gill Worthy planned and performed the systematic review
and interpretation of evidence. Isaac Corro Ramos, Nasuh Büyükkaramikli and Maiwenn Al
planned and performed the cost-effectiveness analyses and interpreted results. Nigel
Armstrong contributed to planning and interpretation of cost-effectiveness analyses and
acquisition of input data for modelling. Steve Ryder contributed to obtaining input data for
the modelling. Steven Duffy devised and performed the literature searches and provided
information support to the project. Jos Kleijnen and Hans Severens provided senior advice
and support to the assessment. All parties were involved in drafting and/or commenting on the
report.
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TABLE OF CONTENTS
Table of Tables .......................................................................................................................... 6
Table of Figures......................................................................................................................... 9
Glossary ................................................................................................................................... 10
List of Abbreviations ............................................................................................................... 12
1
1.1
1.2
1.3
1.4
1.5
1.6
Executive Summary ......................................................................................... 13
Background ...................................................................................................... 13
Objectives ......................................................................................................... 13
Methods ............................................................................................................ 14
Results .............................................................................................................. 15
Conclusions ...................................................................................................... 17
Suggested research priorities ............................................................................ 17
2.1
2.2
2.3
Background and definition of the decision problem(s) .................................... 19
Population......................................................................................................... 19
Description of technologies under assessment ................................................. 21
Comparators ..................................................................................................... 23
2
3
Objective .......................................................................................................... 24
4
4.1
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
4.2
4.2.1
4.2.2
4.2.3
4.2.4
4.2.5
4.2.6
4.3
4.3.1
4.3.2
4.3.3
Assessment of clinical effectiveness ................................................................ 25
Systematic review methods .............................................................................. 25
Inclusion and exclusion criteria ........................................................................ 25
Search strategy ................................................................................................. 26
Inclusion screening and data extraction ........................................................... 28
Quality assessment ........................................................................................... 28
Methods of analysis/synthesis .......................................................................... 29
Results of the assessment of clinical effectiveness .......................................... 30
Results of literature searches ............................................................................ 30
Effectiveness of interventions in adults............................................................ 34
Effectiveness of interventions in children ........................................................ 45
Effectiveness of interventions in pregnant women .......................................... 50
Additional analyses for the economic model ................................................... 50
Ongoing studies ................................................................................................ 54
Summary of results........................................................................................... 57
Studies in adults ............................................................................................... 57
Studies in children ............................................................................................ 58
Studies in pregnant women .............................................................................. 59
5.1
5.1.1
5.1.2
5.1.3
5.1.4
5.2
5.2.1
5.3
5.3.1
5.3.2
5.3.3
5.3.4
5.3.5
Assessment of cost-effectiveness ..................................................................... 60
Review of economic evaluations ...................................................................... 60
Search methods ................................................................................................ 60
Inclusion criteria ............................................................................................... 60
Quality assessment ........................................................................................... 67
Results .............................................................................................................. 69
Model structure and methodology .................................................................... 70
Model structure ................................................................................................ 70
Model input parameters .................................................................................... 74
Baseline population characteristics .................................................................. 75
Costs ................................................................................................................. 77
Utilities ............................................................................................................. 84
Treatment effects .............................................................................................. 85
Disease management parameters...................................................................... 87
5
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5.3.6
5.4
5.4.1
5.4.2
5.5
5.6
5.6.1
5.6.2
5.6.3
5.7
5.7.4
Disease natural history parameters ................................................................... 87
Sensitivity and scenario analyses ..................................................................... 88
Probabilistic sensitivity analysis ...................................................................... 88
Scenario analyses ............................................................................................. 88
Model assumptions........................................................................................... 92
Results of cost-effectiveness analyses .............................................................. 94
Base case results ............................................................................................... 94
Results of the probabilistic sensitivity analyses ............................................... 96
Results of scenario analyses ........................................................................... 100
Extension of the health economic analysis for children and adolescent patients
110
Parameters subject to extreme uncertainty in the clinical effectiveness evidence
for children and adolescent patients ............................................................... 110
Parameters for disease progression and treatment within the IMS CDM for
children and adolescent patients ..................................................................... 111
Health economic analyses in T1DM for children and adolescent patients in
other NICE guidelines/assessment reports ..................................................... 114
Conclusion...................................................................................................... 115
6.1
6.1.1
6.1.2
6.2
6.2.1
6.2.2
6.3
6.3.1
6.3.2
Discussion ...................................................................................................... 116
Statement of principal findings ...................................................................... 116
Clinical effectiveness ..................................................................................... 116
Cost-effectiveness .......................................................................................... 117
Strengths and limitations of assessment ......................................................... 118
Clinical effectiveness ..................................................................................... 118
Cost-effectiveness .......................................................................................... 120
Uncertainties................................................................................................... 121
Clinical effectiveness ..................................................................................... 121
Cost-effectiveness .......................................................................................... 121
7.1
7.2
Conclusions .................................................................................................... 122
Implications for service provision .................................................................. 122
Suggested research priorities .......................................................................... 122
5.7.1
5.7.2
5.7.3
6
7
8
References ...................................................................................................... 123
Appendices ............................................................................................................................ 139
Appendix 1: Literature search strategies ........................................................................... 139
Appendix 2: Risk of Bias assessment – results ................................................................. 179
Appendix 3: Data extraction tables ................................................................................... 180
Appendix 4: Table of excluded studies with rationale ...................................................... 220
Appendix 5: Conversion Tables for HbA1c and Glucose Values ..................................... 267
Appendix 6: Detailed description of IMS CDM ............................................................... 270
Appendix 7: Disease natural history parameters and transition probabilities ................... 273
Appendix 8: Results (full incremental and intervention versus comparator) of base case and
scenario analyses ............................................................................................................... 280
Appendix 9: Guidance relevant to the treatment of type 1 diabetes ................................. 287
Appendix 10: PRISMA check list ..................................................................................... 291
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Table of Tables
Table 1: The assessment of Risk of Bias in included RCTs .................................................... 28
Table 2: Included studies and comparisons ............................................................................ 32
Table 3: Characteristics of included studies ........................................................................... 33
Table 4: In/exclusion criteria used in included studies for HbA1c and hypoglycaemic events
................................................................................................................................................. 34
Table 5: Included studies for adults........................................................................................ 35
Table 6: Results for the MiniMed Veo versus an integrated CSII+CGM system at three
months follow-up in adults ...................................................................................................... 36
Table 7: Results of network analysis for change in HbA1c at three month follow-up (WMD,
95% CI) ................................................................................................................................... 37
Table 8: Results of network analysis for DKA at three months follow-up (RR, 95% CI) ..... 38
Table 9: Results for the integrated CSII+CGM versus CSII+SMBG at six months follow-up
in adults ................................................................................................................................... 38
Table 10: Results for the integrated CSII+CGM system versus MDI+SMBG at 3, 6 and 12
months follow-up in adults ...................................................................................................... 40
Table 11: Results of network analysis for proportion of patients with severe hypoglycaemia
at three months follow-up in adults (RR, 95% CI) .................................................................. 43
Table 12: Results of network analysis for ‘Change in HbA1c’ at six months follow-up in
adults (WMD, 95% CI) ........................................................................................................... 43
Table 13: Results of network analysis for ‘HbA1c < 7%’ at six months follow-up in adults
(RR, 95% CI) ........................................................................................................................... 44
Table 14: Results of network analysis for ‘Quality of Life (DTSQ)’ at six months follow-up
in adults (WMD, 95% CI) ....................................................................................................... 45
Table 15: Included studies for children .................................................................................. 47
Table 16: Results for the MiniMed Veo system versus CSII+SMBG at six months follow-up
in a mixed population (mainly children) ................................................................................. 47
Table 17: Results of network analysis for change in HbA1c at six month follow-up (WMD,
95% CI) ................................................................................................................................... 48
Table 18: Results for the integrated pump+CGM versus pump+SMBG at six months followup in children ........................................................................................................................... 49
Table 19: Results for the integrated CSII+CGM system versus CSII+SMBG at 12 months
follow-up in children ............................................................................................................... 49
Table 20: Included studies for pregnant women .................................................................... 50
Table 21: Results of the network analysis for change in HbA1c at all follow-up time points in
adults and mixed populations (WMD, 95% CI) ...................................................................... 52
Table 22: Results of the network analysis for severe hypoglycaemic event rate at all followup time points in adults and mixed populations (RR, 95% CI) ............................................... 53
Table 23: Ongoing studies ...................................................................................................... 55
Table 24: Summary of included full papers ........................................................................... 62
Table 25: Summary of conference abstracts........................................................................... 64
Table 26: Quality assessment of studies, using Drummond 1996 .......................................... 67
Table 27: Mapping IMS CDM input parameter databases into conventional input parameter
categories ................................................................................................................................. 74
Table 28: Cohort baseline characteristics (base case analysis) ............................................... 75
Table 29: Management costs in type 1 diabetes patients......................................................... 78
Table 30: Costs of type 1 diabetes-related complications ....................................................... 78
Table 31: Equipment costs of MiniMed Paradigm Veo system and Vibe/G4 Platinum CGM
system based on 2014 costs ..................................................................................................... 80
Table 32: Price and market share of stand-alone insulin pumps in UK .................................. 81
Table 33: Price and market share of stand-alone CGM devices in UK in 2014 ...................... 81
Table 34: Comparison of blood glucose tests costs ................................................................. 82
Table 35: SAP and CSII (short-acting) insulin costs............................................................... 82
Table 36: MDI (long-acting insulin detemir and short-acting insulin) costs........................... 83
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Table 37: Annual outpatient care related costs........................................................................ 84
Table 38: Summary of annual treatment-related costs per technology ................................... 84
Table 39: Utilities per health state ........................................................................................... 85
Table 40: Mean (SE) change in HbA1c with respect to baseline for all treatments included in
the analysis .............................................................................................................................. 86
Table 41: Rate per 100 patient years of severe hypoglycaemic episodes for all treatments
included in the analysis ........................................................................................................... 86
Table 42: Disease management parameters............................................................................. 87
Table 43: Baseline characteristics that change with respect to the base case .......................... 88
Table 44: Blood glucose tests and costs for the additional scenarios ...................................... 89
Table 45: MDI (long-acting insulin detemir and short-acting insulin) costs based on 55 units
per day ..................................................................................................................................... 90
Table 46: Severe hypoglycaemia rates (no of events per 100 pt years) for different scenarios
................................................................................................................................................. 91
Table 47: Main model assumptions ......................................................................................... 92
Table 48: Base case model results (all technologies) probabilistic simulation ....................... 94
Table 49: Base case model results (intervention versus comparator only) probabilistic
simulation ................................................................................................................................ 95
Table 50: Base case model results (all technologies) deterministic simulation ...................... 95
Table 51: Base case model results (intervention versus comparator only) deterministic
simulation ................................................................................................................................ 95
Table 52: Model results (all technologies), scenario with different baseline population
characteristics ........................................................................................................................ 100
Table 53: Model results (all technologies), scenario with two (CGM) versus eight (SMBG)
blood glucose testing per day ................................................................................................ 101
Table 54: Model results (all technologies), scenario with no HbA1c progression ................ 102
Table 55: Cost-effectiveness results when no treatment effect (in terms of HbA1c change) in
the first year is assumed (all technologies)............................................................................ 102
Table 56: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (all technologies) ................................................................................... 103
Table 57: Cost-effectiveness results mortality due to severe hypoglycaemia scenario (all
technologies) ......................................................................................................................... 104
Table 58: Cost-effectiveness results minimum QALY estimation method scenario (all
technologies) ......................................................................................................................... 105
Table 59: Four year time horizon scenario (all technologies) ............................................... 105
Table 60: Cost-effectiveness results fear of hypoglycaemia scenario (all technologies) ...... 107
Table 61: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (all technologies) ..................................................................................................... 109
Table 62: Uncertainties regarding modelling children and adolescent population with the IMS
CDM ...................................................................................................................................... 111
Table 63: Risk of Bias assessment for all included studies .................................................. 179
Table 64: Study characteristics for included studies in adults .............................................. 180
Table 65: Study characteristics for included studies in children .......................................... 183
Table 66: Study characteristics for included studies in mixed populations.......................... 184
Table 67: Study characteristics for included studies in pregnant women ............................ 185
Table 68: Baseline characteristics for included studies in adults ......................................... 186
Table 69: Baseline characteristics for included studies in children ...................................... 190
Table 70: Baseline characteristics for included studies in mixed populations ..................... 192
Table 71: Baseline characteristics for included studies in pregnant women ........................ 194
Table 72: Results – change from baseline in HbA1c – adults .............................................. 195
Table 73: Results – change from baseline in HbA1c – children .......................................... 199
Table 74: Results – change from baseline in HbA1c – mixed populations .......................... 201
Table 75: Results – change from baseline in HbA1c – pregnant women ............................. 202
Table 76: Results – proportion achieving HbA1c ≤7% – adults .......................................... 203
Table 77: Results – proportion achieving HbA1c ≤7% – children....................................... 204
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Table 78: Results – proportion achieving HbA1c ≤7% – mixed populations ...................... 205
Table 79: Results – hypoglycaemia ...................................................................................... 206
Table 80: Results – hypoglycaemia event rate ..................................................................... 209
Table 81: Results – HRQoL – adults (no data for children, mixed populations and pregnant
women) .................................................................................................................................. 213
Table 82: Results – adverse events ....................................................................................... 217
Table 83: Results – adverse events – pregnant women ........................................................ 219
Table 84: Summary of reasons for exclusion for excluded studies at full paper screening
stage ....................................................................................................................................... 220
Table 85: Excluded studies at full paper screening stage with reason for exclusion............ 221
Table 86: HbA1c Conversion Table - Older DCCT-aligned (%) and newer IFCC- ............ 267
Table 87: Glucose Values Conversion Table (mg/dl - mmol/l) ........................................... 269
Table 88: Disease natural history parameters. ...................................................................... 273
Table 89: Transition probabilities dependencies and sources .............................................. 278
Table 90: Base case model results (all technologies) probabilistic simulation .................... 280
Table 91: Base case model results (intervention versus comparator only) probabilistic
simulation .............................................................................................................................. 280
Table 92: Base case model results (all technologies) deterministic simulation ................... 280
Table 93: Base case model results (intervention versus comparator only) deterministic
simulation .............................................................................................................................. 280
Table 94: Model results (all technologies), scenario with different baseline population
characteristics ........................................................................................................................ 281
Table 95: Model results (intervention versus comparator only), scenario with different
baseline population characteristics ........................................................................................ 281
Table 96: Model results (all technologies), scenario with two (CGM) versus eight (SMBG)
blood glucose testing per day ................................................................................................ 281
Table 97: Model results (intervention versus comparator only), scenario with two (CGM)
versus eight (SMBG) blood glucose testing per day ............................................................. 281
Table 98: Model results (all technologies), scenario with increased amount of daily insulin
for MDI.................................................................................................................................. 282
Table 99: Model results (intervention versus comparator only), scenario with increased
amount of daily insulin for MDI ........................................................................................... 282
Table 100: Model results (all technologies), scenario with no HbA1c progression ............. 282
Table 101: Model results (intervention versus comparator only), scenario with no HbA1c
progression ............................................................................................................................ 282
Table 102: Cost-effectiveness results when no treatment effect (in terms of HbA1c change)
in the first year is assumed (all technologies)........................................................................ 283
Table 103: Cost-effectiveness results when no treatment effect (in terms of HbA1c change)
in the first year is assumed (intervention versus comparator only) ....................................... 283
Table 104: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (all technologies) ................................................................................... 283
Table 105: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (intervention versus comparator only) .................................................. 283
Table 106: Cost-effectiveness results mortality due to severe hypoglycaemia scenario (all
technologies) ......................................................................................................................... 284
Table 107: Cost-effectiveness results mortality due to severe hypoglycaemia scenario
(intervention versus comparator only)................................................................................... 284
Table 108: Cost-effectiveness results minimum QALY estimation method scenario (all
technologies) ......................................................................................................................... 284
Table 109: Cost-effectiveness results minimum QALY estimation method scenario
(intervention versus comparator only)................................................................................... 284
Table 110: Four year time horizon scenario (all technologies) ............................................ 285
Table 111: Four year time horizon scenario (intervention versus comparator only)............ 285
Table 112: Cost-effectiveness results fear of hypoglycaemia scenario (all technologies) ... 285
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Table 113: Cost-effectiveness results fear of hypoglycaemia scenario (intervention vsersus
comparator only) ................................................................................................................... 285
Table 114: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (all technologies) ..................................................................................................... 286
Table 115: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (intervention versus comparator only) .................................................................... 286
Table of Figures
Figure 1: Flow of studies through the review process ............................................................. 31
Figure 2: Network of studies comparing ‘change in HbA1c’ and DKA at three months followup in adults .............................................................................................................................. 37
Figure 3: Network of studies comparing ‘severe hypoglycaemia’ at three months follow-up in
adults ....................................................................................................................................... 42
Figure 4: Network of studies comparing ‘Change in HbA1c’ at six months follow-up in adults
................................................................................................................................................. 43
Figure 5: Network of studies comparing ‘HbA1c < 7%’ at six months follow-up in adults ... 44
Figure 6: Network of studies comparing ‘Quality of Life’ at six months follow-up in adults 45
Figure 7: Network of studies comparing ‘Change in HbA1c’ at six months follow-up in
children .................................................................................................................................... 48
Figure 8: Network of studies comparing ‘Change in HbA1c’ at all follow-up time points in
adults and mixed populations .................................................................................................. 52
Figure 9: Network of studies comparing ‘Severe hypoglycaemic event rate’ at all follow-up
time points in adults and mixed populations ........................................................................... 53
Figure 10: IMS CDM model structure .................................................................................... 73
Figure 11: Breakdown of costs per treatment .......................................................................... 96
Figure 12: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
patients..................................................................................................................................... 97
Figure 13: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes patients
................................................................................................................................................. 98
Figure 14: Cost-effectiveness acceptability curves for all non-MDI treatments in type 1
diabetes patients ...................................................................................................................... 99
Figure 15: Cost-effectiveness acceptability curves for CGM treatments in type 1 diabetes
patients................................................................................................................................... 100
Figure 16: Cost-effectiveness acceptability curves for all treatments when there is no HbA1c
treatment effect ...................................................................................................................... 103
Figure 17: Cost-effectiveness acceptability curves for CGM treatments only nonzero
mortality due to severe hypoglycaemia scenario ................................................................... 104
Figure 18: Cost-effectiveness acceptability curves for all treatments four year time horizon
scenario.................................................................................................................................. 106
Figure 19: Cost-effectiveness acceptability curves for CGM treatments only; four year time
horizon scenario .................................................................................................................... 106
Figure 20: Cost-effectiveness acceptability curves for reduced fear of hypoglycaemia scenario
............................................................................................................................................... 108
Figure 21: Cost-effectiveness acceptability curves for CGM treatments only fear of
hypoglycaemia scenario ........................................................................................................ 108
Figure 22: Cost-effectiveness acceptability curves cost of stand-alone CSII+CGM without
market share scenario ............................................................................................................ 109
Figure 23: Cost-effectiveness acceptability curves for CGM treatments only cost of standalone CSII+CGM without market share scenario.................................................................. 110
Figure 24: IMS CDM software model structure.................................................................... 270
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GLOSSARY
Cost-effectiveness
analysis
An economic analysis that converts effects into health terms and
describes the costs for additional health gain.
Decision modelling
A mathematical construct that allows the comparison of the
relationship between costs and outcomes of alternative healthcare
interventions.
Diabetic ketoacidosis
Occurs when the body is unable to use blood glucose because of
inadequate insulin. Instead, fat is broken down as an alternative
source of fuel; a process that leads to a build-up of a by-product
called ketones.
False negative
Incorrect negative test result – number of diseased persons with a
negative test result.
False positive
Incorrect positive test result – number of non-diseased persons
with a positive test result.
HbA1c
The term HbA1c refers to glycated haemoglobin. The HbA1c test
measures diabetes management over two to three months.
Hyperglycaemic and
hypoglycaemic AUC
The area under the curve is the product of the magnitude and
duration of the sensor measured glucose level above or below a
specified cutoff level. Higher values for this calculation indicate
more numerous, severe, or protracted glycemic events.
Hypocalcaemia
Low blood calcium level.
Hypomagnesaemia
Low levels of magnesium in the blood.
Impaired awareness of
hypoglycaemia
When people with diabetes, usually type 1 diabetes, are frequently
unable to notice when they have low blood sugar.
Incremental costThe difference in the mean costs of two interventions in the
effectiveness ratio (ICER) population of interest divided by the difference in the mean
outcomes in the population of interest.
Index test
The test whose performance is being evaluated.
Integrated CSII+CGM
An integrated CGM and insulin pump system intended to aid the
effective management of diabetes, without Low Glucose Suspend
function.
Ketonaemia
The presence of an abnormally high concentration of ketone
bodies in the blood.
Ketonuria
The presence of abnormally high amounts of ketones and ketone
bodies (a by-product of the breakdown of cells) in the urine.
Ketonuria is a sign seen in badly controlled diabetes.
Low Glucose Suspend
function
Stops insulin delivery for 2 hours if there is no response to a low
glucose warning.
Markov model
An analytic method particularly suited to modelling repeated
events, or the progression of a chronic disease over time.
Meta-analysis
Statistical techniques used to combine the results of two or more
studies and obtain a combined estimate of effect.
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Meta-regression
Statistical technique used to explore the relationship between
study characteristics and study results.
MiniMed Paradigm Veo
System
An integrated CGM and insulin pump system intended to aid the
effective management of diabetes, with added insulin suspend
function intended to prevent hypoglycaemia, including nocturnal
hypoglycaemia.
Opportunity costs
The cost of forgone outcomes that could have been achieved
through alternative investments.
Polycythaemia
An abnormally increased concentration of haemoglobin in the
blood, either through reduction of plasma volume or increase in
red cell numbers.
Publication bias
Bias arising from the preferential publication of studies with
statistically significant results.
Quality of life
An individual’s emotional, social and physical well-being, and
their ability to perform the ordinary tasks of living.
Quality-adjusted life year A measure of health gain, used in economic evaluations, in which
(QALY)
survival duration is weighted or adjusted by the patient’s quality of
life during the survival period.
Receiver Operating
Characteristic (ROC)
curve
A graph which illustrates the trade-offs between sensitivity and
specificity which result from varying the diagnostic threshold.
Reference standard
The best currently available diagnostic test, against which the
index test is compared.
Retinopathy
Diabetic retinopathy is a common complication of diabetes. It
occurs when high blood sugar levels damage the cells at the back
of the eye (known as the retina). If it isn't treated, it can cause
blindness.
Sensitivity
Proportion of people with the target disorder who have a positive
test result.
Specificity
Proportion of people without the target disorder who have a
negative test result.
True negative
Correct negative test result – number of non-diseased persons with
a negative test result.
True positive
Correct positive test result – number of diseased persons with a
positive test result.
Type 1 diabetes
Diabetes where the body does not produce insulin.
Vibe and G4 PLATINUM An integrated CGM and insulin pump system intended to aid the
CGM system
effective management of diabetes, without Low Glucose Suspend
function.
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LIST OF ABBREVIATIONS
Technical terms and abbreviations are used throughout this report. The meaning is usually
clear from the context, but a glossary is provided for the non-specialist reader.
ADA
AE
AUC
BG
BNF
CADTH
CGM
CI
CRD
CSII
DAP
DAR
DCCT
DIC
DKA
EAG
EASD
EUR
HFS
HR
HRQoL
HUS
ICER
ISPOR
KSR
LGS
MD
MDI
MTAC
MTC
NA
NHS
NICE
NR
NS
OR
PSSRU
QALY
QUADAS
RCT
ROC
RR
SAPT
SD
SMBG
SROC
T1DM
T2DM
WMD
American Diabetes Association
Adverse Event
Area Under the Curve
Blood Glucose
British National Formulary
Canadian Agency for Drugs and Technologies
Continuous Glucose Monitoring
Confidence Interval
Centre for Reviews and Dissemination
Continuous Subcutaneous Insulin Infusion
Diagnostics Assessment Programme
Diagnostics Assessment Report
Diabetes Control and Complications Trial
Deviance Information Criterion
Diabetic Ketoacidosis
External Assessment Group
European Association for the Study of Diabetes
Erasmus University Rotterdam
Hypoglycaemia Fear Survey
Hazard Ratio
Health-Related Quality of Life
Hypoglycemia Unawareness Score
Incremental Cost-Effectiveness Ratio
International Society for Pharmacoeconomics and Outcomes Research
Kleijnen Systematic Reviews
Low Glucose Suspend
Mean Difference
Multiple Daily Insulin Injections
Medical Technologies Advisory Committee
Mixed Treatment Comparison
Not Applicable
National Health Service
National Institute for Health and Clinical Excellence
Not Reported
Not Significant
Odds Ratio
Personal Social Services Research Unit
Quality-Adjusted Life Year
Quality Assessment of Diagnostic Accuracy Studies tool
Randomised Controlled Trial
Receiver Operating Characteristic
Relative Risk
Sensor-Augmented Pump Therapy
Standard Deviation
Self-Monitoring of Blood Glucose
Summary Receiver Operating Characteristic
Type 1 diabetes mellitus
Type 2 diabetes mellitus
Weighted Mean Difference
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1
EXECUTIVE SUMMARY
1.1
Background
Diabetes affects an estimated 3.75 million people in the UK. Approximately 250,000 of these
3.75 million will have type 1 diabetes.
This assessment will focus on integrated sensor-augmented pump therapy systems in type 1
diabetes.
The characteristic feature of diabetes is high blood glucose levels – hyperglycaemia. Type 1
diabetes is due to destruction of the pancreatic beta cells that produce insulin, and the
mainstay of treatment is injections of insulin, which are necessary to sustain life. Intensive
insulin treatment, aimed at tight control of blood glucose, reduces the risk of the long term
complications of diabetes such as retinopathy and renal disease. Intensive insulin treatment is
a package of care consisting of either multiple daily insulin injections (MDI) or continuous
subcutaneous insulin infusion (CSII) with an insulin pump, frequent testing of blood glucose,
self-adjustment of insulin dosages in response to blood glucose levels, and lifestyle
interventions such as diet and physical activity.
Provision of an insulin pump alone is not enough; for a pump to be used effectively it should
be accompanied by intensive management. Hyperglycaemia can be controlled by increasing
the amount of insulin injected. However, this can lower blood glucose too far. Low blood
glucose is called hypoglycaemia, and this is a limiting factor in attempts to control
hyperglycaemia. Hypoglycaemia events can be very frightening, especially in children and
for their parents, and fear of hypoglycaemia is very common, not just amongst those with
diabetes but also amongst relatives and friends.
In recent years meters for continuous monitoring of interstitial fluid glucose have been
introduced to help people with type 1 diabetes to achieve better control of their disease.
Increasingly sophisticated integrated methods of glucose monitoring and insulin delivery are
designed to provide a closer approximation to the body’s natural system and achieve
acceptable glycaemic control whilst minimising the risk of hypoglycaemic episodes. Current
continuous glucose monitoring (CGM) systems rely on the user taking action, and this may
not occur, particularly at night. Hypoglycaemia events at night are known as nocturnal
hypoglycaemia. Alarms may wake people up, but those having nocturnal hypoglycaemia
events often sleep through them and recurrent hypoglycaemia events can lead to
hypoglycaemia unawareness.
A recent development in CGM/pump technology, available in the UK since 2009, is the
MiniMed Paradigm Veo System wherein the CGM device can stop (suspend) the insulin
infusion from the pump for up to two hours. After that, insulin infusion is restored at a basal
rate.
The population for the current assessment are adults and children with type 1 diabetes. The
interventions to be assessed (integrated CGM and insulin pump systems with or without a
suspend function) aim to provide better monitoring and dose adjustment and hence achieve
acceptable glycaemic control whilst minimising hypoglycaemic episodes.
1.2
Objectives
The overall objective of this project is to summarise the evidence on the clinical and costeffectiveness of the MiniMed Paradigm Veo System and the Vibe and G4 PLATINUM CGM
system for the management of type 1 diabetes in adults and children.
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The following research questions have been defined to address the review objectives:

1.3
What is the clinical and cost-effectiveness of integrated insulin pump systems
compared with:
o
Capillary blood testing with continuous subcutaneous insulin infusion
(CSII+SMBG)
o
Capillary blood testing with multiple daily insulin injections (MDI+SMBG)
o
Continuous glucose monitoring with continuous subcutaneous insulin
infusion (non-integrated) (CSII+CGM)
o
Continuous glucose monitoring with multiple daily injections (MDI+CGM)
Methods
Assessment of clinical effectiveness
A systematic review following the principles outlined in the Centre for Reviews and
Dissemination (CRD) guidance for undertaking reviews in health care, and NICE Diagnostic
Assessment Programme manual was conducted to summarise the evidence on the clinicaleffectiveness of the MiniMed Paradigm Veo System and, the Vibe and G4 PLATINUM CGM
system for the management of type 1 diabetes in adults and children.
Study populations eligible for inclusion were adults, including pregnant women, and children
with type 1 diabetes and the relevant setting is self-use supervised by primary or secondary
care. The interventions are those described above and the main outcomes are HbA1c,
frequency of hyperglycaemia events and frequency of hypoglycaemia events.
We searched over 15 databases, trial registries and conference proceedings from inception up
to September 2014. Two reviewers independently screened the titles and abstracts of all
reports identified by searches and any discrepancies were discussed and resolved by
consensus. Full text copies of all studies deemed potentially relevant, after discussion, were
obtained and the same two reviewers independently assessed these for inclusion; any
disagreements were resolved by consensus. Data relating to study details, participants,
intervention and comparator tests, and outcome measures were extracted by one reviewer,
using a piloted, standard data extraction form. A second reviewer checked data extraction and
any disagreements were resolved by consensus. The assessment of the methodological quality
of each included study was based on the Cochrane Collaboration quality assessment checklist.
Quality assessment was carried out independently by two reviewers. Any disagreements were
resolved by consensus.
In the absence of RCTs directly comparing the MiniMed Paradigm Veo System or an
integrated CSII+CGM system such as the Vibe and G4 PLATINUM CGM system with the
comparators, indirect treatment comparisons were performed, where possible. Where metaanalysis was considered unsuitable for some or all of the data identified (e.g. due to the
heterogeneity and/or small numbers of studies), we employed a narrative synthesis.
Assessment of cost-effectiveness
We assessed the cost-effectiveness of the MiniMed Paradigm Veo System and Vibe and G4
PLATINUM CGM systems compared with CSII+CGM, CSII+SMBG, MDI+CGM and
MDI+SMBG for the management of type 1 diabetes.
A commercially available cost-effectiveness model, IMS CORE diabetes model (IMS CDM),
was chosen for this assessment. The model is an internet based, interactive simulation model
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that predicts the long-term health outcomes and costs associated with the management of type
1 diabetes (T1DM) and type 2 diabetes (T2DM). The model consists of 15 submodels
designed to simulate diabetes-related complications, non-specific mortality, and costs over
time. As the model simulates individual patients over time, it updates risk factors and
complications to account for disease progression.
Given the degree of validation of the model1, 2, and in order to be in line with the currently
updated T1DM NICE guideline CG15,3 for this evaluation it was believed important not to
use an alternative model or develop a de novo cost-effectiveness model. When possible we
estimated input parameters based on the studies identified in the systematic review. This was
done to properly reflect our base case population, i.e. type 1 diabetes, eligible for an insulin
pump. We used the results of indirect comparisons of change in HbA1c and rate ratios of
severe hypoglycaemic events to model the treatment effects.
Since the IMS CDM is not suitable to model long term outcomes for children and pregnant
women (the background risk adjustment/risk factor progression equations are all based on
adults) we had to limit the population being assessed to adults only.
The impact of uncertainty about a number of input parameters and model assumptions on the
model outcomes was explored through probabilistic sensitivity analyses and scenario
analyses.
1.4
Results
Fifty-four publications of 19 studies were included in the review. Two studies compared the
MiniMed Paradigm Veo system with an integrated CSII+CGM system and with
CSII+SMBG, respectively. Seven other studies compared an integrated CSII+CGM system
with CSII+SMBG (three studies4-6) or with MDI+SMBG (four studies7-10). The remaining
studies compared CSII+SMBG with MDI+SMBG (10 studies). None of the studies included a
treatment arm with one of the following comparators: CSII+CGM and MDI+CGM. Although
several studies included the integrated CSII+CGM system as a treatment arm, it is important
to note that none of these studies looked at the Vibe and G4 PLATINUM CGM system; in the
included studies, the integrated CSII+CGM system was always a MiniMed Paradigm pump
with integrated CGM system.
Twelve studies reported data for adults, five studies reported data for children, and five
studies reported data for mixed populations (adults and children). Two of these studies
reported data for all three groups. One study included pregnant women.
Most studies were rated as high risk of bias (11 out of 19), four studies were rated unclear risk
of bias and another four studies were rated low risk of bias.
Twelve studies were included in the analyses for adults. The main conclusions from these
trials is that the MiniMed Paradigm Veo system reduces hypoglycaemic events in adults in
comparison with the integrated CSII+CGM system, without any differences in other
outcomes, including change in HbA1c. Nocturnal hypoglycemic events occurred 31.8% less
frequently in the Minimed Veo group than in the integrated CSII+CGM group (1.5±1.0 vs.
2.2±1.3 per patient week, P<0.001). Similarly, the Minimed Veo group had significantly
lower weekly rates of combined daytime and night-time events than the integrated
CSII+CGM group (P<0.001). Indirect evidence seems to suggest that that there are no
significant differences between the MiniMed Paradigm Veo system and CSII+SMBG and
MDI+SMBG in ‘change in HbA1c’ at three months follow-up. However, if all studies are
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combined (combining different follow-up times and including mixed populations), the
MiniMed Paradigm Veo system is significantly better than MDI+SMBG in terms of HbA1c.
For the integrated CSII+CGM system versus other treatments head-to-head results showed
significant effects in favour of the integrated CSII+CGM system in comparison with
MDI+SMBG for HbA1c, but not when compared with CSII+SMBG; and significant results in
favour of the integrated CSII+CGM system in comparison with MDI+SMBG and with
CSII+SMBG for quality of life.
When comparing CSII versus MDI, only one of the six trials showed a significant difference
between CSII+SMBG and MDI+SMBG in terms of change in HbA1c. DeVries et al (2002)
found a significant difference in favour of CSII+CGM: at 16 weeks mean HbA1c was 0.84%
(95% CI: -1.31, -0.36) lower in the CSII+SMBG group compared with the MDI+SMBG
group. No differences were found in any trial for the number of severe hypoglycaemic events.
Six studies were included in the analyses for children. None of the studies in children made
a direct comparison between the MiniMed Paradigm Veo system and the integrated
CSII+CGM system. An indirect comparison was possible, using data at six months follow-up
from Ly 2013 and Hirsch 2008, but only for HbA1c, which showed no significant difference
between groups.
One study compared the MiniMed Paradigm Veo system with CSII+SMBG. The only
significant difference between treatment groups was the rate of moderate and severe
hypoglycaemic events, which favoured the MiniMed Paradigm Veo system.
One study compared the integrated CSII+CGM system with CSII+SMBG, this trial found no
significant difference in HbA1c scores between groups. One study compared the integrated
CSII+CGM system with MDI+SMBG, this trial showed a significant difference in HbA1c
change scores in favour of the integrated CSII+CGM system, but no significant difference in
the number of children achieving HbA1c ≤7%. Hyperglycaemic AUC (>250 mg/dL) was
significantly lower in the integrated CSII+CGM group, but hypoglycaemic AUC (<70 mg/dL)
showed no significant difference. Other outcomes showed no significant differences between
groups.
For pregnant women we found only one trial comparing CSII+SMBG with MDI+SMBG
which is not relevant to the decision problem.
The comparator MDI+CGM was not included in the cost-effectiveness analyses since no
evidence was found in our systematic review. In the absence of data on comparing the clinical
effectiveness of integrated CSII+CGM systems against stand-alone CSII+CGM systems, we
assumed in our cost-effectiveness analyses that both technologies would be equally effective.
The immediate consequence of this assumption is that stand-alone CSII+CGM systems
always dominate the integrated CSII+CGM systems since the stand-alone system is cheaper,
according to our estimated cost, whilst being equally effective.
Overall, the cost-effectiveness results suggested that the technologies using SMBG (either
with CSII or MDI) are more likely to be cost-effective since the higher quality of life and/or
life expectancy provided by the technologies using CGM did not compensate for the
difference in costs. The MiniMed Paradigm Veo is extendedly dominated by CSII+CGM
stand-alone. This means that CSII+CGM is both more effective than Minimed Paradigm
Veo, but also better value i.e. the increase in cost compared to the next most effective choice,
which is CSII+SMBG, is less for CSII+CGM. We estimated that the ICER of CSII+CGM
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stand-alone compared to the next most effective choice, CSII+SMBG, is £660,376 and the
ICER of CSII+SMBG compared to the least effective choice, MDI+SMBG, is £46,123. Thus,
assuming the common threshold of £30,000 per QALY gained, MDI+SMBG, whilst being the
least effective, would be considered the optimal choice. When uncertainty is taken into
account we see that at that threshold MDI+SMBG would have a 95% probability of being the
optimal choice.
That CSII+CGM is more effective than Minimed Paradigm Veo might appear to contradict
the clinical effectiveness conclusions, but this is explained by effectiveness being affected by
both difference in hypoglycaemic event rate and HbA1c level. Whilst the evidence shows
that Minimed Paradigm Veo is probably better in terms of hypoglycaemic event rate it does
show a small albeit not statistically significant disadvantage in terms of HbA1c. Even this
small difference seems to be sufficient, through the consequences of hyperglycaemia, to
outweigh the difference in the relatively rare hypoglycaemia with generally less severe
consequences. However, note that all of these results should be interpreted with caution as
some studies on which effect estimates were based included all type 1 patients, whereas
others included patients who had been on a pump for at least six months already and others
included patients without pump experience but with poor glycaemic control at baseline.
Superseded
see Erratum
-
These results remained largely unchanged in scenario analyses, used to assess the potential
impact of various input parameters on the model outcomes. Even when a large array of
scenarios is considered, in all of them MDI+SMBG would be considered the optimal choice
assuming a threshold of £30,000 per QALY gained.
1.5
Conclusions
Overall, the evidence seems to suggest that the MiniMed Paradigm Veo system reduces
hypoglycaemic events in comparison with other treatments, without any differences in other
outcomes, including change in HbA1c. In addition we found significant results in favour of
the integrated CSII+CGM system in comparison with MDI+SMBG for HbA1c and quality of
life. However, the evidence base was poor. The quality of included studies was generally low
and often there was only one study to compare treatments in a specific population and at a
specific follow-up time. In particular, the evidence for the two interventions of interest was
limited, with only one study comparing the MiniMed Paradigm Veo system with an
integrated CSII+CGM system and one study in a mixed population comparing the MiniMed
Paradigm Veo system with CSII+SMBG.
Cost-effectiveness analyses indicated that MDI+SMBG is the option most likely to be costeffective, given the current threshold of £30,000 per QALY gained, whereas integrated
CSII+CGM systems and MiniMed Paradigm Veo are dominated and extendedly dominated,
respectively, by CSII+CGM stand-alone. Scenario analyses, used to assess the potential
impact of changing various input parameters, did not alter these conclusions. No costeffectiveness modelling was conducted for children and pregnant women.
1.6
Suggested research priorities
In adults, a trial comparing the MiniMed Paradigm Veo system with CSII+SMBG is
warranted. Similarly a trial comparing the Vibe and G4 PLATINUM CGM system or any
integrated CSII+CGM system with CSII+SMBG is warranted. In children, a trial comparing
the MiniMed Paradigm Veo system with the Vibe and G4 PLATINUM CGM system or any
integrated CSII+CGM system is warranted, as is a trial comparing an integrated CSII+CGM
system with CSII+SMBG. For pregnant women, trials comparing the MiniMed Paradigm Veo
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system and the Vibe and G4 PLATINUM CGM system or any integrated CSII+CGM system
with other interventions are warranted.
Future trials should include longer term follow-up and include EQ-5D at various time points
with a view to informing improved cost-effectiveness modelling.
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2
BACKGROUND AND DEFINITION OF THE DECISION PROBLEM(S)
2.1
Population
Diabetes affects an estimated 3.75 million people in the UK.11, 12 Approximately 250,000 of
these 3.75m will have type 1 diabetes.13
Type 1 diabetes, where the body does not produce insulin, is most commonly first diagnosed
in the teenage years and accounts for around 5–15% of all diabetes cases. Type 2 diabetes,
where the body develops a resistance to insulin, usually affects people over the age of 40
years. Type 2 diabetes is becoming increasingly more prevalent in younger people, and may
be more common in people of South-Asian, African Caribbean or Middle Eastern descent.
People who are overweight, have inactive lifestyles or a family history of diabetes are at
greater risk of developing the disease.12, 14, 15
This assessment will focus on integrated sensor-augmented pump therapy systems in type 1
diabetes.16
The characteristic feature of diabetes is high blood glucose levels – hyperglycaemia. Type 1
diabetes is due to destruction of the pancreatic beta cells that produce insulin, and the
mainstay of treatment is injections of insulin, which are necessary to sustain life. The
Diabetes Control and Complications Trial17 and other studies18 have shown that intensive
insulin treatment, aimed at tight control of blood glucose, reduces the risk of the long term
complications of diabetes such as retinopathy and renal disease. Diabetes is one of the
commonest causes of blindness and end-stage renal failure.
Intensive insulin treatment is a package of care consisting of either multiple daily insulin
injections (MDI) or continuous subcutaneous insulin infusion (CSII) with an insulin pump,
frequent testing of blood glucose, self-adjustment of insulin dosages in response to blood
glucose levels, as well as lifestyle circumstances such as diet and physical activity.
However, insulin injections cannot provide the sort of fine tuning that can be done by a
normal pancreas controlled by the body’s normal feedback mechanisms, and many people
with type 1 diabetes do not succeed in achieving good control of their diabetes. This is
particularly so in children. The best measure of blood glucose control is glycated
haemoglobin, known as HbA1c. An audit of diabetic control in Scottish children showed that
only about 10% achieved the NICE target of an HbA1c of 7.5% or less.19 In England and
Wales, about 17% of children and young people with diabetes achieved the NICE target.20 In
2008 NICE recommended continuous subcutaneous insulin infusion (CSII or 'insulin pump')
therapy as a treatment option for adults and children 12 years and older with type 1 diabetes
mellitus.16 NICE concluded that CSII therapy had a valuable effect on blood glucose control
by reducing HbA1c levels and reductions in complications.
Provision of an insulin pump alone is not enough; for a pump to be used effectively it should
be accompanied by intensive management. Hyperglycaemia can be controlled by increasing
the amount of insulin injected. However, this can lower blood glucose too far. Low blood
glucose is called hypoglycaemia, and this is the limiting factor in attempts to control
hyperglycaemia. NICE was also persuaded that CSII therapy could reduce the rate of
hypoglycaemic episodes, and it heard from the patient experts that when hypoglycaemia
occurs in people using CSII therapy, it does so gradually and with sufficient time for the
pump user to take remedial action.
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The symptoms of hypoglycaemia range from feelings of hunger, faintness, sweating, anxiety
and sleepiness at the mild end of the spectrum, to confusion, difficulty in speaking, and
disturbances of behaviour, and at the severe end of the spectrum to loss of consciousness,
convulsions and rarely, death. Hypoglycaemia is assumed to be the main cause of the “found
dead in bed” cases,21 which luckily are rare.
Hypoglycaemia events can be very frightening, especially in children and for their parents,
and fear of hypoglycaemia is very common, not just amongst those with diabetes but also
amongst relatives and friends. There is particular anxiety amongst parents of younger
children, some of whom may allow blood glucose levels to run high in order to avoid
hypoglycaemia (“hypo avoidance behaviour”).22
Parents of younger children express considerable anxiety, and may feel a need to get up
during the night to check blood glucose (BG) in their children. Blood glucose control may be
easier if children are on an insulin pump, but even then parents are likely to set alarms to get
up during the night to check that their child is not having hypoglycaemia. Many severe
hypoglycaemia events in children occur at night.
As soon as people with diabetes recognise the symptoms, they can take some form of fast
acting carbohydrate in the form of sugar-containing food, or just sugar itself, and thereby
raise blood glucose again. However, there is a particular problem known as hypoglycaemic
unawareness, wherein some people do not get the warning symptoms. Being unaware of
impending hypoglycaemia, they may be unable to take food or sugar in time to prevent a
serious hypoglycaemia event. Hypoglycaemia unawareness usually follows frequent
hypoglycaemia events, and a vicious circle can develop where frequent hypoglycaemia events
cause hypoglycaemia unawareness, which lead to more, and more severe, hypoglycaemia,
associated with failure of the body to release the counter-regulatory hormones like adrenaline
that cause warning symptoms.
Until recently, self-monitoring of blood glucose (SMBG) meant pricking a part of the body
such as the fingertip with a needle to make it bleed (sometimes up to 15 times a day), putting
a drop of blood on a test strip, and measuring blood glucose with the aid of a meter.
Depending on the result, the patient then adjusts insulin dose or diet in order to try to keep the
blood glucose on the optimum range.
In recent years meters for continuous monitoring of interstitial fluid glucose have been
introduced to help people with type 1 diabetes to achieve better control of their disease.
Increasingly sophisticated integrated methods of monitoring and insulin delivery are designed
to provide a closer approximation to the body’s natural system and achieve acceptable
glycaemic control whilst minimising the risk of hypoglycaemic episodes. Interventions to
help people with type 1 diabetes to achieve better control include structured education (the
DAFNE course23 or similar courses) and CSII with an insulin pump.
CSII provides for flexible administration of insulin, trying to mimic the body’s natural pattern
of a little insulin all the time (basal infusion) and with peaks of insulin release following
meals (boluses), aided by self-monitoring of blood glucose by capillary blood testing.
However, there are limits to what can be done with capillary blood testing (and it is painful –
more so than insulin injections). In recent years, devices which continually measure blood
glucose (strictly speaking, they measure the level of glucose in the subcutaneous tissue) have
been introduced. These use a cannula inserted under the skin connected to a glucose meter.
The first of these continuous glucose monitoring (CGM) systems merely recorded blood
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glucose levels for later downloading, but now we have CGM devices which display
interstitial glucose levels – so-called “real-time CGM”. So users can look to see what their
most recent level was (CGM is not exactly continuous, but every 5-10 minutes). The
psychosocial impact of CGM is mixed however with both positive results from greater control
over diabetes but also negative impact from intrusive false alarms, additional burden and
visibility of disease.24, 25 In addition, CGM does not make capillary blood testing redundant; a
minimum of two tests per day is still required to calibrate CGM.
The next step was to have alarm facilities, whereby the meter can alert the user to BG levels
that are too high or too low. In theory, the user can then adjust insulin dosage, for example
reducing the infusion rate if BG is too low, or showing a falling trend. These integrated
systems are called “sensor-augmented pump therapy” (SAPT).
Current CGM systems rely on the user taking action, and this may not occur, particularly at
night. Hypoglycaemia events at night are known as nocturnal hypoglycaemia. Alarms may
wake people up, but those having nocturnal hypoglycaemia events often sleep through them
and recurrent hypoglycaemia events can lead to hypoglycaemia unawareness.
CGM may initially raise anxiety, because it provides much more data on blood glucose levels,
and this can lead to more anxiety amongst patients and parents. False alarms are a particular
problem, leading to distrust of the device and lack of willingness to take appropriate action.
A recent (in UK since 2009) development in CGM/pump technology is the Medtronic Veo
suspend combination wherein the CGM device can stop (suspend) the insulin infusion from
the pump for up to two hours. After that, insulin infusion is restored at a basal rate. In
practice, few suspensions are for as long as two hours, because in most cases the pump user
takes corrective action.26 From UK centres, it is reported that in a small study (31 patients for
three weeks), 66% of suspend durations were for 10 minutes or less. Most long episodes
occurred at night and there was a reduction in nocturnal hypoglycaemia.
After insulin infusion is stopped, it does take 30 minutes for blood glucose to rise, 27 so
hypoglycaemia events may be shortened or made less severe, rather than always avoided.
Suspension can be done manually by the user, responding to an alarm or after checking realtime results, or automatically by the device. Patients can over-ride the pump and cancel the
suspension, taking food to raise blood glucose. One problem reported is that sleeping position
may cause falsely low readings because of tissue compression.28
The population for the current assessment are adults and children with type 1 diabetes. The
interventions to be assessed (integrated CGM and insulin pump systems with or without a
suspend function) aim to provide better monitoring and dose adjustment and hence achieve
acceptable glycaemic control whilst minimising hypoglycaemic episodes.
2.2
Description of technologies under assessment
The MiniMed Paradigm Veo System and the Vibe and G4 PLATINUM CGM system are
integrated CGM and insulin pump systems intended to aid the effective management of
diabetes. The MiniMed Paradigm Veo System has an added insulin suspend function intended
to prevent hypoglycaemia, including nocturnal hypoglycaemia.
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The MiniMed Paradigm Veo System
The MiniMed Paradigm Veo System has three components:
1. A small glucose sensor, placed under the skin, which measures glucose levels every five
minutes 24-hours a day (the sensor requires replacement every six days)
2. The MiniLink transmitter which sends the information to the Paradigm Veo insulin
pump
3. The Paradigm Veo insulin pump.
The system is complete and stand-alone and not directly interchangeable with other
manufacturers’ pumps or sensors. Many insulin formulations can be used in the insulin pump.
In this report we will focus on fast-acting insulins only, because this is the preferred clinical
practice when using insulin pumps in the UK.29
Continuous glucose monitors measure the level of tissue glucose electronically on a
continuous basis (every few minutes). They use a subcutaneous, disposable glucose sensor
placed just under the skin to measure interstitial glucose levels. The glucose sensor is replaced
every six days. The sensor is connected to a non-implanted transmitter (MiniLink) which
communicates glucose levels wirelessly to the Paradigm Veo pump. The pump displays blood
glucose levels with nearly continuous updates, as well as monitoring rising and falling trends.
The pump can prompt for the person with diabetes or a carer to take action to maintain their
glucose levels. The insulin pump delivers continuous subcutaneous insulin according to a preprogrammed pattern which can be adapted by the user or a carer in response to real-time
glucose trends.
The MiniMed Paradigm Veo System appears to be unique in that the system will actively
suspend insulin delivery if it predicts a hypoglycaemic episode. This ‘Low Glucose Suspend’
(LGS) function stops insulin delivery for two hours if there is no response to a low glucose
warning.
The system requires regular capillary blood glucose tests (such as a finger prick test; a
minimum of two of these blood glucose tests per day), as the CGM measures interstitial fluid
glucose levels, not capillary blood glucose levels. Further finger prick tests are required to
confirm the CGM value before making any adjustments to diabetes therapy.
The pump can be worn on a belt or in a pouch underneath clothes. Insulin is delivered through
a small tube (or “infusion set”) placed under the skin. The transmitter connects directly to the
glucose sensor, which is inserted through the skin, usually in the stomach area. The
manufacturer information for use document states that the infusion set should be replaced
every three days.
The Vibe and G4 PLATINUM CGM system
The Vibe and G4 PLATINUM CGM system is a CGM-enabled insulin pump (Animas),
integrated with the G4 PLATINUM sensor (Dexcom). It is similar to the MiniMed Paradigm
Veo system in that the glucose sensor is placed under the skin and measures interstitial
glucose levels rather than capillary blood glucose levels. Confirmatory capillary blood
glucose tests are also required to confirm the value displayed by the continuous glucose
monitor before making any adjustments to diabetes therapy. The sensor is approved for up to
seven days of wear.
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The insulin pump in the Vibe and G4 PLATINUM CGM system also delivers insulin
continuously from a refillable storage reservoir by means of a subcutaneously placed cannula
and the pump can be programmed to deliver a basal rate of insulin throughout the day, with
the option of triggering higher infusion rates at meal times either as a bolus dose or over a
period of time. The pump can be programmed to enable different basal rates of insulin at
different times of the day and night.
The system produces glucose level readings in real-time, alerts for high and low readings, and
glucose trend information. It does not have an automated low glucose suspend function.
2.3
Comparators
The scope as defined by NICE, specifies the following comparator technologies:

Capillary blood testing with continuous subcutaneous insulin infusion (CSII+SMBG)

Capillary blood testing with multiple daily insulin injections (MDI+SMBG)

Continuous glucose monitoring with continuous subcutaneous insulin infusion (nonintegrated) (CSII+CGM)

Continuous glucose monitoring with multiple daily injections (MDI+CGM)
To qualify as continuous glucose monitoring with continuous subcutaneous insulin infusion
(non-integrated CSII+CGM) requires the simultaneous use by the patients of both a CGM and
a pump to deliver the insulin. The two interventions (Veo and Vibe) also imply the same. The
difference is that the two devices are supplied separately in the former and as a ‘system’ in the
latter: hence the term ‘integrated’. Although in terms of monitoring and insulin delivery they
might or might not differ, this review will seek to find any difference in terms of effectiveness
and cost-effectiveness (see Objectives below)
Within groups of comparator studies there may be differences between studies (populations,
interventions and outcomes). The possibility of pooling results from different trials will
depend on the extent of these differences. In addition, there might be a problem with the
comparability of populations in studies evaluating insulin pumps and MDI. NICE
recommends CSII ‘as a treatment option for adults and children 12 years and over, who suffer
disabling hypoglycaemia (including anxiety about hypoglycaemia) when attempting to
achieve HbA1c below 7.5%, or who have HbA1c persistently above 8.5%, while on multiple
daily injection therapy (MDIT). CSII is also recommended for children under 12 years of age
for whom MDIT is considered impractical.’16 In other words, insulin pumps are
recommended for people with type 1 diabetes for whom MDI is not suitable. Therefore, it
might be problematic to find studies comparing insulin pumps (especially modern pumps
such as the integrated systems) with MDI in comparable populations.
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3
OBJECTIVE
The overall objective of this project is to summarise the evidence on the clinical and costeffectiveness of the MiniMed Paradigm Veo System and the Vibe and G4 PLATINUM CGM
system for the management of type 1 diabetes in adults and children.
The following research questions have been defined to address the review objectives:


What is the clinical effectiveness of integrated insulin pump systems compared with:
o
Capillary blood testing with continuous subcutaneous insulin infusion
(CSII+SMBG)
o
Capillary blood testing with multiple daily insulin injections (MDI+SMBG)
o
Continuous glucose monitoring with continuous subcutaneous insulin
infusion (non-integrated) (CSII+CGM)
o
Continuous glucose monitoring with multiple daily injections (MDI+CGM)
What is the cost-effectiveness of integrated insulin pump systems compared with:
o
Capillary blood testing with continuous subcutaneous insulin infusion
(CSII+SMBG)
o
Capillary blood testing with multiple daily insulin injections (MDI+SMBG)
o
Continuous glucose monitoring with continuous subcutaneous insulin
infusion (non-integrated) (CSII+CGM)
o
Continuous glucose monitoring with multiple daily injections (MDI+CGM)
There are two interventions and four comparators. In this report we will use the following
names for these interventions and comparators:

MiniMed Veo system: an integrated CGM and insulin pump system with ‘Low
Glucose Suspend’ (LGS) function.

Integrated CSII+CGM: an integrated CGM and insulin pump systems without LGS
function (such as the Vibe and G4 PLATINUM CGM system). Although the only
integrated system available in the UK is the Vibe and G4 PLATINUM CGM system,
all integrated systems without LGS will be included in this category. This also
includes integrated Medtronic systems (such as Paradigm Revel and Paradigm
Realtime).

CSII+CGM: an insulin pump with stand-alone continuous glucose monitor.

CSII+SMBG: an insulin pump with self-monitoring of blood glucose

MDI+CGM: multiple daily injections with a continuous glucose monitor

MDI+SMBG: multiple daily injections with self-monitoring of blood glucose
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4
ASSESSMENT OF CLINICAL EFFECTIVENESS
4.1
Systematic review methods
A systematic review was conducted to summarise the evidence on the clinical effectiveness of
the MiniMed Paradigm Veo System and, the Vibe and G4 PLATINUM CGM system for the
management of type 1 diabetes in adults and children. Systematic review methods followed
the principles outlined in the Centre for Reviews and Dissemination (CRD) guidance for
undertaking reviews in health care,30 and NICE Diagnostic Assessment Programme manual.31
4.1.1 Inclusion and exclusion criteria
Participants
Study populations eligible for inclusion were adults, including pregnant women, and children
with type 1 diabetes.
Setting
The relevant setting is self-use supervised by primary or secondary care.
Interventions
The main intervention technology for this appraisal was:
 MiniMed Paradigm Veo with CGM System and suspend function
In addition we included fully integrated insulin pump systems as an alternative technology,
including the only existing fully integrated system currently available in the UK:
 The Vibe and G4 PLATINUM CGM system
Comparators
The scope as defined by NICE, specified the following comparator technologies:




Capillary blood testing with continuous subcutaneous insulin infusion
Capillary blood testing with multiple daily insulin injections
Continuous glucose monitoring with continuous subcutaneous insulin infusion (nonintegrated)
Continuous glucose monitoring with multiple daily injections
Studies comparing CSII with MDI often use different types of monitoring (SMBG or CGM).
Unless results were reported separately for the different types of monitoring, these studies
were excluded from our review, because they do not allow a comparison of a relevant
intervention with the comparators. The same applies to studies comparing CGM with SMBG,
without specifying the type of insulin device (CSII or MDI) used.
Outcomes
The main outcomes were:
 HbA1c (change from baseline, and number of participants achieving specified level
of control)
 Frequency of hyperglycaemia events and number of hyperglycaemia episodes,
stratified by severity into mild and severe where data are available.
 Frequency of (nocturnal) hypoglycaemia events and number of hypoglycaemia
episodes, stratified by severity into mild and severe where data are available.
Possible secondary outcomes were:
 Mean blood glucose levels including fasting glucose levels
 Postprandial glucose level
 Amount of insulin being administered
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







Episodes of diabetic ketoacidosis and number of ketone tests
Health related quality of life
Long term complications of diabetes and treatment including retinopathy, neuropathy,
cognitive impairment and end stage renal disease
Morbidity and mortality
Adverse events from testing, false results, treatment and sequelae
Acceptability of testing and method of insulin administration
Anxiety about experiencing hypoglycaemia
Costs, including support from health professionals.
In pregnant women, additional type 1 diabetes-related clinical outcomes included:
 Premature birth
 Macrosomia (excessive birth weight)
 Respiratory distress syndrome in newborn
Study design
The following study designs were eligible for inclusion:
 Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) where no
RCTs are available for comparisons of interventions and comparators.
 Observational studies for additional information for interventions, if no RCTs are
found.
Subgroup analyses
If evidence and the structure of the cost-effectiveness model permit, the following subgroups
may be explored:
 Pregnant women, and women planning pregnancy (not including gestational diabetes)
 People who need to self-monitor their blood glucose level more than 10 times a day
 People with type 1 diabetes who are having difficulty managing their condition.
These difficulties include:
o not maintaining the recommended HbA1c level of 8.5% (69.4 millimoles/mole)
or below
o nocturnal hypoglycaemia
o impaired awareness of hypoglycaemia.
o severe hypoglycaemia defined as having low blood glucose levels that requires
assistance from another person to treat
4.1.2 Search strategy
Systematic literature searches were conducted to identify studies about sensor-augmented
pump therapy for type 1 diabetes (specifically the MiniMed Paradigm Veo system, and the
Vibe and G4 Platinum system), as well as RCTs and economic evaluations of insulin
pump/infusion therapy and multiple daily injections for type 1 diabetes. Search strategies
were developed using the recommendations of the Centre for Reviews and Dissemination
(CRD) guidance for undertaking reviews in health care30, and the Cochrane Handbook 32. The
search strategies combined relevant search terms comprising indexed keywords (e.g. Medical
Subject Headings, MeSH and EMTREE) and free text terms appearing in the titles and/or
abstracts of database records. Search terms were identified through discussion between the
review team, by scanning background literature and ‘key articles’ already known to the
review team, and by browsing database thesauri. The search strategies were structured using
search terms for ‘type 1 diabetes’ in combination with search terms for ‘sensor-augmented
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pump therapy’. Two further facets of search terms were included to capture ‘insulin infusion’
and ‘multiple daily injections’. In addition, the search strategy for clinical effectiveness
studies included a sensitive methodological search filter designed to identify RCTs. The
Embase search strategy was translated to run effectively in each of the databases searched. No
date or language limits were applied. The main Embase search strategies were independently
peer reviewed by a second Information Specialist using the CADTH Peer Review checklist.33
The full search strategies are presented in Appendix 1.
The following databases and resources were searched for relevant RCTs, systematic reviews
and health technology assessments:
 MEDLINE (OvidSP): 1946-2014/Aug week 4
 MEDLINE In-Process Citations and Daily Update (OvidSP): up to 2014/09/04
 PubMed (NLM): up to 2014/09/05
 EMBASE (OvidSP): 1974-2014/week 34
 Cochrane Database of Systematic Reviews (CDSR ) (Wiley Online Library): issue
9/Sep 2014
 Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Online Library):
issue 8/Aug 2014
 Database of Abstracts of Reviews of Effects (DARE) (Wiley Online Library): issue
3/Jul 2014
 Health Technology Assessment Database (HTA) (Wiley Online Library): issue 3/Jul
2014
 Science Citation Index (SCI) (Web of Science): 1988-2014/08/29
 LILACS (Latin American and Caribbean Health Sciences Literature)
(http://lilacs.bvsalud.org/en/): 1982-2014/09/05
 NIHR Health Technology Assessment Programme (www.hta.ac.uk/): up to
2014/09/05
 PROSPERO (http://www.crd.york.ac.uk/prospero/): up to 2014/09/05
 US Food and Drug Administration (FDA) (www.fda.gov): up to 2014/09/05
 Medicines
and
Healthcare
Products
Regulatory
Agency
(MHRA)
(www.mhra.gov.uk/): up to 2014/09/05
Completed and ongoing trials were identified by searches of the following trials registries:
 NIH ClinicalTrials.gov (http://www.clinicaltrials.gov/): up to 2014/09/02
 Current Controlled Trials (http://www.controlled-trials.com/): up to 2014/09/05
 WHO
International
Clinical
Trials
Registry
Platform
(ICTRP)
(http://www.who.int/ictrp/en/): up to 2014/09/05
The following conference proceedings were searched: Diabetes UK, European Association
for the Study of Diabetes (EASD) and American Diabetes Association (ADA).
The bibliographies of identified research and review articles were checked for relevant
studies. As a number of databases were searched, there was some degree of duplication. In
order to manage this issue, the titles and abstracts of bibliographic records were downloaded
and imported into EndNote reference management software and duplicate records removed.
Rigorous records were maintained as part of the searching process. Individual records within
the Endnote reference libraries were tagged with searching information, such as searcher, date
searched, database host, database searched, search strategy name and iteration, theme and
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search question. This enabled the information specialist to track the origin of each individual
database record, and its progress through the screening and review process.
4.1.3 Inclusion screening and data extraction
Two reviewers independently screened the titles and abstracts of all reports identified by
searches and any discrepancies were discussed and resolved by consensus. Full text copies of
all studies deemed potentially relevant, after discussion, were obtained and the same two
reviewers independently assessed these for inclusion; any disagreements were resolved by
consensus. Details of studies excluded at the full paper screening stage are presented in
Appendix 4.
Data relating to study details, participants, intervention and comparator tests, and outcome
measures were extracted by one reviewer, using a piloted, standard data extraction form. A
second reviewer checked data extraction and any disagreements were resolved by consensus.
4.1.4 Quality assessment
The methodological quality of included studies was assessed using standard tools. 30 The
assessment of the methodological quality of each included study was based on the Cochrane
Collaboration quality assessment checklist as detailed in Table 1.32
Table 1: The assessment of Risk of Bias in included RCTs
Domain
Item
Description
The method used to generate the
Sequence Generation Was the allocation
allocation sequence should be described
sequence adequately
in sufficient detail to allow an
generated?
assessment of whether it should produce
comparable groups.
The method used to conceal the
Allocation
Was allocation
Concealment
adequately concealed? allocation sequence should be described
in sufficient detail to determine whether
intervention allocations could have been
foreseen in advance of, or during,
enrolment.
All measures used, if any, to blind study
Blinding of
Was knowledge of the
participants and personnel from
participants,
allocated intervention
knowledge of which intervention a
personnel and
adequately prevented
participant received, should be
outcome assessors
during the study?
Assessments will be
described. Any information relating to
made for each main
whether the intended blinding was
outcome (or class of
effective should also be reported.
outcomes).
The completeness of outcome data for
Incomplete outcome
Were incomplete
each main outcome should be
data
outcome data
Assessments will be
adequately addressed? described, including attrition and
made for each main
exclusions from the analysis. The
outcome (or class of
authors should report any attrition and
outcomes).
exclusions, the numbers in each
intervention group (compared with total
randomized participants), reasons for
attrition/exclusions and any re-
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Domain
Item
Other sources of bias
Was the study
apparently free of
other problems that
could put it at a high
risk of bias?
Description
inclusions in analyses.
Overall, the study should be free from
any important concerns about bias (i.e.
bias from other sources not previously
addressed by the other items).
Each study was awarded a ‘yes’, ‘no’ or ‘unclear/unknown’ rating for each individual item in
the checklist. Any additional clarifications or comments were also recorded.
Quality assessment was carried out independently by two reviewers. Any disagreements were
resolved by consensus. The results of the quality assessment were used for descriptive
purposes to provide an evaluation of the overall quality of the included studies and to provide
a transparent method of recommendation for design of any future studies. Based on the
findings of the quality assessment, recommendations are made for the conduct of future
studies.
4.1.5 Methods of analysis/synthesis
Where meta-analysis was considered unsuitable for some or all of the data identified (e.g. due
to the heterogeneity and/or small numbers of studies), we employed a narrative synthesis.
Typically, this involves the use of text and tables to summarise data. These allow the reader
to consider any outcomes in the light of differences in study designs and potential sources of
bias for each of the studies being reviewed. Studies were organised by comparison.
Superseded –
see Erratum
The methods used to synthesise the data were dependent on the types of outcome data
included and the clinical and statistical similarity of the studies. Possible methods include the
following types of analysis.
Dichotomous outcomes
Dichotomous data were analysed by calculating the relative risk (RR) for each trial using the
DerSimonian and Laird random effects method and the corresponding 95% confidence
intervals (CIs).34
Continuous outcomes
Continuous data were analysed by calculating the weighted mean difference (WMD) between
groups and the corresponding 95% CI. If the standard deviations and means were not
determinable, they were estimated from the data that was provided or using a representative
value from other studies.
Systematic differences between studies (heterogeneity) are likely; therefore, the randomeffects model was used for the calculation of relative risks or weighted mean differences.
Heterogeneity was initially assessed by measuring the degree of inconsistency in the studies'
results (I2). This measure (I2) describes the percentage of total variation across studies that
was due to heterogeneity rather than the play of chance. The value of I2 can lie between 0%
and 100%. Low, moderate and high I2 values correspond to 25%, 50%, and 75%.
If important heterogeneity was identified, we planned to formally investigate this using metaregression. In particular, a model was planned to be used to explore the possible modifying
effects of the following pre-specified factors: methodological quality of the primary studies,
underlying illness, and different age groups. The coefficient describing the predictive value
of each factor and the overall effect on the main outcome would be modelled, using a fixed-
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CONFIDENTIAL UNTIL PUBLISHED
effect model. However, due to the limited number of studies for each comparison this was not
possible.
A funnel plot (plots of logarithm of the RR for efficacy against the precision of the logarithm
of the RR) was planned in order to estimate potential asymmetry, which would be indicative
of small study effects. HbA1c was chosen as an outcome since this is likely to be reported by
the majority of included studies. In addition, the Egger regression asymmetry test was
planned in order to facilitate the prediction of potential publication biases. This test detects
funnel plot asymmetry by determining whether the intercept deviates significantly from zero
in a regression of the standardised effect estimates against their precision. However, due to
the limited number of studies for each comparison this was not possible.
Network meta-analysis methods
In the absence of RCTs directly comparing the MiniMed Veo System or the integrated
CSII+CGM system (such as Animas Vibe Pump with Dexcom G4 CGM) with the
comparators (i.e. CSII+CGM/SMBG or MDI+CGM/SMBG), indirect treatment comparisons
were performed, where possible. As only limited networks could be formed a mixed treatment
comparison was not possible. However, where it was possible indirect comparisons were
made. Although ‘head-to-head’ comparisons are preferred to indirect methods in health
technology assessment they are generally considered acceptable and all methods need to be
applied with consideration for the basic assumptions of homogeneity, similarity, and
consistency as reported in Song 2009.35 For this appraisal, where ‘head-to-head’ trials (i.e. A
versus B) of the MiniMed Paradigm Veo with CGM System versus the comparators (CSII+
CGM/SMBG or MDI+CGM/SMBG) were missing, the effect sizes (RR or MD) for A versus
B were estimated using ‘indirect’ methods e.g. from A versus C and B versus C, where C is a
common control group (e.g. CSII+CGM (i.e. CSII with a stand-alone CGM)). All indirect
comparisons were consistent with ISPOR taskforce recommendations for the conduct of
direct and indirect meta-analysis and used the Bucher method.36 A practical issue for indirect
comparisons concerns the limitations in availability of the same outcomes in the studies of
interventions that are candidates for an indirect comparison. Only studies that provide the
same outcome measures at the same follow-up time can be compared with each other which
may limit the availability of suitable trial networks. Dependent on the data available, separate
network analyses were performed for each of the subgroups specified in this protocol. Indirect
meta-analysis were performed using Microsoft Excel 2007 according to the method
developed by Bucher 1997.36 Effect sizes with 95% CIs were calculated using results from the
direct head-to-head meta-analysis. Direct head-to-head meta-analyses were performed using
random effects models in STATA (STATA™ for Windows, version 13, Stata Corp; College
Station, TX).
Superseded –
see Erratum
4.2
Results of the assessment of clinical effectiveness
4.2.1 Results of literature searches
The literature searches of bibliographic databases identified 9,870 references. After initial
screening of titles and abstracts, 555 were considered to be potentially relevant and ordered
for full paper screening. Of the total of 555 publications considered potentially relevant, 29
could not be obtained within the time scale of this assessment. Most of these 29 unobtainable
studies were older (pre-2000) or conference abstracts; only four were possibly relevant trials
published after 2000, based on their abstracts it was unclear whether they fulfilled the
inclusion criteria. Figure 1 shows the flow of studies through the review process, and
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CONFIDENTIAL UNTIL PUBLISHED
Appendix 4 provides details, with reasons for exclusions, of all publications excluded at the
full paper screening stage.
Figure 1: Flow of studies through the review process
Titles and abstracts identified
from bibliographic databases and
screened for potential relevance
n=9,870
Excluded at title and
abstract screening
n=9,315
Total potentially relevant
publications obtained as full text
n=555
Excluded at full paper
screening
n=453
Could not be obtained
n=29
Population
Intervention
Outcome
Study design
SR
BG
Duplicate
Ongoing studies
n=19 (publications)
n=18 (trials)
8
86
109
206
36
3
5
Total number of studies
included in the review
n=54 (publications)
n=19 (trials)
Based on the searches and inclusion screening described above, 54 publications of 19 studies
were included in the review. In addition, 19 publications of 18 ongoing studies were found.
These are described in Chapter 4.2.6.
Two studies compared the MiniMed Veo system (with suspend function) with an integrated
CSII+CGM system (MiniMed Veo without suspend function)37 and with CSII+SMBG,38
respectively. Seven other studies compared an integrated CSII+CGM system with
CSII+SMBG (three studies4-6) or with MDI+SMBG (four studies7-10). The remaining studies
compared CSII+SMBG with MDI+SMBG (10 studies39-48). None of the studies included a
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treatment arm with one of the following comparators: CSII+CGM and MDI+CGM (see Table
2). Although several studies included the integrated CSII+CGM system as a treatment arm, it
is important to note that none of these studies looked at the Vibe and G4 PLATINUM CGM
system; in the included studies, the integrated CSII+CGM system was always a MiniMed
Paradigm pump with integrated CGM system.
Out of 19 studies, eight were performed in North America and eight in Europe. The remaining
three studies were performed in Australia (2x) and Israel (1x). Three out of the eight
European studies included patients from the UK.
Table 2: Included studies and comparisons
Study ID
Veo
CSII+CGM
integrated
ASPIRE in-home37
Ly 201338
Hirsch 20084
O'Connell 20095
RealTrend6
Eurythmics7
Lee 20078
Peyrot 20099
STAR-310
Bolli 200939
DeVries 200240
Nosadini 198841
OSLO42
Thomas 200743
Tsui 200144
Weintrob 200345
Thrailkill 201146
Doyle 200447
Nosari 199348


CSII+
CGM
CSII+
SMBG
MDI+
CGM
MDI+
SMBG














1





















1) Nosadini 1988 was a three arm study that compared two different versions of CSII+SMBG versus
MDI+SMBG
Twelve studies reported data for adults, five studies reported data for children, and five
studies reported data for mixed populations (adults and children). Two of these studies
reported data for all three groups. One study included pregnant women (see Table 3).
Most studies were rated as high risk of bias (11 out of 19), four studies were rated unclear risk
of bias and another four studies were rated low risk of bias (see Appendix 2). Most
problematic in the risk of bias assessment was the lack of blinding in the included studies
(participants, physicians and outcome assessors). For participants and physicians it is almost
impossible to perform a trial with true blinding with this type of interventions. Nevertheless,
the fact that participants and physicians were not blinded may bias the results and outcome
assessment for HbA1c measurement can be done blinded. Selective outcome reporting was
assessed as high risk of bias in only three trials. Incomplete data reporting was assessed as
high risk of bias in 12 trials; this was rated as unclear in four trials. Overall, there was a high
risk of bias in the included trials.
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Table 3: Characteristics of included studies
Study ID
Population
Baseline
(Age
Age,
range)
Mean (SD)
ASPIRE inA (16-70)
43 (13)
home37
Ly 201338
M (4-50)
19 (12)
M (12-72)
Hirsch 20084
A (18-72)
33 (16)
C (12-17)
O'Connell 20095
M (13-40)
23 (8.4)
6
RealTrend
M (2-65)
28 (16)
Eurythmics7
A (18-65)
38 (11)
Lee 20078
A (NR)
NR
Peyrot 20099
A (NR)
47 (13)
M (7-70)
32 (17)
STAR-310
A (19-70)
41 (12)
C (7-18)
12 (3)
Bolli 200939
A (18-70)
40 (11)
DeVries 200240
A (18-70)
37 (10)
Nosadini 198841
? (A)
34 (6)
OSLO42
A (18-45)
26 (21)
Thomas 200743
A (NR)
43 (10)
44
Tsui 2001
A (18-60)
36 (11)
Weintrob 200345
C (8-14)
12 (1.5)
Thrailkill 201146
C (8-18)
12 (3)
47
Doyle 2004
C (8-21)
13 (3)
Nosari 199348
P (NR)
26 (2.4)
Baseline
HbA1c
Mean, SD
7.2 (0.7)
Pump
use
Follow-up
(months)
>6m
3m
7.5 (0.8)
M 8.4 (0.7)
A 8.3 (0.6)
C 8.7 (0.9)
7.4 (0.7)
9.2 (1)
8.6 (0.9)
9 (0.9)
8.6 (1)
>6m
6m
>6m
6m
>3m
NR
Naive
Naive
NR
3m
6m
6m
3.5m
3.7m
8.3 (0.5)
Naive
12m
7.7 (0.7)
9.4 (1.4)
NR
8.5 (NR)
8.5 (1.5)
8 (0.6)
8 (1)
11.5 (2.4)
8.1 (1.2)
NR
Naive
Naive
NR
NR
NR
Naive
NR
Naive
Naive
Naive
6m
3.7m
12m
3, 6, 12, 24m
4, 6m
9m
3.5m
6, 12m
3.7m
9m
Superseded
see Erratum
–
A=Adults, C=Children, M=Mixed, P=Pregnant women; NR=Not reported; m=months.
Table 4 shows the inclusion criteria regarding HbA1c and hypoglycaemic events used in the
included studies. Further details of the characteristics of study participants and the
interventions, comparators and results are reported in the data extraction tables presented in
Appendix 3. It is clear from Table 3 that most studies include patients who have never used a
pump before. However, the two studies looking at the MiniMed Veo system (ASPIRE and Ly
2013), both include patients who have at least 6 months experience using an insulin pump. In
addition, baeline HbA1c differs considerably between studies. DeVries et al (2002) included
patients with poor control at baseline who are pump-naive. The two studies looking at the
MiniMed Veo system included patients with relatively good glycaemoc control at baseline,
but that might be as a result of using an insulin pump for at least six months. Other studies,
such as Bolli et al (2009), included patients with relatively good glycaemoc control at
baseline without any previous pump experience. Therefore, there is considerable
heterogeneity between study populations.
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Table 4: In/exclusion criteria used in included studies for HbA1c and hypoglycaemic events
In/exclusion criteria regarding
Study ID
HbA1c
hypoglycaemia
5.8-10% Included: experienced >=2 nocturnal hypoglycaemic events
ASPIRE induring the run in phase. Excluded: >1 episode of severe
home37
hypoglycaemia in previous 6 months
≤8.5%
Included: having impaired awareness of hypoglycaemia
38
Ly 2013
(HUS >= 4). Mean HUS-score: 6.2 (SD 1.5)
≥7.5%
Hirsch 20084
There were no exclusions for hypoglycemia unawareness
≤8.5%
RealTrend6
>8%
Excluded: co-existent illness that otherwise predisposes to
hypoglycaemia (e.g. adrenal insufficiency) or a history of
severe hypoglycaemia while using insulin pump therapy
NR
Eurythmics7
≥8.2%
NR
≥7.5%
NR
NR
O'Connell 20095
Lee 2007
8
Peyrot 2009
9
Tsui 200144
NR
Weintrob 200345
NR
NR
Excluded: hypoglycemia unawareness (two or more severe
hypoglycemia episodes without warning of low BG levels
within the previous 1 year)
Excluded: those who had more than two severe
hypoglycaemic events in the previous 6 months
NR
NR
NR
Included: long-standing Type 1 diabetes complicated by at
least one episode of severe hypoglycaemia within the
preceding 6 months
Excluded: those who had a history of more than two severe
hypoglycaemic episodes in the last year
NR
Thrailkill 201146
NR
NR
Doyle 200447
6.5-11%
NR
Nosari 199348
NR
NR
STAR-310
7.49.5%
Bolli 200939
6.5-9%
DeVries 200240
Nosadini 198841
OSLO42
≥8.5%
NR
NR
NR
Thomas 200743
HUS=Hypoglycemia unawareness score; NR=Not reported
In the following chapters we will discuss the results of the included studies by population:
adults, children and pregnant women, and by follow-up time-point: three months, six months
and nine months or more.
4.2.2 Effectiveness of interventions in adults
We found 12 studies that reported data for adults. As can be seen in Table 5, the age ranges
differed considerably; therefore, we asked a panel of four expert committee members whether
they thought the results of these studies could be pooled. Three clinical experts agreed the
studies were similar enough as far as the differences in age ranges were concerned, the fourth
clinical expert did not respond.
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Table 5: Included studies for adults
Study ID
Veo
Integrated
CSII+CGM
ASPIRE in-home37
Hirsch 20084
Eurythmics7
Lee 20078
Peyrot 20099
STAR-310
Bolli 200939
DeVries 200240
Nosadini 198841
OSLO42
Thomas 200743
Tsui 200144







CSII+
SMBG
MDI+
SMBG
Baseline Age,
Mean (SD), Range
Baseline HbA1c
Mean, SD
Pump
use
Follow-up
(months)
43 (13), 16-70
33 (16), 18-72
38 (11), 18-65
NR
47 (13), NR
41 (12), 19-70
40 (11), 18-70
37 (10), 18-70
34 (6), NR
26 (21), 18-45
43 (10), NR
36 (11), 18-60
7.2 (0.7)
8.3 (0.6)
8.6 (0.9)
9 (0.9)
8.6 (1)
8.3 (0.5)
7.7 (0.7)
9.4 (1.4)
NR
8.5 (NR)
8.5 (1.5)
8 (0.6)
>6m
>6m
Naive
Naive
NR
Naive
Naive
Naive
NR
NR
NR
Naive
3m
6m
6m
3.5m
3.7m
12m
6m
3.7m
12m
3, 6, 12, 24m
4, 6m
9m
Superseded – see
Erratum



1













1) Nosadini 1988 was a three arm study that compared two different versions of CSII+SMBG versus MDI+SMBG
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VEO versus integrated CSII+CGM
One study compared the MiniMed Veo with an integrated CSII+CGM system at three months
follow-up in adults (ASPIRE in-home).37 The results of this study for the head-to-head
comparison of the MiniMed Veo system with an integrated CSII+CGM system are reported in
Table 6.
No results were found for the MiniMed Veo system versus any other treatment at six months
or longer follow-up.
Table 6: Results for the MiniMed Veo versus an integrated CSII+CGM system at three months follow-up
in adults
MiniMed Veo system (n=121)
Integrated CSII+CGM (n=126)
Difference at
3m
Baseline
3m follow-up
Baseline
3m follow-up
Change in HbA1c
7.26% (0.71)
7.24% (0.67)
7.21% (0.77)
7.14% (0.77)
0.05 (95% CI:
-0.05, 0.15)
Nocturnal hypogly1.5 (1.0)
2.2 (1.3)
NR, p<0.001
caemic events per
patient-week (glucose <3.6 mmol/L)
Day and night hypo3.3 (2.0)
4.7 (2.7)
NR, p<0.001
glycaemic events per
patient-week (glucose <3.6 mmol/L)
Nocturnal
980 (1200)
1568 (1995)
NR, p<0.001
hypoglycaemic AUC
Day and night
798 (965)
1164 (1590)
NR, p<0.001
hypoglycaemic AUC
Meter Blood Glucose 151.4 (24.3)
167.5 (24.7)
151.8 (23.6)
163.9 (32.1)
NS
(last 2 weeks,mg/dL)
Insulin Use (U, per
47.8 (19.40)
46.5 (21.66)
NS
patient/day)
DKA
0
0
No difference
EQ-5D
NR
NR
NR
NR
No difference
Device-related
0
0
No difference
serious AEs
AE- Death
0
0
No difference
DKA=Diabetic ketoacidosis; AE=Adverse event; AUC=Area under the curve
Nocturnal hypoglycemic events occurred 31.8% less frequently in the MiniMed Veo group
than in the integrated CSII+CGM group (1.5±1.0 vs. 2.2±1.3 per patient week, P<0.001).
Similarly, the MiniMed Veo group had significantly lower weekly rates of combined daytime
and night-time events than the integrated CSII+CGM group (P<0.001).
The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the MiniMed Veo
group than in the integrated CSII+CGM group (980±1200 mg per decilitre [54.4±66.6 mmol
per liter] × minutes vs. 1568±1995 mg per decilitre [87.0±110.7 mmol per litre] × minutes,
P<0.001). The mean AUC for day and night hypoglycemic events was also significantly in
favour of the threshold suspend group.
The other outcomes showed no significant differences between groups.
VEO versus integrated CSII+CGM, CSII+SMBG and MDI+SMBG
For two outcomes (‘Change in HbA1c’ and Diabetic ketoacidosis (DKA)) results of the
MiniMed Veo system versus other treatments were available at three months follow-up in
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CONFIDENTIAL UNTIL PUBLISHED
adults from more than one study, which could be combined in a network analysis. These two
outcomes are reported below.
We found four studies comparing ‘Change in HbA1c’ at three months follow-up in adults,
allowing a comparison of the MiniMed Veo system with an integrated CSII+CGM,
CSII+SMBG and MDI+SMBG.8,9,37,40 Figure 2 shows the network linking these interventions
and Table 7 shows the results.
Change in HbA1c
Three months follow-up:
Figure 2: Network of studies comparing ‘change in HbA1c’ and DKA at three months followup in adults
Note: Blue boxes represent the interventions; Lines represent comparisons between interventions at
different follow-up times (Blue = 3 months); Transparant boxes represent studies in adults.
Table 7: Results of network analysis for change in HbA1c at three month follow-up (WMD,
95% CI)
Integrated
CSII+SMBG
MDI+SMBG
CSII+CGM
0.04 (-0.07, 0.15)
0.41 (-0.31, 1.13)
-0.43 (-0.95, 0.10)
Veo
Integrated
CSII+CGM
CSII+SMBG
xxx
0.37 (-0.34, 1.08)
-0.47 (-0.98, 0.04)
xxx
xxx
-0.84 (-1.33, -0.35)
WMD<0 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 0 (these are in bold).
Results of the network analysis show that there are no significant differences between the
MiniMed Veo system and any other intervention in ‘change in HbA1c’ at three months
follow-up. Similarly, there are no significant differences between the Integrated CSII+CGM
system and any other intervention in ‘change in HbA1c’ at three months follow-up. The only
significant difference found in this analysis is the difference between CSII+SMBG versus
MDI+SMBG, favouring CSII+SMBG.
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Diabetic ketoacidosis
Three months follow-up:
The same four studies provided data for Diabetic Ketoacidosis (DKA) at three months followup in adults, allowing a comparison of the MiniMed Veo system with an integrated
CSII+CGM system, CSII+SMBG and MDI+SMBG. However, the study which compared the
MiniMed Veo system with the integrated CSII+CGM system (ASPIRE in-home) could not be
included in the analysis as no events were reported in either arm.
Table 8: Results of network analysis for DKA at three months follow-up (RR, 95% CI)
Integrated CSII+CGM
CSII+SMBG
MDI+SMBG
No events
No events
No events
Integrated CSII+CGM
xxx
0.26 (0.01, 8.53)
0.32 (0.04, 2.86)
CSII+SMBG
xxx
xxx
1.25 (0.08, 19.22)
Veo
RR<1 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 1 (these are in bold).
Results of this network analysis show that there are no significant differences between the
Integrated CSII+CGM system and any other intervention in DKA at three months follow-up.
The comparison between CSII+SMBG and MDI+SMBG also showed no significant
difference.
Integrated CSII+CGM versus CSII+SMBG
One study compared the integrated CSII+CGM system (Paradigm 722 System, Medtronic)
with CSII+SMBG (Paradigm 715 Insulin Pump, Medtronic) at six months follow-up in adults
(Hirsch et al, 2008).4
At six months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus CSII+SMBG were available for one outcome: change in HbA1c.
Other outcomes were not reported separately for adults. The results for change in HbA1c are
reported in Table 9,
Table 9: Results for the integrated CSII+CGM versus CSII+SMBG at six months follow-up
in adults
Integrated CSII+CGM
CSII+SMBG (n=49)
Difference at 6m
(n=49)
Baseline
6m followBaseline
6m followup
up
Change in HbA1c
8.37% (0.6) 7.68% (0.84) 8.30% (0.54) 7.66% (0.67)
-0.0364 (SE
0.1412), p=0.80
Results for the head-to-head comparison of the integrated CSII+CGM system versus
CSII+SMBG at six months follow-up in adults showed no significant difference in HbA1c
scores between groups.
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Integrated CSII+CGM versus MDI+SMBG
Four studies compared the integrated CSII+CGM system (MiniMed Paradigm REAL-Time
722 System) with MDI+SMBG in adults. Two of these had results at three months followup,8, 9 one at six months,7 and one at 12 months.10
At three months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus MDI+SMBG were available for the following outcomes: change in
HbA1c, hypoglycaemic events, DKA and adverse events. These results are reported in Table
10,
At six months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus MDI+SMBG were available for: change in HbA1c, proportion
achieving HbA1c ≤7%, hypoglycaemic events, hyperglycaemic events, insulin use and
quality of life. These results are also reported in Table 10, together with the results at 12
months for change in HbA1c, proportion achieving HbA1c ≤7%, proportion with severe
hypoglycaemia, rate of severe hypoglycaemic events, hypoglycaemic AUC, hyperglycaemic
AUC, DKA and quality of life.
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Table 10: Results for the integrated CSII+CGM system versus MDI+SMBG at 3, 6 and 12 months follow-up in adults
Integrated CSII+CGM
MDI+SMBG
3 months follow-up
Baseline
3 months
Baseline
3 months
Change in HbA1c:
- Peyrot 2009 (n=27)
8.87 (0.89), n=14
7.16 (0.75)
8.32 (1.05), n=13
7.30 (0.92)
- Lee 2007 (n=16)
9.45 (0.55), n=8
7.40 (0.66)
8.58 (1.30), n=8
7.50 (1.01)
Hypoglycaemic events (patients with events/ total
patients):
- Peyrot 2009 (n=27), nr of severe events
0/14
3/13
- Lee 2007 (n=16), proportion of patients
0/8
1/8
DKA
- Peyrot 2009 (n=27)
0/14
1/13
- Lee 2007 (n=16)
0/8
1/8
Serious AE
0/8
1/8
Integrated CSII+CGM (n=41)
MDI+SMBG (n=36)
6 months follow-up
Baseline
6m follow-up
Baseline
6m follow-up
Change in HbA1c
8.46 (0.95)
7.23 (0.65)
8.59 (0.82)
8.46 (1.04)
Proportion achieving HbA1c ≤7%
14/41
0/36
Hypoglycaemic events
0.7 (SD 0.7)
0.6 (SD 0.7)
(Mean number per day, glucose <
4.0 mmol/L)
Hyperglycaemic events
2.1 (SD 0.8)
2.2 (SD 0.7)
(Mean number per day, glucose >
11.1 mmol/L)
Insulin Use (total daily dose)
46.7 (16.5)
57.8 (18.1)
–
Superseded
Erratum
QoL:
SF-36 General Health
55.5 (20.3)
67.7 (21.6)
59.8 (22.3)
63.1 (19.1)
Difference at 3m
-0.69, p=0.071
-0.97, p=0.02
see
NS
NS
NS
NS
NS
Difference at 6m
-1.1 (95% CI -1.47, -0.73)
p<0.001
0.1 (95% CI -0.2, 0.5)
-0.2 (95% CI -0.5, 0.2)
-11.0 units per day; 95% CI -16.1 to 5.9, p< 0.001
7.9 (95% CI 0.5, 15.3), p=0.04
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12 months follow-up
Change in HbA1c
Proportion achieving HbA1c ≤7%
Severe hypoglycaemia
(patients with events/ total patients)
Severe hypoglycaemic event rate
(per 100 person-year; HbA1c <50
mg.dL)
Hypoglycaemic AUC
(Threshold <70 mg/dL)
Hyperglycaemic AUC
( >250 mg/dL)
Patients with DKA
QoL: SF-36 General Health
HFS
Integrated CSII+CGM (n=169)
Baseline
12m follow-up
8.3 (0.5)
7.3 (NR)
57/166
17/169
MDI+SMBG (n=167)
Baseline
12m follow-up
8.3 (0.5)
7.9 (NR)
19/163
13/167
Difference at 12m
-0.6 (95% CI -0.8, -0.4), p<0.001
p<0.001
NS
Superseded – see
Erratum
15.31/169
17.62/167
p=0.66
0.25 (0.44)
0.29 (0.55)
p=0.63
3.74 (5.01)
7.38 (8.62)
p<0.001
2/169
Change: +2.7 (8.07)
Change: -9 (16.04)
0/167
Change: -0.3
(7.13)
Change: -2.4
(15.88)
NS
3 (SD 7.75;
95% CI 1.36, 4.64)
-6.5 (SD 16.0;
95% CI -9.76, -3.27)
DKA = Diabetic ketoacidosis; HFS=Hypoglycaemia Fear Survey; NS=Not significant
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At three months follow-up, results were available from two small RCTs, with 27 and 16 adult
respondents respectively. Change in HbA1c favoured the integrated CSII+CGM system over
CSII+SMBG, but this was not significant in one of the trials. There were more
hypoglycaemic events, DKA and serious adverse events for CSII+SMBG at three months.
None of these results were significant; however, study sizes were small and the number of
events was limited.
At six months follow-up, results were available from one small RCT with 77 adult
respondents. This trial showed a significant difference in HbA1c change scores in favour of
the integrated CSII+CGM system and a significantly higher number of patients achieving
HbA1c ≤7%. Insulin use was significantly less in the integrated CSII+CGM group and quality
of life was significantly more improved in the integrated CSII+CGM group compared to the
CSII+SMBG group. The number of hypoglycaemic events and hyperglycaemic events
showed no differences between groups.
Superseded –
see Erratum
At 12 months follow-up, results were available from one RCT with 336 adult participants.
This trial also showed a significant difference in HbA1c change scores in favour of the
integrated CSII+CGM system and a significantly higher number of patients achieving HbA1c
≤7%. Hyperglycaemic AUC was significantly lower in the integrated CSII+CGM group, but
hypoglycaemic AUC showed no significant difference. Results for severe hypoglycaemia
showed no differences between groups; nor did the number of patients with DKA. Quality of
life was significantly more improved in the integrated CSII+CGM group compared to the
CSII+SMBG group. The Hypoglycaemia Fear Survey showed significantly more reductions
in fear in the integrated CSII+CGM group compared to the CSII+SMBG group, for both
hypoglycaemia worries and hypoglycaemia avoidant behaviour.
Integrated CSII+CGM versus CSII+SMBG and MDI+SMBG
Results at three months follow-up:
Proportion of patients with severe hypoglycaemia
Figure 3: Network of studies comparing ‘severe hypoglycaemia’ at three months follow-up in
adults
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Table 11: Results of network analysis for proportion of patients with severe hypoglycaemia at
three months follow-up in adults (RR, 95% CI)
CSII+SMBG
MDI+SMBG
Integrated CSII+CGM
CSII+SMBG
0.33 (0.03, 3.87)
0.19 (0.02, 1.51)
xxx
0.63 (0.17, 2.31)
RR<1 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 1 (these are in bold).
Results of the network analysis show that there are no significant differences between the
Integrated CSII+CGM system and any other intervention in the ‘Proportion of patients with
severe hypoglycaemia’ at three months follow-up. The comparison between CSII+SMBG and
MDI+SMBG also showed no significant difference.
Results at six months follow-up:
Change in HbA1c
Figure 4: Network of studies comparing ‘Change in HbA1c’ at six months follow-up in adults
Table 12: Results of network analysis for ‘Change in HbA1c’ at six months follow-up in adults
(WMD, 95% CI)
CSII+SMBG
MDI+SMBG
Integrated CSII+CGM
CSII+SMBG
-0.05 (-0.31, 0.21)
-1.10 (-1.46, -0.74)
xxx
-0.10 (-0.52, 0.32)
WMD<0 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 0 (these are in bold).
Results of the network analysis show that there are no significant differences between the
Integrated CSII+CGM system and CSII+SMBG in ‘Change in HbA1c’ at six months followup. The comparison between CSII+SMBG and MDI+SMBG also showed no significant
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difference. The comparison between the Integrated CSII+CGM system versus MDI+SMBG
did show a significant difference, favouring the Integrated CSII+CGM system.
Proportion of patients achieving HbA1c < 7%
Figure 5: Network of studies comparing ‘HbA1c < 7%’ at six months follow-up in adults
Table 13: Results of network analysis for ‘HbA1c < 7%’ at six months follow-up in adults
(RR, 95% CI)
CSII+SMBG
MDI+SMBG
Integrated CSII+CGM
1.45 (0.74, 2.84)
25.55 (1.58, 413.59)
CSII+SMBG
xxx
17.56 (1.002, 307.87)
RR>1 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 1 (these are in bold).
Results of the network analysis show that there are no significant differences between the
Integrated CSII+CGM system and CSII+SMBG in ‘HbA1c < 7%’ at six months follow-up.
The comparison between the Integrated CSII+CGM system versus MDI+SMBG did show a
significant difference, favouring the Integrated CSII+CGM system. Similarly, the comparison
between CSII+SMBG and MDI+SMBG also showed a significant difference, favouring the
CSII+SMBG.
Quality of Life
Different tools were used to measure health-related quality of life. Only those studies using
the same questionnaire could be combined in the analysis. Two studies reported results at six
months for the Diabetic Treatment Satisfaction Questionnaire (Eurythmics and Bolli 2009),
using a scale from 0 to 36 with higher scores indicating more satisfaction with treatment. Two
studies reported results for the Hypoglycaemia Fear Survey (Eurythmics and Thomas 2007);
however, these could not be analysed together as one reported the worry subscale only
whereas the other reported the total score.
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Figure 6: Network of studies comparing ‘Quality of Life’ at six months follow-up in adults
Table 14: Results of network analysis for ‘Quality of Life (DTSQ)’ at six months follow-up in
adults (WMD, 95% CI)
CSII+SMBG
MDI+SMBG
Integrated CSII+CGM
5.90 (2.22, 9.58)
8.60 (6.28, 10.92)
CSII+SMBG
xxx
2.70 (-0.16, 5.56)
WMD>0 favours interventions listed in the left column. Differences are significant if the
confidence interval does not include 0 (these are in bold).
Results of the network analysis show that the integrated CSII+CGM system had significantly
improved quality of life score at six months follow-up when compared to CSII+SMBG and
with MDI+SMBG. There was no significant difference between CSII+SMBG and
MDI+SMBG.
4.2.3 Effectiveness of interventions in children
We found five studies that reported data for children. In addition, there was one study that
included a mixed population of patients between 4 and 50 years old. About 70% of patients
were children (<18 years).
We asked our panel of four expert committee members whether they thought the results of
these studies could be pooled, especially whether the study by Ly 2013 (age range: 4 to 50
years, with 70% <18 years) could be included as if it was a study in children. One clinical
expert agreed the six studies were similar enough as far as the differences in age ranges were
concerned to be pooled. A second clinical expert agreed five studies were similar enough as
far as the differences in age ranges were concerned to be pooled, but given that approximately
one third of participants are aged 18-50 it would be difficult to include the Ly 2013 study with
the children’s’ analysis (if the adult age group had been a younger cohort e.g. 18-25 it might
have been different). The third clinical expert also thought the Ly 2013 study could not
reasonably be included in analyses for either group (children or adults); and also thought that
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teenage children behave in a different way from pre-teen children and that therefore the 8 to
14 year-cohort may be significantly different and perhaps should be excluded from analyses.
The fourth clinical expert did not respond.
However, the study by Ly et al (2013) is the only study looking at the MiniMed Veo system
in children; therefore, we will present results from analyses where this study is included as if
it is a study in children. In addition, the study by Weintrob et al (2003), with children aged 8
to 14 years old, is the only study with results at six months linking MDI+SMBG to the
MiniMed Veo system and the integrated CSII+CGM system; therefore, we will include this
study in the analyses as well. The results of these analyses should be interpreted with great
caution due to the differences in age ranges between studies.
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Table 15: Included studies for children
Study ID
Veo
CSII+CGM
integrated
Ly 201338
Hirsch 20084
STAR-310
Weintrob 200345
Thrailkill 201146
Doyle 200447



CSII+
SMBG
MDI+
SMBG
Baseline Age,
Mean (SD), Range




19 (12), 4-50
33 (16), 12-17
12 (3), 7-18
12 (1.5), 8-14
12 (3), 8-18
13 (3), 8-21





Baseline
HbA1c
Mean, SD
7.5 (0.8)
8.7 (0.9)
8.3 (0.5)
8 (1)
11.5 (2.4)
8.1 (1.2)
Pump
use
Follow-up
(months)
>6m
>6m
Naive
NR
Naive
Naive
6m
6m
12m
3.5m
6, 12m
3.7m
Superseded – see
Erratum
VEO versus CSII+SMBG
One study compared the MiniMed Veo system with CSII+SMBG at six months follow-up in a mixed population of patients between 4 and 50 years old.
Results were not reported separately for adults and children. However, about 70% of patients were children (<18 years). As explained above, we have
included this study as a study in children.
No results were found for the MiniMed Veo system versus any other treatment at three months or nine months or longer follow-up.
Table 16: Results for the MiniMed Veo system versus CSII+SMBG at six months follow-up in a mixed population (mainly children)
MiniMed Veo system (n=46)
CSII+SMBG (n=49)
6 months follow-up
Difference at 6m
Baseline
6m follow-up
Baseline
6m follow-up
Change in HbA1c
7.6% (95%
7.5 (95% CI 7.3,
7.4 (95% CI
7.4 (95% CI 7.2, 0.07 (95% CI: -0.2, 0.3),
CI 7.4, 7.9)
7.7)
7.2, 7.6)
7.7)
p=0.55
Number of people with hypoglycaemic
0/41
6/45
NS
events
Rate of hypoglycaemic events (Incidence rate
9.5 (95% CI 5.2,
34.2 (95% CI
IRR=3.6 (95% CI 1.7,
per 100 patient-months)
17.4)
22.0, 53.3)
7.5), p<0.001
HUS
5.9 (95% CI
4.7 (95% CI 4.0,
6.4 (95% CI
5.1 (95% CI 4.5,
-0.2 (95% CI -0.9, 0.5),
5.5, 6.4)
5.1)
5.9, 6.8)
5.6)
p=0.58
HUS=Hypoglycaemia Unawareness Score (Clarke questionnaire), higher is worse; IRR=Incidence rate ratio
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The only significant difference between treatment groups was the rate of moderate and severe
hypoglycaemic events, which favoured the MiniMed Veo system. All other outcomes showed
no significant differences between groups.
VEO versus integrated CSII+CGM and CSII+SMBG
Results at six months follow-up:
Change in HbA1c
Figure 7: Network of studies comparing ‘Change in HbA1c’ at six months follow-up in children
Table 17: Results of network analysis for change in HbA1c at six month follow-up (WMD,
95% CI)
Integrated CSII+CGM
CSII+SMBG
Veo
Integrated CSII+CGM
0.38 (-0.16, 0.92)
-0.04 (-0.26, 0.18)
xxx
-0.42 (-0.92, 0.08)
WMD<0 favours interventions listed in the left column. Differences are significant if the confidence
interval does not include 0 (these are in bold).
Results of the network analysis show that there were no significant differences in change in
HbA1c at six months follow-up in children between any of the interventions.
Integrated CSII+CGM versus CSII+SMBG
One study compared the integrated CSII+CGM system with CSII+SMBG at six months
follow-up in children.4
At six months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus CSII+SMBG were available for one outcome: change in HbA1c.
Other outcomes were not reported separately for children. The results for change in HbA1c
are reported in Table 18.
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Table 18: Results for the integrated pump+CGM versus pump+SMBG at six months follow-up in children
6 months followup
Change in HbA1c
Integrated CSII+CGM (n=17)
Baseline
6m follow-up
8.82 (1.05)
8.02 (1.11)
MDI+SMBG (n=23)
Baseline
6m follow-up
8.59 (0.80)
8.21 (0.97)
Difference at 6m
0.4894 (SE 0.2899),
p=0.10
Results for the head-to-head comparison of the integrated CSII+CGM system versus
CSII+SMBG at six months follow-up in children showed no significant difference in HbA1c
scores between groups.
Superseded –
see Erratum
Integrated CSII+CGM versus MDI+SMBG
One study compared the integrated CSII+CGM system with MDI+SMBG at 12 months
follow-up in children.10
At 12 months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus MDI+SMBG were available for: change in HbA1c, proportion
achieving HbA1c ≤7%, proportion with severe hypoglycaemia, rate of severe hypoglycaemic
events, hypoglycaemic AUC, hyperglycaemic AUC, DKA and quality of life. These results
are reported in Table 19.
Table 19: Results for the integrated CSII+CGM system versus CSII+SMBG at 12 months
follow-up in children
Integrated CSII+CGM
CSII+SMBG (n=81)
12 months follow-up
(n=78)
Difference at 12m
Baseline
12m
Baseline
12m
follow-up
follow-up
Change in HbA1c
8.3 (0.6)
7.9 (NR)
8.3 (0.5)
8.5 (NR) -0.5 (95% CI -0.8, 0.2), p<0.001
Proportion achieving
10/78
4/78
p=0.15
HbA1c ≤7%
Number of people with
4/78
4/81
NS
Severe hypoglycaemic
events
Severe hypoglycaemic
8.98/78
4.95/81
p=0.35
event rate (per 100
person-year; HbA1c <50
mg.dL)
Hypoglycaemic AUC
0.23
0.25
p=0.79
(Threshold <70 mg/dL)
(0.41)
(0.41)
Hyperglycaemic AUC
9.2 (8.08)
17.64
p<0.001
( >250 mg/dL)
(14.62)
Patients with DKA
1/78
1/81
NS
QoL:
PedsQL – Psychosocial
78.38 (14.59) Change:
78.76 (10.27)
Change:
NS
PedsQL – Physical
86.99 (12.93)
3.39
88.37 (11.16)
3.64
NS
HFS-Worry
28.88 (9.74)
Change:
26.97 (8.06)
Change:
NS
HFS-Avoidance
30.60 (5.43)
2.53
29.70 (6.04)
1.41
NS
Change: Change: 3.62
2.43
Change: Change: 4.01
2.25
DKA = Diabetic ketoacidosis; HFS=Hypoglycaemia Fear Survey (Higher is worse); PedsQL=Pediatric
Quality of Life (Higher is better)
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At 12 months follow-up, results were available from one RCT including 159 children. This
trial showed a significant difference in HbA1c change scores in favour of the integrated
CSII+CGM system, but no significant difference in the number of children achieving HbA1c
≤7%. Hyperglycaemic AUC was significantly lower in the integrated CSII+CGM group, but
hypoglycaemic AUC showed no significant difference. Results for severe hypoglycaemia
showed no differences between groups; nor did the number of patients with DKA. Quality of
life scores showed no significant differences between groups. The Hypoglycaemia Fear
Survey showed that fear was significantly reduced in both groups (both worry and avoidance
behaviour), but there was no difference between groups at 12 months follow-up.
4.2.4 Effectiveness of interventions in pregnant women
We found one RCT that reported data for pregnant women. The study included 32
pregnancies and 31 pregnant women. The number of pregnancies was the unit of analysis.
The study compared CSII+SMBG with MDI+SMBG; as these are not the relevant
interventions described by NICE, the results will not be further discussed in this chapter. Full
results are reported in Appendix 3.
Table 20: Included studies for pregnant women
Study ID
Veo
Nosari 199348
CSII+CGM
integrated
CSII+
SMBG
MDI+
SMBG


Baseline Age,
Mean (SD),
Range
26 (2.4) NR
Baseline
HbA1c
Mean, SD
NR
Pump
use
Follow-up
(months)
Naive
9m
Several non-RCTs (controlled clinical trials and observational studies) were identified;
however, none of these looked at the MiniMed Veo system or an integrated CSII+CGM
system. One ongoing study was identified; this is reported in Chapter 4.2.6.
4.2.5 Additional analyses for the economic model
So far, we have adhered to the usual methods of meta-analyses, where studies are only
combined in one analysis if they compare similar interventions in similar populations at
similar follow-up time-points, using similar outcomes.
We checked with clinical experts/committee members whether they agreed with the intended
analyses and there was general agreement on the following points:
-
Age – Studies in children and adults should be analysed separately and studies in
mixed age groups (adults and children, where data are not reported separately by age
group) should not be included in analyses for children or adults.
-
Follow-up: Studies with results at 3, 6, or 9 months should be analysed separately.
Studies with results between 2 and 4 months follow-up can be pooled in a group with
three months follow-up and studies with results at nine or more months follow-up can
be pooled in a group with 9+ months follow-up.
Where our clinical experts differed from our suggested analyses, the clinical experts were
always more cautious. For instance, it was suggested not to treat Ly 2013 as a study in
children because one third of participants are aged 18-50; therefore, it will be difficult to
include this study with the children’s analysis. If the adult age group had been a younger
cohort e.g. 18 to 25 it may have been different. Similarly, teenage children were considered to
behave in a different way from pre-teen children; therefore the study by Weintrob 2003 (8 to
14 years) may be significantly different from the other studies in children (up to 18 years) and
perhaps should be excluded.
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Due to the lack of data, we have included the studies by Ly et al and Weintrob et al in the
analyses for children. As a consequence the results of these analyses are less reliable due to
clinical heterogeneity between studies.
Despite trying to include as many studies as possible in the analyses for adults, we still have
missing results for key comparisons for the economic model. Most importantly, results for
comparisons of the MiniMed Veo system and the integrated CSII+CGM system with the
comparators (CSII+CGM, CSII+SMBG, MDI+CGM and MDI+SMBG) are missing for the
outcomes: ‘Change in HbA1c’ and ‘Severe hypoglycaemic event rates’. As can be seen in
Table 2, none of the included studies looked at CSII+CGM and MDI+CGM. Therefore, a
comparison with these comparators cannot be made. However, it is possible to calculate
results for the outcomes: ‘Change in HbA1c’ and ‘Severe hypoglycaemic event rates’ when
comparing the MiniMed Veo system and the integrated CSII+CGM system with CSII+SMBG
and with MDI+SMBG in a full network analysis, if we accept the following assumptions:
-
All studies can be pooled, irrespective of length of follow-up (3, 6 or more than 9
months).
-
Studies in mixed populations (including children and adults without reporting
separate results by age group) can be pooled in one analysis. This means, we will
include O’Connell 2009 (30 adults, 32 children), RealTrend (81 adults, 51 children),
and Hirsch 2008 (98 adults, 40 children) in the analyses for adults. Ly 2013 (30
adults, 65 children) will still be excluded from these analyses.
-
For event rates we assumed that when numbers of events were reported, the rate
could be derived assuming all patients were observed for the follow-up duration of
the trial.
It should be taken in to account that the following analyses, including any subsequent
analyses such as the economic model, are based on these assumptions and that the clinical
experts advised against using these wide inclusion criteria for pooling studies in one analysis.
The results of these analyses are therefore likely to be considerably less reliable due to
increasing clinical heterogeneity between studies included in these analyses for adults.
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Change in HbA1c
Figure 8: Network of studies comparing ‘Change in HbA1c’ at all follow-up time points in adults
and mixed populations
Notes: Blue boxes represent the interventions; Lines represent comparisons between interventions at
different follow-up times (Blue = 3m, Green = 6m, Orange = 9+ months); Transparant boxes represent
studies (Red = mixed population; Black = Adults).
Table 21: Results of the network analysis for change in HbA1c at all follow-up time points in
adults and mixed populations (WMD, 95% CI)
Integrated
CSII+SMBG
MDI+SMBG
CSII+CGM
0.04 (-0.07, 0.15)
-0.07 (-0.31, 0.17)
Veo
-0.66 (-1.05, -0.27)
Integrated CSII+CGM
xxx
-0.11 (-0.32, 0.10)
-0.70 (-1.05, -0.30)*
CSII+SMBG
xxx
xxx
-0.46 (-1.18, 0.27)**
Mean difference < 0 favours interventions listed in the left column. Statistically significant differences
are those where the 95% confidence interval does not include 0 (shown in bold).
* This result was from a random effects analysis as I2 was 62.5%.
** This result was from a random effects analysis as I 2 was 80.2%.
Results of the network analysis show that there were no significant differences in change in
HbA1c in adults (including mixed populations) between the MiniMed Veo system and the
integrated CSII+CGM system. Similarly, there were no significant differences in change in
HbA1c in adults (including mixed populations) between the MiniMed Veo system and the
integrated CSII+CGM system on the one hand and CSII+SMBG on the other. There was a
significant difference in change in HbA1c in adults (including mixed populations) between
the MiniMed Veo system and the integrated CSII+CGM system when both systems are
compared with MDI+SMBG, favouring the MiniMed Veo system and the integrated
CSII+CGM system. Overall, integrated systems (the MiniMed Veo system and the integrated
CSII+CGM system) are superior to SMBG (with CSII or MDI) in terms of HbA1c. However,
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as reported above, the results of these analyses are less reliable due to increasing
heterogeneity between studies included in the analyses. This is particularly the case for, the
comparison between the MiniMed Veo system and CSII+SMBG, which is not only based on
an indirect comparison (using data from the Aspire-in-home trial, O’Connell 2009, Hirsch
2008 and RealTrend), but also relies on data at three months follow-up (Aspire-in-home and
O’Connell 2009) combined with data at six months follow-up (Hirsch 2008 and RealTrend),
and combines data from adults (Aspire-in-home and Hirsch 2008) with data from mixed
populations (O’Connell 2009 and RealTrend).
Severe hypoglycaemic event rate
Figure 9: Network of studies comparing ‘Severe hypoglycaemic event rate’ at all follow-up time
points in adults and mixed populations
Notes: Blue boxes represent the interventions; Lines represent comparisons between interventions at
different follow-up times (Blue = 3m, Green = 6m, Orange = 9+ months); Transparant boxes represent
studies (Red = mixed population; Black = Adults; Green = Adults and All hypoglycaemic events).
Table 22: Results of the network analysis for severe hypoglycaemic event rate at all follow-up
time points in adults and mixed populations (RR, 95% CI)
Integrated
CSII+SMBG
MDI+SMBG
CSII+CGM
0.12 (0.01, 2.14)
0.39 (0.02, 8.40)
0.10 (0.01, 1.93)
Veo
Integrated CSII+CGM
xxx
3.23 (1.10, 9.49)
0.86 (0.51, 1.46)
CSII+SMBG
xxx
xxx
0.67 (0.38, 1.20)
RR<1 favours interventions listed in the left column. Statistically significant differences are those
where the 95% confidence interval does not include 1 (shown in bold).
Results of the network analysis show that there were no significant differences in ‘Severe
hypoglycaemic event rate’ in adults (including mixed populations) between the MiniMed Veo
system and any of the other treatments. Similarly, there were no significant differences in
change in ‘Severe hypoglycaemic event rate’ between the integrated CSII+CGM system and
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MDI+SMBG. There was a significant difference in ‘Severe hypoglycaemic event rate’
between the integrated CSII+CGM system and CSII+SMBG, favouring CSII+SMBG.
However, as reported above, the results of these analyses are less reliable due to increasing
clinical heterogeneity between studies included in the analyses. Looking at the significant
difference in particular, it is important to point out that this result relies upon the data from
three trials with different follow-up (three months for O’Connell and six months for Hirsch
2008 and RealTrend), and that data from all three trials are from mixed populations, including
adults and children.
Overall, the main conclusion regarding the evidence for HbA1c and hypoglycaemic event rate
in adults is that the evidence is limited and when all available evidence is combined, the
results become highly unreliable.
4.2.6 Ongoing studies
We found 18 ongoing studies, 17 RCTs and one observational study looking at the use of the
Threshold Suspend feature at home with a sensor-augmented insulin pump (Mini Med 530G).
Most ongoing studies are in children (12 out of 18), five are in a general population (adults or
adults and children), and one study is in pregnant women. Seven studies include the MiniMed
Veo system and four studies include the Integrated CSII+CGM system. Details of ongoing
studies are reported in Table 21.
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Table 23: Ongoing studies
Study ID
Lawson49
Year
2014
Intervention
Veo vs CSII+SMBG
RCT
YES
Troub50
Blair51
2013
2010
YES
YES
Assistance Publique Hôpitaux de Paris
NCT0094922152
Steno Diabetes Center
NCT0145470053
2012
Veo vs CSII+CGM
CSII+SMBG vs
MDI+SMBG
Veo vs CSII+SMBG
YES
CSII plus CGM (Medtronic MiniMed Paradigm REAL-Time System OR Veo)
versus MDI
General
Medtronic Diabetes
NCT0212079454
2014
Veo vs Integrated
CSII+CGM vs
MDI+SMBG
Veo
OBS
2-15 y
Vastra Gotaland Region
NCT0209205155
University of British
Columbia NCT0206402356
2014
MDI+CGM vs
MDI+SMBG
CSII+SMBG vs
MDI+SMBG
YES
Use of Threshold Suspend (TS) feature at home with a sensor-augmented insulin
pump (Mini Med 530G) in Pediatrics 2-15 years with Type 1 diabetes over a
period of 1 year
CGM versus SMBG in Individuals With Type 1 Diabetes Treated With MDI
Pregnant
Sheffield Teaching
Hospitals NHSFT
(REPOSE Trial)
NCT01616784
EUCTR2010-023198-21GB57
Seattle Children's Hospital
NCT0087529058
2013
Veo vs CSII+SMBG vs
MDI+SMBG
YES
Comparison of Continuous Subcutaneous Insulin Infusion (CSII) With Multiple
Daily Injections (MDI) for the Treatment of Pregestational Diabetes During
Pregnancy (T1DM & T2DM)
CSII (Insulin Pump) plus DAFNE versus MDI (levemir® & quick acting
insulin) plus DAFNE
2011
CSII+CGM vs
CSII+SMBG
YES
CSII alone versus CSII + Real Time Sensor Augmentation (RTSA) in patients 03 yrs old with T1DM
0-3y
2012
2014
YES
YES
Comment
Complex design. Trial uses the Medtronic Veo system. Patients are randomised
to Simultaneous initiation of pump + CGM Vs Initiation of pump with CGM
added 6 months later. Outcomes are 6 and 12 months. Group B is pump +
SMBG for 6mth then pump + CGM for next 6 months.
CSII compared to MDI regimens in children and young people at diagnosis of
TIDM - Protocol only
Device: monitor Paradigm 754 VEO, MINILINK Real Time, Medtronic, CE
(3m+9m SMBG vs 12m Veo)
Age
5-18 y
General
Children
2-18 y
General
18+y
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Study ID
Nemours Children's Clinic
NCT0035789059
EUCTR2005-004526-72GB60
ACTRN1260600004957261
Year
2012
Intervention
CSII+SMBG vs
MDI+SMBG
CSII+CGM vs
MDI+SMBG
Integrated CSII+CGM
vs CSII+SMBG
RCT
YES
Comment
MDI versus CSII in Adolescents (12-17y) With Newly Diagnosed T1DM
Age
12-17y
YES
CSII versus MDI in preschool aged children with Type 1 diabetes.
YES
ACTRN1261400051064062 2014
Veo vs Integrated
CSII+CGM
YES
ACTRN1261000060509963 2010
CSII+SMBG vs
MDI+SMBG
Integrated CSII+CGM
vs CSII+CGM
CSII+SMBG vs
MDI+SMBG
CSII+SMBG vs
MDI+SMBG
YES
MiniMed Paradigm Real Time Insulin Pump and Continuous Glucose
Monitoring System (MMT 722) versus pre-trial insulin pump device (no new
intervention)
CSII + rt-CGM system and predictive low glucose suspend feature (Medtronic
Minimed 640G) versus Standard sensor augmented pump therapy - CSII + rtCGM
CSII versus MDI in children and adolescents with type 1 diabetes
Under
18y
13-39y
2006
2006
ACTRN1261100014293264 2011
ISRCTN2925527565
2010
NCT0133892266
2011
YES
8-20y
9-16y
YES
Patients own pump versus the new integrated pump (Unclear which type of
monitoring with own pump)
CSII versus MDI in children with T1DM
Under
18y
1-15y
YES
CSII versus MDI in children with T1DM
6-16y
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4.3
Summary of results
In this summary of results, we will describe the results by population (adults, children and
pregnant women) and by comparison. First we will describe comparisons between the
MiniMed Veo system and other treatments, then comparisons between the integrated
CSII+CGM system and other treatments, and finally we will describe the main remaining
comparisons.
Nineteen trials were included, 12 reported data for adults, six reported data for children and
one trial reported data for pregnant women. Four trials were in mixed populations (adults and
children); two of these reported data separately for adults and children and are included in the
12 trials for adults and six trials for children. Two trials did not report data separately for
adults and children (O’Connell 2009 and RealTrend). Therefore, the results from these trials
were not used in the main analyses. However, the data are reported in the data extraction
tables in Appendix 3 and they are used in the additional analyses for the economic model (see
Chapter 4.2.5).
4.3.1 Studies in adults
Twelve studies were included in the analyses for adults. One of these studies (Hirsch 20084)
only reported change in HbA1c separately for adults. None of these studies looked at CSII or
MDI+CGM. Table 5 shows an overview of these 12 studies, their comparisons and their
baseline data. Further details are reported in Appendix 3.
MiniMed Veo system versus the integrated CSII+CGM system
Only one study (ASPIRE in-home37) with data for adults (N=247) included the MiniMed Veo
system as one of the treatment arms. This study compared the MiniMed Veo with an
integrated CSII+CGM system at three months follow-up. Results of this study showed that
there was no significant difference in change in HbA1c at three months follow-up; but both
nocturnal hypoglycaemic event rates and day and night hypoglycaemic event rates were
significantly reduced for patients using the MiniMed Veo system. There were no significant
differences in any of the other reported outcomes (blood glucose level at follow-up, insulin
use, DKA, quality of life and adverse events). Therefore, the conclusion from this trial is that
the MiniMed Veo system reduces hypoglycaemic events in adults in comparison with the
integrated CSII+CGM system, without any differences in other outcomes, including change in
HbA1c.
MiniMed Veo system versus other treatments
Indirect evidence seems to suggest that that there are no significant differences between the
MiniMed Veo system and CSII+SMBG and MDI+SMBG in ‘change in HbA1c’ at three
months follow-up.
However, if all studies are combined (see Chapter 4.2.5 - Additional analyses for the
economic model), the MiniMed Veo system is significantly better than MDI+SMBG in terms
of HbA1c.
The integrated CSII+CGM system versus other treatments
Five studies compared the integrated CSII+CGM system with other treatments. One of these
compared the integrated CSII+CGM system with CSII+SMBG at six months follow-up
(Hirsch 2008),4 but this study only reported change in HbA1c separately for adults. The other
four studies compared the integrated CSII+CGM system with MDI+SMBG, at three months
follow-up (Lee 2007 and Peyrot 2009), at six months follow-up (Eurythmics), and at 12
months follow-up (STAR-3).
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Results of the trial comparing the integrated CSII+CGM system with CSII+SMBG at six
months follow-up in adults showed no significant difference in HbA1c scores between
groups. Other outcomes in this trial were not reported separately for adults. An indirect
comparison showed that quality of life was significantly more improved in the integrated
CSII+CGM group compared to the CSII+CGM group.
For the comparison of the integrated CSII+CGM system with MDI+SMBG, the most reliable
data from the largest trial with 12 months follow-up (STAR-3) show that there is a significant
difference in change in HbA1c and in the proportion of patients achieving HbA1c ≤ 7%,
favouring the integrated CSII+CGM system. For hypoglycaemic event rates none of the
studies showed a significant difference between groups. Similarly, there were no significant
differences in DKA between groups. Insulin use was significantly lower in patients using the
integrated CSII+CGM system, and Quality of Life was significantly more improved in the
integrated CSII+CGM group compared to the CSII+SMBG group. Overall, results showed
significant results in favour of the integrated CSII+CGM system in comparison with
MDI+SMBG for HbA1c and quality of life.
CSII versus MDI
We found six trials with data for adults comparing CSII+SMBG with MDI+SMBG. No trials
were found with data for adults including the treatments: CSII+CGM and MDI+CGM.
In terms of Change in HbA1c, only one of the six trials showed a significant difference
between CSII+SMBG and MDI+SMBG: DeVries et al (2002) found a significant difference
in favour of CSII+CGM (at 16 weeks mean HbA1c was 0.84% (95% CI: -1.31, -0.36) lower
in the CSII+SMBG group compared with the MDI+SMBG group). Significance was not
reported in the OSLO trial and in Nosadini 1988, while the difference between groups was
not significant in Bolli 2009, Thomas 2007 and Tsui 2001.
In terms of the number of severe hypoglycaemic events, three trials found no significant
differences between groups (Bolli 2009, DeVries 2002 and Thomas 2007), while this was not
reported in the other three trials.
4.3.2 Studies in children
Six studies were included in the analyses for children. One of these studies (Hirsch 20084)
only reported change in HbA1c separately for children. None of these studies looked at CSII
or MDI+CGM. Table 15 shows an overview of these six studies, their comparisons and their
baseline data. Further details are reported in Appendix 3.
MiniMed Veo system versus the integrated CSII+CGM system
None of the studies in children made a direct comparison between the MiniMed Veo system
and the integrated CSII+CGM system.
An indirect comparison was possible, using data at six months follow-up from Ly 2013 and
Hirsch 2008, but only for HbA1c, which showed no significant difference between groups.
MiniMed Veo system versus other treatments
One study compared the MiniMed Veo system with CSII+SMBG at six months follow-up in
a mixed population of patients between 4 and 50 years old (Ly 2013). No results were found
for the MiniMed Veo system versus any other treatment at three months or nine months or
longer follow-up.
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The only significant difference between treatment groups was the rate of moderate and severe
hypoglycaemic events, which favoured the MiniMed Veo system. All other outcomes showed
no significant differences between groups.
The integrated CSII+CGM system versus other treatments
One study compared the integrated CSII+CGM system with CSII+SMBG at six months
follow-up in children (Hirsch 2008). This trial found no significant difference in HbA1c
scores between groups.
One study compared the integrated CSII+CGM system with MDI+SMBG at 12 months
follow-up in children (STAR-3). This trial showed a significant difference in HbA1c change
scores in favour of the integrated CSII+CGM system, but no significant difference in the
number of children achieving HbA1c ≤7%. Hyperglycaemic AUC was significantly lower in
the integrated CSII+CGM group, but hypoglycaemic AUC showed no significant difference.
Other outcomes showed no significant differences between groups.
4.3.3 Studies in pregnant women
We found one RCT that reported data for pregnant women. The study included 32
pregnancies and 31 pregnant women. The number of pregnancies was the unit of analysis.
The study compared CSII+SMBG with MDI+SMBG; therefore, the results are not relevant
for comparisons with the MiniMed Veo system and the integrated CSII+CGM system.
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5
ASSESSMENT OF COST-EFFECTIVENESS
In this chapter we explore the cost-effectiveness of integrated insulin pump systems in the
management of type 1 diabetes in UK adults.
5.1
Review of economic evaluations
5.1.1 Search methods
Literature searches were undertaken to identify published economic evaluations for MiniMed
Veo and Animas Vibe. The search strategy for economic evaluations included a filter
designed to identify cost and economic studies in those databases that are not health economic
specific.
The following databases and resources were searched for relevant economic evaluations and
cost studies:
 NHS Economic Evaluation Database (NHS EED) (Wiley Online Library): issue 3/Jul
2014
 Health Economic Evaluations Database (HEED) (Wiley Online Library): up to
2014/09/05
 MEDLINE (OvidSP): 1946-2014/Aug week 4
 MEDLINE In-Process Citations and Daily Update (OvidSP): up to 2014/09/05
 PubMed (NLM): up to 2014/09/05
 EMBASE (OvidSP): 1974-2014/week 34
 EconLit (EBSCO): 1969-20140801
 CEA Registry (www.cearegistry.org): up to 2014/09/05
 Research Papers in Economics (RePEc) (http://repec.org/): up to 2014/09/05
In addition economic searches specifically for MiniMed Paradigm Veo and Animas Vibe
were conducted using the same resources listed above.
The full search strategies are presented in Appendix 1.
Relevant studies were then identified in two stages. Titles and abstracts returned by the search
strategy were examined independently by two researchers (MA and ICR) and screened for
possible inclusion. Disagreements were resolved by discussion. Full texts of the identified
studies were obtained. Two researchers (MA and ICR) examined these independently for
inclusion or exclusion, and disagreements were resolved by discussion.
5.1.2 Inclusion criteria
The initial search identified a total of eight abstracts, six of which were of conference
abstracts and thus not included. Both of the full papers were identified as relevant to our
review. These studies were by Kamble et al67 and Ly et al68. The one by Kamble et al
evaluated Animas Vibe (integrated CSII+CGM) versus MDI+SMBG in the US whereas the
study by Ly et al. evaluated the MiniMed Paradigm Veo (CSII+CGM+Suspend) versus
CSII+SMBG in Australia. The first evaluation showed that the Animas Vibe was not costeffective compared to multiple daily injections despite taking all health effects into account
through the IMS CDM. On the other hand, the second study showed that the MiniMed Veo
system was cost-effective compared to continuous subcutaneous insulin infusion, whilst only
taking the impact of the reduction of severe hypoglycaemic events into account.
The characteristics of these studies are summarised in Table 24.
Of the six (excluded) conference abstracts one was an abstract that was later published as full
paper69 and already included in one of the two selected full papers.67 While we will not
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formally discuss the conference abstracts, we still present the characteristics, in as far as they
can be found in the abstracts, in Table 25.70-74
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Table 24: Summary of included full papers
Study,
Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
QALYs
(intervention,
comparator)
Costs (currency)
(intervention,
comparator)
ICER
( per QALY
gained)
Sensitivity analyses
Kamble
S67
2012
US
 CORE Diabetes Model
(Markov model for
diabetes, includes a
large number of
complications)
Integrated
CSII+CGM vs
MDI+SMBG
Adult inadequately
controlled type 1
diabetes patients.
QALYs
 10.794
Cost:
3-d sensor
 10.418
 $253,493
Incremental
costeffectiveness
ratio
 Sensitivity analysis
indicated that ICER would
only substantially reduce
(below $100,000) when
assuming only 1 test strip
per sensor change with the
integrated system or when
assuming a 0.0329 utility
increment associated with
less fear of hypoglycaemia
throughout the remaining
lifetimes of patients the
integrated system
 US health care
perspective
 Time horizon: 60 years
 Discount rate 3% for
costs and effects

Clinical data from
STAR 3 trial 37
 Utilities: Mixed, for
some complications
EQ-5D, for some
direct elicitation
 Deterministic and
probabilistic sensitivity
analysis conducted
 Age 41.3
 HbA1c 8.3%
 $167,170
6-d sensor
 $230,352
 $167,170
 3-d sensor
$229,675/
QALY
 6-d sensor
$168,104/
QALY
 PSA indicated that at a
willingness to pay threshold
of $50,000/QALY the
probability of integrated
CSII+CGM being costeffective was 0%.
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Study,
Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
QALYs
(intervention,
comparator)
Costs (currency)
(intervention,
comparator)
ICER
( per QALY
gained)
Sensitivity analyses
Ly TT68
2014
Australia
 Decision analytical
model with only severe
hypoglycaemia as
event
CSII+CGM +
Suspend vs
CSII+SMBG
Severe
hypoglycemic
events
All patients /
≥12 years

 Time horizon 6 months

Age 18.6


 No discounting
HbA1c 7.5%
Total costs
(intervention costs
+ other medical
costs due to
severe
hypoglycemic
event)
All patients / ≥12
years
≥12 years
AU$ 40,803
 Australian healthcare
system perspective
Patients with type1
diabetes who have
impaired awareness of
hypoglycaemia
(Subgroup analysis for
≥12 years)
 Clinical data from trial
ACTRN12610000024
04438
 Utilities: EQ-5D
 One way sensitivity
analyses conducted

0/0
0.08607/
0.1052
QALYs
≥12 years

0.036650

-0.00017

AU$ 4382 /
AU$ 4432

AU$ 2867 /
AU$2929
Sensitivity analysis
indicated that ICER
would only substantially
increase (above
$100,000) when the
utility values were
changed to 0.0075
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Table 25: Summary of conference abstracts
Study,
Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
QALYs
(intervention,
comparator)
Costs (currency)
(intervention,
comparator)
ICER
( per QALY
gained)
Gomez A.71
2013
Colombia
 CORE Diabetes Model
(Markov model for
diabetes, includes a large
number of complications)
SensorAugmented
Insulin Pump
(SAP).
Comparator not
stated.
Mode population not
described. Trial
population 217 IDDM
patients
(average baseline
HbA1c of 8.97%, mean
age 34 years, and
average diabetes
duration of 14 years)
QALYs not
presented; LY
gain 3.51
No costs
presented
$44,889,916
COP
($24,939US)
per QALY
gained based on
direct costs only
SensorAugmented
Insulin Pump
(SAP) vs MDI
The inputs were taken
from a Colombian real
life clinical study of
217 T1D on SAP
therapy
LY gain 3.51;
Diabetes
complications
delayed by 1.74
years.
 Perspective not stated
 Time horizon: not stated
 Discount rate not stated
 Clinical data trial (no
reference)
Sensitivity
analyses
Extensive
sensitivity
analyses showed
the robustness of
the results.
 Utilities: not mentioned.
The reduction in the fear
of hypoglycaemic events
on quality of life was
included.
 Deterministic sensitivity
analysis conducted
Gomez A.70
2014
Colombia
 This study is copy of
study above, but now only
reports on effects, not on
costs.
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Study,
Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
QALYs
(intervention,
comparator)
Costs (currency)
(intervention,
comparator)
ICER
( per QALY
gained)
Lindholmer
Olinder72
2014
Sweden
 Abstract does not indicate
if a model was used. Aim
of study systematic review
to establish available
evidence on effects of
CGM and SAP (sensoraugmented pump) in
adults (A), children (C)
and pregnant women (P)
compared to SMBG (selfmonitored blood-glucose).
CGM and SAP
(sensoraugmented
pump) versus
SMBG.
Patients with type1
diabetes:
No QALYs
presented
Calculations of
costs
demonstrated an
increased cost of
€3026 for CGM
vs. SMBG and
€4216 for SAP
vs. MDI and
SMBG.
No ICER
presented
 CORE Diabetes Model
(Markov model for
diabetes, includes a large
number of complications)
Integrated
CSII+CGM vs
CSII
(way of bloodglucose
monitoring not
stated)
Adult inadequately
controlled type 1
diabetes patients.
1.27 QALYs
gained
Extra annual
costs €1258 per
patient
ICER €27,796
per QALY
gained
Roze73
2014
France
 Perspective not stated
 Time horizon: life time
 Discount rate not stated
 Adults
 Children
 Pregnant women
 Age 36
 HbA1c 9%
Sensitivity
analyses
 Sensitivity
analysis on key
drivers confirmed
robustness of
results under a
wide range of
assumptions
 Effectiveness data from
meta-analysis
 Reduced fear of
hypoglycaemic events in
Integrated CSII+CGM
group accounted for in
QALY
 Sensitivity analysis
conducted
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Study,
Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
QALYs
(intervention,
comparator)
Costs (currency)
(intervention,
comparator)
ICER
( per QALY
gained)
Sensitivity
analyses
Roze74
2014
UK
 CORE Diabetes Model
(Markov model for
diabetes, includes a large
number of complications)
Integrated
CSII+CGM vs
CSII
(way of bloodglucose
monitoring not
stated)
Adult inadequately
controlled type 1
diabetes patients.
3.1 QALYs
gained
Extra annual
costs £1143 per
patient
ICER £16,986
per QALY
gained
 Sensitivity
analysis on key
drivers confirmed
robustness of
results under a
wide range of
assumptions
 Perspective not stated
 Time horizon: life time
 Discount rate not stated
 Age 27
 HbA1c 10%
 Effectiveness data from
meta-analysis and real life
observational study
 Reduced fear of
hypoglycaemic events in
Integrated CSII+CGM
group accounted for in
QALY
 Sensitivity analysis
conducted
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5.1.3 Quality assessment
A quality appraisal was carried out on the two studies, using the Drummond checklist. 75 A
summary of the results are provided in Table 26.
Table 26: Quality assessment of studies, using Drummond 1996
Kamble S,67 2012
Ly TT,69 2014
1. Was the research question stated?
Yes
Yes
2. Was the economic importance of the research question
stated?
Yes
Yes
3. Was/were the viewpoint(s) of the analysis clearly stated and
justified?
Yes
Yes
No, CEA based
on clinical trial so
alternative based
on that.
Partially; not easy
to find if glucose
monitoring is
CGM or SMBG
Yes
Yes
Yes
Justification was given, but
doubtful if choice is
reasonable
Yes
Yes
Yes; most details
in separate paper
Yes; most details in separate
paper
10. Were details of the methods of synthesis or meta-analysis of
estimates given (if based on an overview of a number of
effectiveness studies)?
NA
NA
11. Were the primary outcome measure(s) for the economic
evaluation clearly stated?
Yes
Yes
12. Were the methods used to value health states and other
benefits stated?
Yes
Yes; however after seeing
QALY outcomes,
explanation clearly
insufficient
13. Were the details of the subjects from whom valuations were
obtained given?
NA; utilities from
literature
Yes
14. Were productivity changes (if included) reported separately?
NA
NA
15. Was the relevance of productivity changes to the study
question discussed?
NA
NA
Yes for all
treatment related
costs; no for
complication
costs
Yes
Yes
Criteria
Study design
4. Was a rationale reported for the choice of the alternative
programmes or interventions compared?
5. Were the alternatives being compared clearly described?
6. Was the form of economic evaluation stated?
7. Was the choice of form of economic evaluation justified in
relation to the questions addressed?
Yes
Yes
Data collection
8. Was/were the source(s) of effectiveness estimates used
stated?
9. Were details of the design and results of the effectiveness
study given (if based on a single study)?
16. Were quantities of resources reported separately from their
unit cost?
17. Were the methods for the estimation of quantities and unit
costs described?
Yes
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Kamble S,67 2012
Yes
Ly TT,69 2014
19. Were details of price adjustments for inflation or currency
conversion given?
Yes
NA
20. Were details of any model used given?
Yes
Yes
No justification
why IMS CDM
in paper
A justification was given, i.e.
the clinical trial was
modelled and extrapolation
was not considered of
interest. Unlikely that only
looking at hypoglycaemic
events and not long term
complications is of interest
for decision maker
22. Was the time horizon of cost and benefits stated?
Yes
Yes
23. Was the discount rate stated?
Yes
NA
24. Was the choice of rate justified?
Yes
NA
25. Was an explanation given if cost or benefits were not
discounted?
NA
Yes
26. Were the details of statistical test(s) and confidence intervals
given for stochastic data?
Yes
Yes
27. Was the approach to sensitivity analysis described?
Yes
Yes
28. Was the choice of variables for sensitivity analysis justified?
Yes
No justification given, but
choices appear reasonable
29. Were the ranges over which the parameters were varied
stated?
Yes
Yes
30. Were relevant alternatives compared? (That is, were
appropriate comparisons made when conducting the incremental
analysis?)
Yes
Yes
31. Was an incremental analysis reported?
Yes
Yes
32. Were major outcomes presented in a disaggregated as well
as aggregated form?
Yes
Yes; this highlighted lack of
face validity: QALYs in
both arms were 0.036650
and
-0.00017, whilst perfect
health would yield 0.5 per
arm
33. Was the answer to the study question given?
Yes
Yes
34. Did conclusions follow from the data reported?
Yes
Yes
35. Were conclusions accompanied by the appropriate caveats?
Yes
Not fully; authors did not
discuss impact of
intervention in trial on
HbA1c and how that would
impact cost-effectiveness
36. Were generalisability issues addressed?
No
Yes
Criteria
18. Were currency and price data recorded?
21. Was there a justification for the choice of model used and
the key parameters on which it was based?
Yes
Analysis and interpretation of results
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5.1.4 Results
5.1.4.1 Study design
Both studies were modelling studies, each based primarily on one clinical study. As a result,
one of the studies did not explain why the comparator had been chosen. They both stated
their research question and the approach to economic evaluation clearly.
In one study, results were presented both as cost per severe hypoglycaemic events avoided
(all patients) and as costs per QALY gained (patients≥12). A clear rationale was provided (i.e.
the EQ-5D was administered to parents and carers on behalf of children aged younger than 12
years) why cost per QALY could only be estimated for patients of 12 years and older. The
outcomes per severe hypoglycaemic events avoided are unlikely to be informative for
decision makers who want to know what the cost effectiveness is from a health care
perspective.
5.1.4.2 Data
As mentioned above, both studies were based on a single clinical study. The current papers
described the details of the study design only briefly but referred to the papers specifically
presenting the clinical results. The study based on the IMS CDM did not provide a rationale
why the IMS CDM was chosen to work with. The other study explained the choice of model
by stating that this was a trial-based economic evaluation so costs and effects were not
extrapolated beyond the six month clinical trial period. This means that the long term impact
of changes in HbA1c seen during the clinical study were not taken into consideration, only
the direct impact of avoiding severe hypoglycaemic events are accounted for.
For the study based on the IMS CDM, all utilities and costs of complications were taken from
literature. Hence, in this paper no information was available regarding the subjects from
whom valuations of quality of life were obtained and resources for complications were not
reported separately from their unit cost. The costs relating to the technologies and insulin
treatment did provide both resource use and unit costs.
For the six month study, all details regarding utilities and resource use were clearly presented.
However, once the results were presented, it became clear that the explanation regarding the
calculation of utilities and quality adjusted life years (QALYs) was lacking. For example, the
paper reported for the Standard Pump group (CSII+SMBG) a QALY accumulation of 0.00017, which would only be possible if patients were in a health state worse than death. A
likely explanation is the definition of QALY used in the paper, but this is nowhere clarified.
5.1.4.3 Analysis and interpretation of results
Both studies were in general performed appropriately, although the study by Kamble et al67
did not discuss any issues pertaining to generalisability.
In summary, only one study was found for the Animas Vibe and one for the MiniMed Veo
system, both with different comparators and for different countries. The latter study is of
limited importance to the current diagnostic appraisal, given it short time horizon of six
months and very limited model structure. The study of the Animas Vibe by Kamble et al was
better, given that all costs and effects that may be relevant were included. However, IMS has
now published updated utility values that conform to the NICE standard (i.e. based on EQ5D)76 and also updated the IMS CDM several times. Thus, the value of the Kamble paper lies
mostly in helping formulate scenarios and presenting some bench mark against which to
check the validity of outcomes from the de novo cost-effectiveness analysis.
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5.2
Model structure and methodology
This chapter describes the health economic model used to evaluate the cost-effectiveness of
the MiniMed Paradigm Veo system (an integrated CGM and insulin pump system with LGS
function) and the Vibe and G4 PLATINUM CGM system for the management of type 1
diabetes in adults, compared to (1) an insulin pump with stand-alone continuous glucose
monitoring (CSII+CGM), (2) an insulin pump with self-monitoring of blood glucose
(CSII+SMBG), (3) multiple daily injections with a continuous glucose monitor (MDI+CGM),
and (4) multiple daily injections with self-monitoring of blood glucose (MDI+SMBG).
The IMS CORE diabetes model (IMS CDM)77 was chosen to perform the cost-effectiveness
analyses in this assessment. The IMS CDM has been previously used in NICE/NHS related
projects for type 1 diabetes. It is probably the most popular model in the literature and it has
been validated extensively. It was used to assess the cost-effectiveness of CSII against MDI
for type 1 diabetes patients in an HTA report from 2010.78 In that report, it is mentioned that
the IMS CDM was not appropriate for the health economic outcomes for pediatric/adolescent
populations. This was confirmed by the model developers who also mentioned that the model
is not appropriate for pregnant women either. Therefore, these two subgroup populations were
not included in the cost-effectiveness analyses. The IMS CDM has also been used in the
current update of the Clinical Guideline on type 1 diabetes (CG15).3 The model’s time
horizon was set to 80 years. Costs were estimated from the perspective of the NHS in England
and Wales. Consequences were expressed in life years gained and quality adjusted life years
(QALYs). All costs and effects were discounted by 3.5%. The uncertainty about the model
input parameters and the potential impact on the model results was explored through scenario
analyses and probabilistic sensitivity analyses.
5.2.1 Model structure
The IMS CDM is an internet based, interactive simulation model that predicts the long-term
health outcomes and costs associated with the management of T1DM and T2DM. It is
suitable for running cohort (bootstrap) and individual patient-level simulations. It was first
developed by CORE (Center for Outcomes Research) and details of the first version were
published by Palmer et al. in 2004.77 It is widely used in the industry, both by companies of
health technologies as well as payers for those technologies, and it has also been used in
previous NICE technology assessments and clinical guidelines.3, 16, 79-82 The model has been
extensively validated. Since 1999, it has participated in Mount Hood conferences, during
which health economic models on diabetes are compared against each other in terms of their
structure, performance and validity.83-85 Two major validation papers for the IMS CDM have
been published to date.1, 2 The latest one, from 2014, is the basis for the technical model
description provided in this report. This is consistent with the latest version of the model,
which is numbered 8.5. Given the degree of validation of the model, and in order to be in line
with the currently updated T1DM guideline,3 for this evaluation it was believed important not
to use an alternative model or develop a de novo cost-effectiveness model.
The structure of the IMS CDM (from McEwan et al 20142) is shown in Figure 10. The IMS
CDM comprises 17 interdependent sub-models, which represent the most common diabetesrelated complications: angina pectoris, myocardial infarction (MI), congestive heart failure
(CHF), stroke, peripheral vascular disease (PVD), diabetic retinopathy, cataracts,
hypoglycaemia, ketoacidosis, nephropathy, neuropathy, foot ulcer/amputation, macular
oedema, lactic acidosis (T2DM only), (peripheral) oedema (T2DM only), and depression. A
sub-model for non-specific mortality is also included. Each of these sub-models is a Markov
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model that includes different health states depicting the severity/stage of the complication.
Transition probabilities in between the states of a complication sub-model can be time-,
demographics-, state-, physiological factor- and diabetes type- dependent.
Additionally, the non-parametric bootstrapping approach provides additional information on
the uncertainty surrounding the long-term outcomes provided by the model. In this approach,
a cohort population (with a size that can be defined by the model user) is created. Each patient
in this population is unique in the sense of its baseline characteristics (demographics, existing
baseline complications, baseline physiological risk factors and other risk factors like the
number of cigarettes smoked per day). Within the bootstrapping simulation approach, two
types of analysis are possible: deterministic and probabilistic. In the deterministic simulation
the continuous input parameters (baseline age, diabetes duration, HbA1c, etc.) of each patient
in the cohort that is created (say 1,000 patients) will be identical, but binary variables will
differ (gender, presence of a diabetes-related complication like MI, etc.). In each iteration,
one of the patients in this cohort is sampled with replacement and entered into the simulation
(i.e. the complication sub-models) until the patient dies. Applied treatment effects, utilities,
costs, coefficients of cardiovascular disease (CVD) events will be then identical in each
iteration. However, results will differ per iteration due to the differences in the binary input
parameters in the baseline cohort and the way a patient progresses through the model (random
walk). In the probabilistic simulation all variables that are subjected to random sampling (i.e.
cohort baseline parameters, treatment effects, coefficients of the cardiovascular disease risk
equations, health state utilities/adverse event disutilities, and costs) are randomly assigned at
the beginning of the first iteration according to pre-defined probability distributions. Then all
the patients in the cohort (say 1,000) are processed through the model while the parameters
assigned at the start of the iteration are held constant. Those patients will only differ due to
binary variables and random walk. When the model progresses to the next iteration,
parameters are re-sampled again and the next 1,000 patients are progressed though the model
while parameters are held constant again. This is process is repeated for all the bootstrap
iterations.
Note that, due to computational time requirements, not all parameters in the model are
subjected to random sampling. For instance among the baseline risk factors, cigarette and
alcohol consumption per day are not subjected to sampling. The same is true for minor and
severe hypoglycaemia/ketoacidosis rates and coefficients from non-CVD related risk
adjustment equations.
Transition probabilities within each sub-model (i.e. the annual probability of a change in
health state) are dependent on baseline demographic and current physiological patient
characteristics (HbA1c, BMI, etc.), and the existence of other complications and concomitant
treatments (e.g. ACEI, statin or laser). Transition probabilities are further calculated based on
established regression or risk adjustment functions from the literature.86-88 State transitions of
a cohort occur simultaneously in each sub-model. Therefore, it is possible that a patient
develops multiple complications in one year. In the IMS CDM model diabetes-specific
mortality is assumed to be caused by the following complications: MI, stroke, CHF,
nephropathy, foot ulcer/amputation, hypoglycaemia, ketoacidosis and lactic acidosis, whereas
non-specific mortality is based on UK life tables.89 Additional details on the sub-models of
the IMS CDM are given in Appendix 5.
An important limitation of the model is that it is not suitable to model long term outcomes for
children/adolescent population, because the background risk adjustment/risk factor
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progression equations (such as those based on the Framingham studies) are all based on adult
populations. Hence, we had to limit all our analyses to the adult population.
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Figure 10: IMS CDM model structure
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5.3
Model input parameters
This chapter describes the input parameters used in the model for the base case and how their
values were estimated. Six different input parameter databases can be distinguished in the
IMS CDM: (1) cohort, (2) economics (including management costs, costs of complications
and utilities), (3) treatment effects, (4) treatment costs, (5) other management, and (6) clinical.
Table 27 maps the IMS CDM input parameter databases into the conventional model input
categories.
Table 27: Mapping IMS CDM input parameter databases into conventional input parameter
categories
IMS CDM input database
Conventional input parameter category
Cohort database
Demographics (age, diabetes duration, percentage male,
racial profile)
Baseline physiological risk factors (e.g. HbA1c, systolic
blood pressure (SBP), total cholestorol (T-CHOL), body
mass index (BMI) etc.)
Baseline complications (proportion with MI history,
proportion with cataract, etc.)
Other risk factors (proportion smoking, alcohol
consumption, etc.)
Economics database
Cost and effect discount rates
Sampling settings for PSA (for costs)
Management costs (e.g. statin, aspirin, angiotensionconverting-enzyme (ACE)-inhibitors costs, screening costs
for depression, foot ulcer, eye etc.)
Utilities/utility decrements for all relevant health states and
adverse events
Direct costs for:
 Cardiovascular complications (year 1 and 2+ costs for
myocardial infarction, angina, congestive heart failure,
stroke etc.)
 Renal complications (year 1 and 2+ costs for
hemodialysis, renal transplantation etc.)
 Eye diseases/complications (year 1 and 2+ costs for
cataract, severe vision loss etc.)
 Foot ulcer/ amputation/ neuropathy (year 1 and 2+)
 Acute events (severe hypoglycaemia, ketoacidosis, etc.)
Treatment Database
Effect of the treatment on physiological parameters
 For the 1st year: change in the baseline value
 For the consecutive years: progression approach (e.g.
UKPDS, Framingham or user defined clinical tables)
Adverse events
 Minor and severe hypoglycaemic events
 Ketoacidosis events
Risk adjustments for concomitant medicines (e.g. ACEinhibitors, statins)
Treatment Cost Group
Assigns treatment costs to the treatments for year 1 and
Database
afterwards
Management Database
Percentage of patients on concomitant medication (e.g.
statins, ACE-inhibitors)
Percentage of patients on screening or patient management
programs (e.g. renal disease screening or foot ulcer
prevention program)
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IMS CDM input database
Clinical database
Conventional input parameter category
Other
 Risk reductions due to management and
sensitivity/specificity of screening tests
Risk adjustments for
 HbA1c
 SBP
Risk multipliers for
 Myocardial infarction
 Stroke
 Angina
 Congestive heart failure
 Race
 Adverse events
 Other microvascular complications
 Foot ulcer/amputation
 Depression
 Others
Given the degree of validation of the model, only those parameters that need to be adapted to
time (2015), place (UK), the population (Type 1 diabetes, eligible for a pump) and
technologies to be compared were amended in the base case. Furthermore, unless there was
believed to be a more appropriate value, for sake of consistency we chose to follow the
approach from the latest diabetes NICE Guideline (which also adopted the IMS CDM).3 In
addition, many of the parameters were also validated by clinical experts. Further details on
specific input parameters and their probability distributions are described below.
5.3.1 Baseline population characteristics
When possible we estimated cohort baseline parameters based on the studies identified in our
systematic review to properly reflect our base case population, i.e. type 1 diabetes, eligible for
an insulin pump. In this case, only the study by Bergenstal et al37 provided reliable
information for some patient characteristics. For the characteristics not reported in Bergenstal
et al. we used those from the general T1DM population as in the updated clinical guidelines. 3,
90, 91
The cohort baseline characteristics used in our base case analysis and their sources can be
seen in Table 28. For the probabilistic sensitivity analysis (PSA) the input parameters age,
duration of diabetes and baseline risk factors for HbA1c, systolic blood pressure, body mass
index, total cholesterol and LDL are sampled from a normal distribution with means and
standard deviations given in Table 28. Baseline triglyceride and HDL levels are sampled from
a gamma distribution with parameters alpha = mean2/sd2 and beta = mean/sd2.
Table 28: Cohort baseline characteristics (base case analysis)
Parameter
Mean
SD
Source
Patient demographics
Start age (years)
41.6
12.8
Duration of Diabetes (years)
27.1
12.5
Proportion Male
0.38
NA
Baseline risk factors
HbA1c (%-points)
7.26
0.71
Bergenstal et al37
128.27
16.07
National diabetes
audit92
Systolic Blood Pressure (mmHg)
Bergenstal et al 37
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Parameter
Mean
SD
Total cholesterol (mg/dL)
176.50
33.00
HDL (mg/dL)
50.25
13.00
LDL (mg/dL)
109.75
29.00
Triglycerides (mg/dL)
81.50
41.00
Body Mass Index (BMI) (kg/m2)
27.6
15.9
eGFR (ml/min/1.73m2)
77.50
0
HAEM (gr/dL)
14.50
0
WBC (106/ml)
6.80
0
72
0
0.22
NA
Cigarettes/day
12
NA
Alcohol consumption (Oz/week)
9*
NA
Racial Characteristics
Proportion White
0.92
NA
Proportion Black
0.03
NA
Proportion Hispanic
0.05
NA
Proportion Native American
0
NA
Proportion Asian/Pacific Islander
0
NA
Baseline cardiovascular disease complications
Proportion myocardial infarction
0
NA
Heart rate (bpm)
Proportion smoker
0.00298**
NA
0
NA
0.00298¥
NA
Proportion heart failure
0
NA
Proportion atrial fibrillation
Proportion left ventricular
hyperthrophy
Baseline renal complications
0
NA
0
NA
Proportion microalbuminuria
0.181
NA
Proportion gross proteinuria
0
NA
Proportion end stage renal disease
0
NA
0
NA
Proportion angina
Proportion peripheral vascular disease
Proportion stroke
Baseline retinopathy complications
Proportion background diabetic
retinopathy
Source
Nathan et al 200993
Bergenstal et al37
Default IMS CDM
value2, 77 (not used in
our analyses)
National diabetes
audit92
Opinions and
Lifestyle Survey,
Smoking Habits
Amongst Adults,
201294
WHO Global Status
Report on Alcohol
201195
National diabetes
audit92
Assumption
England Health
Survey 201196
Assumption
England Health
Survey 201196
Assumption
National diabetes
audit92
Assumption
Assumption
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Parameter
Proportion proliferative diabetic
retinopathy
Proportion severe vision loss
Source
Mean
SD
0
NA
0
NA
Proportion macular oedema
0
NA
Assumption
Baseline cataract
Proportion cataract
0
NA
Assumption
Baseline foot ulcer complications
Proportion uninfected ulcer
0
NA
Proportion infected ulcer
0
NA
Proportion healed ulcer
0
NA
Proportion history of amputation
0
NA
Baseline neuropathy
Proportion neuropathy
0.049
NA
Nathan et al 200993
Baseline depression
Proportion depression
0.21
NA
Hopkins et al 201297
Baseline macular oedema
*
Assumption
13.37 litres per year; ** Angina in 25 - 34 age group; ¥ Stroke in 25 - 34 age group.
5.3.2 Costs
Direct costs included in the model are:
 management (for primary prevention of complications),
 diabetes-related complications,
 treatment of diabetes (this includes also the costs of pump and/or glucose monitor)
and
 other hospital costs.
Indirect costs parameters were set to 0 in the model as these were not included in our
analyses, given the perspective of the NHS. Treatment costs are not included in the PSA since
it is not possible in the current version of the IMS CDM as the model developers argue that
the uncertainty around the pharmacy/treatment administration costs is very small.
All other direct costs can be included in the PSA. Although in other economic evaluations
cost parameters are typically sampled from different distributions independently, in the IMS
CDM all direct costs are multiplied by the same positive factor which is sampled from a
lognormal distribution with a mean equal to 1 and a user-defined coefficient of variation. In
line with the updated clinical guidelines,3 for our analyses we assumed 20% deviation from
the mean as it is assumed that this would represent a reasonable range of variation. A detailed
description for all four direct cost groups is given below.
5.3.2.1 Disease management unit costs
Management costs include the costs of managing chronic conditions, performing screening
procedures, administering concomitant medication, etc. All costs were sourced from the
update of CG153 and when necessary were further inflated to 2014 prices using the 2013/14
HCHS index available in PSSRU 2014.98 Management costs used in our analyses can be seen
in Table 29.
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Table 29: Management costs in type 1 diabetes patients
Management type
Mean cost per year
ACE-inhibitors
£18.541
Statin
£38.222
NHS Drug Tariff 201499
3
Aspirin
£13.70
Screening for microalbuminuria
£3.124
Screening for gross proteinuria
£2.945
Stopping ACE-inhibitors
due to adverse events
Eye screening
£19.966
NHS Drug Tariff 201499
£35.38
Assumption7
Foot screening program
£42.468
NHS reference cost 2012/13101
£0
Default value in IMS CDM
Anti-depression treatment
and management
£494.44
Updated CG153
Screening for depression
£0
Non-standard ulcer treatment
(for example Regranex)
1
Source
2
Lamb et al 2009100
Assumption9
3
Average cost of 5 generics; Atorvastatin 80mg 28 days; Following ischemic event; 75mg 28 days;
Weighted: 80% once per year; 20% three times per year; unit cost £2.16; 5 2 per year; unit cost £1.42;
6
28 days of Angiotensin receptor antagonist (losartan 50mg or candesartan 8mg); 7 Based on annual
national cost of £70m for 2 million diabetics screen once per year (based on personal communication
of the CG development group with UK National Screening Committee, Dec 2013); 8 Podiatrist
outpatient visit; 9 Included in cost of anti-depression treatment and management.
4
5.3.2.2 Costs of diabetes-related complications
Both ongoing disease complications and acute events are considered here. Costs of ongoing
complications are considered per year until the complication is resolved or the patient dies.
Costs of acute events are assumed to occur only at the time of the event. Costs of the diabetes
complications were sourced from the updated CG153 and when necessary were inflated to
2014 prices using the 2013/14 HCHS index available in PSSRU 2014.98 These can be seen in
Table 30.
Table 30: Costs of type 1 diabetes-related complications
Type of complication
Mean cost
CVD complications
Myocardial infarction, first year
£3,731
Myocardial infarction, each subsequent year
£788
Angina, first year
£6,406
Angina, each subsequent year
£288
Congestive heart failure, first year
£3,596
Congestive heart failure, each subsequent
£2,597
year
Stroke, fatal (within 30 days)
£1,174
Stroke, non-fatal first year
£4,170
Stroke, each subsequent year
£155
Peripheral vascular disease, first year
£952
Peripheral vascular disease, each subsequent
£529
year
Renal complications
Haemodialysis, each year
£30,819
Peritoneal dialysis, each year
£24,793
Source
NICE Lipids guideline
CG181*102, 103
NICE Peritoneal Dialysis
clinical guideline, CG125
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Type of complication
Renal transplant, first year
Renal transplant, each subsequent year
Acute events (cost per event)
Severe hypoglycaemic event
Minor hypoglycaemic event
Ketoacidosis event
Eye disease
Laser treatment
Cataract operation
Following cataract operation
*
Mean cost
£20,600
£7,694
£439
£0
£0
£705
£1,035
£81
Blindness, year of onset
Blindness, each subsequent year
Neuropathy/foot ulcer/amputation
Neuropathy, each year
£5,647
£5,456
Amputation, event based
Amputation with prosthesis, event based
£11,416
£15,420
Gangrene treatment
Healed ulcer
Infected ulcer
Uninfected ulcer
Healed ulcer with history of amputation
£5,483
£266
£7,410
£4,115
£25,577
£362
Source
(2011)104
Updated CG153
NHS reference cost
2012/13: BZ24D Nonsurgical ophthalmology
with interventions101
Weighted NHS reference
cost 2012/13: Nonphacoemulsification
cataract surgery, with
Complication score 0
(BZ03A) and score 1+
(BZ03B)101
NHS reference cost
2012/13: WF01A: Nonadmitted face to face
attendance,
ophthalmology followup101
NICE Glaucoma clinical
guideline, CG85105, 106
MIMS April 2014 (online
version), Duloxetine 60
mg daily (first-line
treatment in CG96)107, 108
NICE Lower limb
peripheral arterial disease
(PAD) clinical guideline
(CG147)109, 110
Ghatnekar et al 2002111
Insight Health Economics
2012109, 110, 112
NICE Lower limb
peripheral arterial disease
(PAD) clinical guideline
(CG147)109, 110
It was assumed that one third of angina episodes would be unstable and two thirds would be stable.
5.3.2.3 Treatment costs
Sensor-augmented pump therapy
In addition to the cost of the MiniMed Paradigm Veo System and the Vibe and G4
PLATINUM CGM system, a number of consumables are needed. These are cannulas,
reservoirs and batteries for the insulin pump and sensors for the CGM device. Prices and
expected lifetime of devices and consumables were reported by the companies. To estimate
equipment costs of the devices the following assumptions were made:
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





Four year lifetime for insulin pumps.
Cannulas and reservoirs would be replaced every three days.
MiniMed Paradigm Veo requires one Energizer AAA alkaline battery. An estimated
replacement time of 8.5 days was assumed (the lifetime of the battery is dependent on
the quality of the battery, the pump use and temperatures, etc).
The Animas Vibe operates on one AA battery. Lithium Batteries are recommended.
The expected battery lifetime is five weeks (35 days) (CGM components are supplied
with a rechargeable battery and a charger).
The MiniLink transmitter is replaced each year and the sensors every six days.
The G4 Platinum is replaced every six months and the sensors every seven days.
Table 31 presents the estimated yearly equipment costs for the MiniMed Paradigm Veo
system and the Vibe and G4 PLATINUM CGM system.
Table 31: Equipment costs of MiniMed Paradigm Veo system and Vibe/G4 Platinum CGM
system based on 2014 costs
Cost component
MiniMed Paradigm Veo
Vibe/G4 Platinum
System
CGM
Insulin pump
£2,679
£2,800
Cannula
£8.70
£9.75
Reservoir
£2.68
£2.46
Batteries
£0.49
*
£1.77**
CGM transmitter
£228.70
£335.0
Sensor
£42.05
£46.50
£2,961.62
£3,195.48
4
4
121.67 (3)
121.67 (3)
121.67 (3)
121.67 (3)
42.94 (8.5)
10.42 (35)
1
0.5
60.83 (6)
52.14 (7)
£4,862.10
£5,298.65
Total Device Cost
Years of use - Insulin pump
Units per year – Cannula
(days of use)
Units per year – Reservoir
(days of use)
Units per year – Batteries
(days of use)
Years of use - CGM
transmitter
Units per year – Sensor
(days of use)
Total cost per year
*
Energizer classic AAA batteries (4 pack)
**
Energizer ultimate lithium AA batteries (4 pack)
Continuous subcutaneous insulin infusion (stand-alone insulin pumps)
The average price of a stand-alone insulin pump in UK was sourced from a study from the
London New Drugs Group in November 2013.113 These were inflated to 2014 prices using the
2013/14 HCHS index available in PSSRU 201498 and can be seen in Table 32. An estimated
market share for each brand has been calculated based on White et al 2013.114, 115 Based on
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this information the estimated weighted average price for a stand-alone pump in UK is
£2,173.54.
Table 32: Price and market share of stand-alone insulin pumps in UK
Cost component
Accu-Chek Dana Animas Medtronic mylife
(all costs net of VAT)
Spirit
Vibe
Paradigm Omnipod
*
*
*
Insulin pump
£2,523
£1,972 £2,831
£2,882*
£425*
Estimated Annual Cost
£631
£493
£708
£720
£106
Estimated Annual Consumables
Cost
£1,324
£1,400
£1,663
£1,282
£3,052
Total cost per year
£1,955
£1,893
£2,371
£2,002
£3,158
30%
3%
23%
35%
9%
(based on 4 years of life)
UK estimated market share¥
Average cost per year
£2,173.54
*
Quoted price for London New Drugs Group November 2013 (produced for use within the NHS) 113
inflated to 2014 prices using the 2013/14 HCHS index available in PSSRU 2014;98 ¥UK market share
per brand derived from White et al. 2013114, 115
Continuous glucose monitoring (stand-alone)
We followed the approach in the updated CG153 and considered the three main CGM
technologies available in the UK: Dexcom G4, Abbott Freestyle Navigator, and Medtronic
Guardian. The items included were receivers, transmitters and sensors. Costs of the three
receivers were sourced from the updated CG15.3 Transmitter and sensor costs and usage for
the Dexcom G4 and the Medtronic Guardian were assumed to be the same as for integrated
systems in Table 31, since this was mentioned by the companies. For the Abbott Freestyle
Navigator sensor costs (there is no transmitter) and usage were assumed to be the same as
reported in the updated CG15.3 Finally, a yearly weighted average cost equal to £3,087.75
was estimated based on the estimated market share from White et al 2013.114, 115 This can be
seen in Table 33.
Table 33: Price and market share of stand-alone CGM devices in UK in 2014
Cost component
Dexcom G4
Freestyle
Medtronic
Navigator
Guardian
CGM receiver
£1,750
£950
£1,059
CGM transmitter
Sensor
Total equipment cost
Years of use – CGM receiver
Years of use – CGM
transmitter
Units per year – Sensor
£335
£0
£228.70
£46.50
£48
£42.05
£2,131.50
£998
£1,329.75
5
5
5
0.5
0
1
52.14 (7)
60.83 (6)
60.83 (6)
£3,444.64
£3,110.00
£2,998.54
15%
20%
65%
(days of use)
Total cost per year
UK estimated market share
Average cost per year
£3,087.75
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Blood glucose tests costs
Glucose tests are needed in all interventions and comparators. Each time a blood glucose test
is conducted a lancet and a test strip are consumed. The estimated cost of a single blood
glucose test (computed as the average of all marketed lancets and test strips) is £0.29
according to the updated CG15.3 We assumed that blood glucose meters are supplied free of
charge. The number of blood glucose tests required for the different interventions and
comparators depend on the method of monitoring glucose, whether it is manual (SMBG) or
continuous (CGM). Our systematic review identified only two studies reporting the number of
blood glucose tests.7, 10 Based on these studies, we defined on average four blood glucose tests
per day for both SMBG and CGM for the base case. Based on clinical opinion, this choice
seems to be somewhat counterintuitive as it would be expected a higher number of tests for
SMBG rather than for CGM. However, we believe that trial values are generally more valid
and consistent within our analyses given that the estimate of effectiveness comes from the
trials and there is likely to be a correlation between frequency of monitoring and outcome.
Nevertheless, since there was some uncertainty around these values, other options were
explored in scenario analyses. Yearly costs associated to self-monitoring of blood glucose for
the base case are shown in Table 34.
Table 34: Comparison of blood glucose tests costs
Cost component
CGM and SMBG
Cost single blood glucose test
Number of tests per day
Total number of tests per year
Total yearly cost
£0.29
4
1460
£423.40
Insulin costs
Both SAP and CSII therapies use short-acting insulin. Based on expert opinion we assumed
the same type and amount of short-acting insulin for both technologies. Following the
approach in the updated CG153 only the cartridges and pre-filled pens were used to calculate
the costs of short-acting insulin. For the base case we assumed 48 units per day of shortacting for pumps as in Bergenstal et al.37 and the updated CG15.3 This choice was validated
by clinical experts/committee members. Total insulin costs per year for patients on insulin
pumps can be seen in Table 35.
Table 35: SAP and CSII (short-acting) insulin costs
Short-acting insulin Cartridges & pens
Insulin Aspart
5 x 3 ml cartridges
5 x 3 ml FlexPen prefilled
5 x 3 ml FlexTouch prefilled
Insulin Glulisine
5 x 3 ml cartridges
5 x 3 ml SoloStar prefilled
Insulin Lispro
5 x 3 ml cartridges
5 x 3 ml KwikPen prefilled
Average insulin cost SAP/CSII
*
Unit cost
£28.31
£30.60
£32.13
£28.30
£28.30
£28.31
£29.46
£29.34
Cost per unit
of insulin*
£0.0188
£0.0204
£0.0214
£0.0188
£0.0188
£0.0188
£0.0196
£0.0196
Yearly cost
per patient**
£330.66
£357.41
£375.28
£330.54
£330.54
£330.66
£344.09
£342.74
Unit cost divided by 1500. ** Based on 48 units per day.
Based on clinical opinion we assumed that patients on MDI would use a regimen with basal
(long-acting) insulin once or twice daily, and bolus (short-acting) insulin with meals, three
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times per day. Furthermore, the updated CG153 concluded that it is likely that insulin detemir
twice daily is the most cost-effective long-acting insulin regimen for people with type 1
diabetes. Therefore, we assumed this for the base case. Based on the information from our
clinical experts we also assumed that the number of insulin units would split 50:50 between
basal and bolus. For the base case we also assumed 48 units per day for MDI as in the
updated CG15.3 Thus, we assumed 24 units per day of long-acting insulin and 24 units per
day of short-acting insulin. The unit cost of the needles was assumed to be £0.11 as in the
updated CG15.3 This was calculated as a weighted average of the prices of the 10 most
commonly used needles, according to Prescription Cost Analysis, England data.116 The annual
cost of needles per patient was then calculated based on a frequency of five injections per day
(long-acting twice daily and short-acting insulin three times per day) as mentioned above.
Total insulin costs (including costs of the needles) per year for patients on MDI can be seen in
Table 36.
Table 36: MDI (long-acting insulin detemir and short-acting insulin) costs
Cost item
Unit cost
Cost per unit
of insulin*
Long-acting insulin detemir
£42.00
£0.0280
Short-acting insulin
£29.34
£0.0196
Needles
£0.11
Total insulin cost MDI
*
Yearly cost
per patient
£245.28**
£171.35**
£200.75±
£617.38
Unit cost divided by 1500. ** Based on 24 units per day. ± Based on five injections per day.
There was some uncertainty around the assumption of equal amount of insulin for pumps and
MDI. Clinical experts have different opinions about this as some of them would expect a
reduction in insulin for pumps with respect to MDI (14% according to Cummins et al.
201078). Therefore, we explored this in a separate scenario.
5.3.2.4 Other hospital costs
Outpatient care related costs
Outpatient care related costs (consultant, diabetic specialised nurse) were estimated based on
clinical expert opinion. We assumed that in the first year during the pump initiation there
were seven appointments and three group sessions of 45 minutes each with diabetic specialist
nurses in a six month period. After the pump initiation period, but still during the first year,
we assumed two appointments of 45 minutes with a consultant and two appointments of 45
minutes with a diabetic specialised nurse. Therefore, in total we assumed for the first year
nine appointments and three group sessions of 45 minutes with a diabetic specialised nurse,
and two appointments of 45 minutes with a consultant. Each subsequent year we assumed two
appointments of 45 minutes with a consultant and two appointments of 45 minutes with a
diabetic specialised nurse. For patients on MDI we assumed two appointments of 45 minutes
with a consultant and two appointments of 45 minutes with a diabetic specialised nurse every
year. NHS outpatient follow-up tariff is £99.117 Total outpatient costs for the base case can be
seen in Table 37.
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Table 37: Annual outpatient care related costs
Outpatient costs
Year 1
Year 2+
Average yearly cost (based on 80 years time horizon)
Insulin pump
£1,386.00
£396.00
£408.38
MDI
£396.00
£396.00
£396.00
HbA1c tests costs
Cost and frequency of HbA1c tests were also estimated based on clinical expert opinion. We
assumed that on average this test would be performed three times a year. The cost of the test
will depend on the hospital, lab, etc. where the test would be performed. Based on the average
of three hospital prices we assumed £3.14 as the average price for an HbA1c test.
5.3.2.5 Summary of treatment and other hospital costs
A summary of treatment-related costs for the six technologies considered in this study can be
seen in Table 38.
Table 38: Summary of annual treatment-related costs per technology
Technology
Equipment +
Blood
Insulin Outpatient
consumables
glucose
tests
£4,862.10
£423.40
£342.74
£379.50
MiniMed Veo system
£5,298.65
£423.40
£342.74
£379.50
Integrated CSII+CGM
(Vibe)
£5,261.29
£423.40
£342.74
£379.50
CSII+CGM
£2,166.13
£423.40
£342.74
£379.50
CSII+SMBG
£3,288.50
£423.40
£617.38
£368.00
MDI+CGM
£200.75
£423.40
£617.38
£368.00
MDI+SMBG
HbA1c
tests
Total
£9.42
£9.42
£6,017.16
£6,453.71
£9.42
£9.42
£9.42
£9.42
£6,416.35
£3,321.20
£4,706.69
£1,618.95
Superseded –
see Erratum
5.3.3 Utilities
Health benefits were expressed in terms of life years and quality-adjusted life years (QALYs)
gained. When more than one complication occurs at the time a multiplicative approach is
applied.118 For the PSA utility and disutility values are sampled from a beta distribution*. The
utilities used in the model are summarised in Table 39.
*
Mean and standard deviation are inputs of the IMS CDM which are parameterized into parameters a
and b of the Beta distribution as follows: a = ((mean2)*(1-mean)/(sd2)); b = (mean*(1-mean)/(sd2))((mean2)*(1-mean)/(sd2)).
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Table 39: Utilities per health state
Mean (dis)utility
value
0.814
-0.055
SE
Source
0.01
0.01
Myocardial infarction, after event
0.759
0.01
Clarke et al 2002119
Beaudet et al 201476
Equal to no
complication minus
event
Angina
Chronic heart failure
Stroke, event year
0.695
0.677
-0.164
0.01
0.01
0.01
Stroke, after event
0.650
0.01
Peripheral vascular disease
0.724
0.01
Microalbuminuria
0.814
0.01
Gross proteinuria
Haemodialysis
Peritoneal dialysis
Renal transplant
Background diabetic retinopathy
Background diabetic retinopathy
wrongly treated
Proliferative diabetic retinopathy laser
treated
Proliferative diabetic retinopathy no
laser treated
Macular oedema
Severe vision loss
Cataract
Neuropathy
0.737
0.621
0.581
0.762
0.745
0.01
0.03
0.03
0.12
0.02
0.745
0.02
0.715
0.02
0.715
0.02
0.745
0.711
0.769
0.701
0.02
0.01
0.02
0.01
Healed ulcer
0.814
0.01
Equal to no
complication
Active ulcer
Amputation event year
0.615
-0.280
0.01
0.01
Beaudet et al 201476
Amputation after event
0.534
0.01
Severe hypoglycaemic event
Minor hypoglycaemic event
-0.012
0
0.00
0.00
Fear of hypoglycaemic event
0
0.00
Ketoacidosis event
Depression non-treated
0
0.6059
0.00
0.00
Depression treated
0.814
0.00
Health state
Type 1 diabetes with no complication
Myocardial infarction, event year
Beaudet et al 201476
Equal to no
complication minus
event
Beaudet et al 201476
Equal to no
complication
Beaudet et al 201476
Equal to no
complication minus
event
Currie et al 2006120
Assumption
Included in the
disutility for severe
hypoglycaemic event
Assumption
Goldney et al 2004121
Equal to no
complication
5.3.4 Treatment effects
We used reduction in HbA1c baseline level and number of severe hypoglycaemic events as
the outcomes to characterise treatment effectiveness. We considered using the number of
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minor hypoglycaemic and ketoacidosis events as well but not enough reliable data was found
to make comparisons.
For HbA1c a baseline value has to be established onto which the treatment effect is applied.
This is the value at the start of treatment (time zero). The mean (SE) baseline value was
7.26% (0.71), based on the relevant population, as shown in Table 28. Treatment effects were
then estimated as the mean reduction from the baseline value from our systematic review. An
indirect meta-analysis was conducted to estimate the weighted mean difference between the
MiniMed Paradigm Veo system and integrated CSII+CGM (used to inform the Vibe and G4
PLATINUM CGM system), CSII+CGM, CSII+SMBG, MDI+CGM and MDI+SMBG. Due
to lack of published clinical data, MDI+CGM had to be excluded from the analysis (see
Figure 8, Chapter 4.2.5) and treatment effects of integrated CSII+CGM and non-integrated
CSII+CGM were assumed to be identical (see Figure 8 and Table 21, Chapter 4.2.5). After
calculating the change in HbA1c from baseline in Bergenstal et al 201337 as -0.02, the change
in HbA1c for other treatments could be found. These values are listed in Table 40.
Table 40: Mean (SE) change in HbA1c with respect to baseline for all treatments included in
the analysis
Treatment
Mean (SE) change in HbA1c compared to baseline
MiniMed Veo system
-0.02 (0.04)
Integrated CSII+CGM (Vibe)
-0.06 (0.05)
CSII+SMBG
0.05 (0.12)
MDI+SMBG
0.64 (0.19)
CSII+CGM
-0.06 (0.05)
Since there is uncertainty and limitations in the indirect meta-analysis (due to heterogeneity
and differences in baseline HbA1c levels), to explore the impact of different HbA1c change
levels, we analysed a hypothetical situation in which the baseline HbA1c levels do not change
after the initiation of the treatment in a separate scenario. Note that in the IMS CDM the
change in HbA1c level is assumed to occur within the first 12 months. After this, an annual
progression rate is applied. In the base case we followed the approach in the CG15 update,3 in
which an annual progression of 0.045% (derived from type 1 diabetes trial, DCCT87) was
used in the base case.
For severe hypoglycaemic events it is not needed to set a baseline values since the IMS CDM
assumes that this is a treatment-specific parameter. Treatment effects were estimated as the
rate ratio (RR) of event rates per 100 patient years obtained from our systematic review (see
Figure 9 and Table 22, Chapter 4.2.5). This was then applied to a reference value for
integrated CSII+CGM, which was derived from a weighted average (by sample size) of the
event rates observed in the CSII+CGM arms of the trials. These values can be seen in Table
41.
Table 41: Rate per 100 patient years of severe hypoglycaemic episodes for all treatments
included in the analysis
Treatment
Rate per 100 patient years of severe
hypoglycaemic episodes
MiniMed Veo system
1.9584
Integrated CSII+CGM (Vibe)
16.32
CSII+SMBG
5.0215
MDI+SMBG
19.584
CSII+CGM
16.32
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For the PSA treatment effects at baseline on HbA1c are sampled from a beta distribution
(mean and standard deviation are converted into beta distribution specific parameters as
explained with the utilities). Event rates of severe hypoglycaemic events are fixed in the IMS
CDM and therefore they are not included in the PSA. In order to explore the uncertainty of
the effects of severe hypoglycaemic episodes on long-term outcomes several scenarios with
different treatment-specific rates were analysed. These scenarios are described in Chapter
5.4.2.6.
5.3.5 Disease management parameters
These parameters will determine the proportion of patients that will receive disease
management regimens such as preventative treatments or screening programs. These
parameters and their sources can be seen in Table 42. With the exception of the proportion on
UK-specific foot ulcer prevention program, for which we followed the approach in the
updated CG15,3 the majority of the inputs are the default values from the IMS CDM, and
were used in the updated clinical guideline as well.
Table 42: Disease management parameters
Parameter
Concomitant medication
Proportion primary prevention aspirin
Proportion secondary prevention aspirin
Proportion primary prevention statins
Proportion secondary prevention statins
Proportion primary prevention ACE-inhibitors
Proportion secondary prevention ACE-inhibitors
Screening and patient management proportions
Proportion on foot ulcer prevention program
Proportion screened eye disease
Proportion screened for renal disease
Proportion receiving intensive insulin after
myocardial infarction
Proportion treated with extra ulcer treatment
Proportion screened for depression - no
complications
Proportion screened for depression - complications
Others
Reduction in incidence foot ulcers with Prevention
Program
Improvement in ulcer healing rate with extra ulcer
treatment
Reduction in amputation rate with foot care
Sensitivity eye screening
Specificity eye screening
Sensitivity gross proteinuria screening
Sensitivity microalbuminuria screening
Specificity microalbuminuria screening
Mean value
Source
0.456
0.755
0.450
0.878
0.500
0.708
Minshall et al 2008122
Gerstein et al 2008123
Minshall et al 2008122
Gerstein et al 2008123
Minshall et al 2008122
Gerstein et al 2008123
0.992
1.000
1.000
National diabetes Audit124
No data
No data
0.877
McMullin et al 2004125
0.570
Lyon 2008126
0.830
Jones et al 2007127
0.830
0.310
O’Meara et al 2000128
1.390
Kantor et al 2001129
0.340
0.920
0.960
0.830
0.830
0.960
O’Meara128
Lopez-Bastida et al 2007130
Cortes-Sanabria et al 2006131
5.3.6 Disease natural history parameters
These are the parameters that will determine the natural course of the disease. These
parameters are either transition probabilities i.e. probability of each of the events (e.g. diabetic
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retinopathy, MI) or the (relative) risk of an event given a particular risk factor (which are
based on physiological measures like HbA1c, BMI or SBP or characteristics like presence of
microalbuminuria). We considered the same values as in the updated CG15,3 where most of
the values were not changed from the IMS CDM default values. For that reason and because
the number of parameters is so large that it may distract the reader’s attention we have
decided to show these parameters in Appendix 6.
It should be noted that one of this parameters is the probability of death from severe
hypoglycaemic event. In line with the updated CG153 this was assumed to be zero for the
base case. However, as deaths due to severe hypoglycaemic events have been reported,132, 133
we expect that this parameter may have impact on our results, as one of the key features of the
MiniMed Paradigm Veo is the LGS function which was shown to reduce the number of
severe hypoglycaemic events, and thus the number of deaths caused by severe
hypoglycaemia. Therefore, other options for this mortality rate were explored in additional
scenarios.
5.4
Sensitivity and scenario analyses
5.4.1 Probabilistic sensitivity analysis
Probabilistic sensitivity analysis (PSA) was used to explore the impact of statistical
uncertainties regarding the model’s input parameters. PSA is an in-built feature of the IMS
CDM, activated if the (2nd order with sampling) option is selected.
PSA results were presented in the cost-effectiveness plane for all the treatments compared.
Cost-effectiveness acceptability curves (CEACs) were used to describe the probability of a
treatment being considered cost-effective given a threshold incremental cost-effectiveness
ratio (ICER). The probability distributions used in the PSA are described throughout Chapter
5.3.
5.4.2 Scenario analyses
Scenario analyses were performed to explore the impact on costs and QALYs of using
different assumptions on the baseline population characteristics, on the number of blood tests
(finger pricks) conducted per day, on the amount of insulin used, on the inclusion of HbA1c
progression after year one, on treatment effects (both in terms of HbA1c level change and in
terms of number of severe hypoglycaemic episodes per treatment), on the inclusion of a
nonzero death probability due to hypoglycaemia, on time horizon, on QALY estimation
methods, on utility benefits associated with less fear of hypoglycaemia and on the cost of the
stand-alone insulin pump and continuous glucose monitoring devices.
5.4.2.1 Baseline population characteristics
The base case assumed baseline population characteristics as in the Bergenstal et al. trial37 In
this scenario, we considered general T1DM population as used in the updated CG15.3 Table
43 shows the patient characteristics that were changed for this scenario.
Table 43: Baseline characteristics that change with respect to the base case
Mean
Mean
Source
Parameter
SD
base case
scenario
Patient demographics
Nathan et al 200993
Start age (years)
41.6
42.98
19.14
Duration of Diabetes (years)
Proportion Male
27.1
0.38
16.92
0.567
13.31
NA
National Diabetes
Audit124
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Baseline risk factors
HbA1c (%-points)
Body Mass Index (BMI)
(kg/m2)
7.26
8.60
4.00
28.27
27.09
5.77
National Diabetes
Audit124
5.4.2.2 Number of blood glucose tests per day
In the base case we assumed four blood glucose tests (finger pricks) for interventions
containing CGM (the MiniMed Paradigm Veo system, integrated CSII+CGM and
CSII+CGM stand-alone) and four blood glucose tests for interventions containing SMBG
(CSII+SMBG and MDI+SMBG). This assumption was based on the results from the
systematic review, where no significant difference in number of tests between the CGM- and
SMBG-containing treatments was observed.7, 37.
In the sensitivity analysis, we followed the approach in the updated CG15 (Appendix P of the
guideline3), and considered two tests per day (for calibration) for CGM-containing treatments
and four tests per day for SMBG-containing treatments, since this is considered as the current
practice. Moreover, we have included eight (the most cost-effective frequency in the
guideline) and 10 times testing per day for SMBG-containing technologies versus two times
testing per day for CGM-containing technologies, as scenarios in our analysis. Unlike the
updated guideline scenarios (Appendix P of the guideline3), we assumed in our analyses that
the number of blood tests per day had no impact on the treatment effect, since such an effect
(e.g. more blood tests may lead to a higher HbA1c decrease) was not observed in our
systematic review. Finally, we also explored a scenario based on the observational study by
Lynch et al. 2012134 which reports an average number of 4.35 blood glucose tests per day for
CGM and 7.11 for SMBG. The costs related to blood glucose testing for the complete list of
the scenarios conducted are given in Table 44.
Table 44: Blood glucose tests and costs for the additional scenarios
Cost component
CGM
Cost single blood glucose test3
SMBG
£0.29
£0.29
2
4
Total number of tests per year (365 days)
730
1460
Total yearly cost (scenario 1)
£212
£423
2
8
Total number of tests per year (365 days)
730
2920
Total yearly cost (scenario 2)
£212
£847
2
10
Total number of tests per year (365 days)
730
3650
Total yearly cost (scenario 3)
£212
£1058.5
Number of tests per day (Lynch et al134)
4.35
7.11
Total number of tests per year (365 days)
1588
2595
Total yearly cost (Lynch et al)134
£460
£753
3
Number of tests per day
Number of tests per day3
3
Number of tests per day
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5.4.2.3 Amount of insulin per day
For the base case we assumed equal units of insulin per day for both MDI-containing
interventions (MDI+SMBG) and insulin pump-containing interventions (the MiniMed
Paradigm Veo system, integrated CSII+CGM, CSII+CGM stand-alone and CSII+SMBG).
However, some of the clinical experts mentioned that they would expect a reduction in insulin
for pumps with respect to MDI. In addition, Cummins et al 201078 reports a 14% reduction of
insulin use of pumps compared to MDI. From the findings of our systematic review, this
seems to be a reasonable assumption.7, 39, 135 Thus, for this scenario we assumed 48 units per
day of short-acting insulin for pump-containing treatments (which is the same as the insulin
use assumption in the base case given in Table 35) and 55 units of insulin per day (14%
increase) for MDI+SMBG treatment. It is also assumed that the insulin used in MDI+SMBG
is split 50:50 between basal and bolus (27.5 units per day of long-acting insulin and 27.5 units
per day of short-acting insulin). The costs pertaining to the insulin use for this scenario
analysis are given Table 45.
Table 45: MDI (long-acting insulin detemir and short-acting insulin) costs based on 55 units
per day
Cost item
Unit cost
Cost per unit
Yearly cost
of insulin*
per patient
Long-acting insulin detemir
£42.00
£0.0280
£281**
Short-acting insulin
£29.34
£0.0196
£196**
Needles
£0.11
£201±
£678
Total insulin cost MDI
*
Unit cost divided by 1500. ** Based on 27.5 units per day. ± Based on five injections per day.
5.4.2.4 HbA1c progression
In the base case analysis, the IMS CDM default value for the annual progression in HbA1c
after year one was used (0.045%). This value was based on the DCCT trial.87 In the updated
CG15,3 it was mentioned that the guideline development group expects that HbA1c levels in
type 1 diabetes patients tend to be more stable than in type 2 diabetes patients. Therefore, an
alternative assumption of no annual progression in HbA1c level (0%) was tested to gain
insight on the effects of HbA1c progression rate on costs and QALYs gained after year one.
5.4.2.5 Treatment effects part-I: HbA1c change in the 1st year
As explained in Chapter 5.3.2.3, treatment effects were estimated as the mean reduction from
the baseline HbA1c value obtained from our systematic review. The baseline HbA1c value
was taken from Bergenstal et al 201337 an indicative of a better controlled glycaemic control
than the patients in National Diabetes Audit.124 As an alternative scenario, we assumed that
the HbA1c value in the baseline is stabilised for one year and it does not change in any of the
treatments (0% change in HbA1c level in the first year).
5.4.2.6 Treatment effects part-II: severe hypoglycaemic event rates
Treatment-specific severe hypoglycaemic event rates were derived from our systematic
review, from which it was observed that the MiniMed Paradigm Veo system had fewer
reported severe hypoglycaemic events compared to the other treatments. In the scenario
analysis, we elaborate on this observation, and for all treatments other than the MiniMed
Paradigm Veo system, we assumed a uniform event rate for severe hypoglycaemia (16.32 per
100 patient years) and applied different relative risks (RR=1, 0.5, 0.25 and 0.125) for the
severe hypoglycaemic event rate for the MiniMed Paradigm Veo system. Note that the value
16.32 stems from the indirect comparison as explained in Chapter 5.3.4, and is the weighted
mean for the severe hypoglycaemic event rate for integrated CSII+CGM, which is chosen as a
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reference treatment in this case, because the number of studies (n=6) that the weighted
average rate was based on is the highest for integrated CSII+CGM and the Bergenstal et al
trial,37 from which the baseline population characteristics were derived, is one of these six
studies.
In addition, we conducted a scenario analysis in which a higher severe hypoglycaemic
episode rate from Hirsch et al4 is taken as the baseline rate for integrated CSII+CGM, and the
RRs from the indirect comparison in Chapter 5.3.4 are applied for other treatments. Severe
hypoglycaemic episode rates (number of events per 100 patient years) are given in Table 46
for each scenario.
Table 46: Severe hypoglycaemia rates (no of events per 100 pt years) for different scenarios
Intervention
Scenario Scenario Scenario 3 Scenario 4: Scenario 5:
1 RR=1
2 RR=0.5 RR=0.25
RR=0.125 Hirsch4
MDI+SMBG
16.32
8.16
4.08
2.04
38.37
CSII+SMBG
16.32
16.32
16.32
16.32
10.20
CSII+CGM stand-alone
16.32
16.32
16.32
16.32
33
MiniMed Veo system
16.32
16.32
16.32
16.32
3.96
Integrated CSII+CGM
(Vibe)
16.32
16.32
16.32
16.32
33
5.4.2.7 Non-zero death probability due to severe hypoglycemia
In the base case, the case fatality rate for severe hypoglycemia was taken as zero. This
assumption is in line with the updated CG153 and systematic review results, since none of the
included studies reported a death due to severe hypoglycemia.
Superseded –
see Erratum
As an extreme scenario, as in CG15, we assumed a case fatality rate of 4.9%, derived from
Ben-Ami et al136, where five patients were reported to die among 102 patients who had druginduced hypoglycemic coma.
5.4.2.8 QALY estimation method
In the base case, a multiplicative approach is applied for the QALY estimation. This
approach, in which the utility values of multiple events are multiplied to derive an overall
utility in case of multiple events/complications, is considered to be appropriate in this
condition, where simultaneous complications develop frequently118. As a scenario analysis,
the minimum approach will be used as an alternative QALY estimation method, where the
minimum of the multiple health state utility values is applied for patients having a history of
multiple events.
5.4.2.9 Different time horizons
In the base case, a lifetime analysis is achieved by selecting 80 years as the model time
horizon. As scenario analyses, a four year time horizon (the average lifetime of an insulin
pump) was selected and the effect of this time horizon on the results was explored.
5.4.2.10 Fear of hypoglycaemia unawareness
In the STAR-3 trial,10 patients using integrated CSII+CGM devices demonstrated an
improvement from baseline values on the “worry” subscale of the Hypoglycemia Fear Survey
98, compared to the MDI group. Later in Kamble et al 2012,67 this improvement was
translated into a utility increment of 0.0329 using the EQ-5D questionnaire index. As a
scenario analysis, we applied this utility increment associated with less fear of hypoglycaemia
throughout the remaining lifetimes of patients using integrated devices (the MiniMed
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Paradigm Veo system and integrated CSII+CGM). This benefit is not applied to nonintegrated devices (CSII+CGM stand-alone, CSII+SMBG and MDI+SMBG), as these nonintegrated devices do not give a warning nor activate/stop releasing of insulin automatically
based on low blood glucose levels.
5.4.2.11 Cost of stand-alone insulin pump and continuous glucose monitoring device
In the base case analysis, the yearly device cost (equipment + consumables) of the stand-alone
CSII+CGM (£5,261.29) was estimated based on the market share obtained from White et al
2013.114, 115 As a scenario analysis, we considered the average costs without the weighting for
market share. Therefore, in this scenario the estimated yearly device cost of the stand-alone
insulin pump was £2,275.80 and £3,184.39 for the stand-alone CGM device. Thus, when the
other cost items are considered (insulin, blood glucose tests, outpatient and HbA1c tests), the
average yearly costs (without using any market share assumptions) of the stand-alone
CSII+CGM was £6,644.13. Hence, the cost of the stand-alone CSII+CGM combination
increased by £198.90 compared to the base case cost. In a similar manner, the yearly cost of
CSII+SMBG is increased by £102.26 compared to the base case cost. Due to these increases
in costs, stand-alone CSII+CGM becomes more expensive than integrated CSII+CGM (Vibe)
in this scenario. Since both technologies are assumed to have the same efficacy, integrated
CSII+CGM (Vibe) will dominate stand-alone CSII+CGM.
5.5
Model assumptions
The main assumptions made in our analyses are summarised in Table 47.
Table 47: Main model assumptions
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
General
For the base case scenario baseline population characteristics as in Bergenstal et al.
trial37 were assumed. In an additional scenario, we considered general type 1 diabetes
population characteristics as in the updated CG15.3
For the costs included in the PSA 20% deviation from the mean was assumed. This is in
line with the updated CG15.3
Costs of initiation training for insulin pumps and CGM were covered by outpatient
costs. This was based on clinical expert opinion.
Sensor-augmented pump therapy
4-year lifetime was assumed for insulin pumps.
Cannulas and reservoirs would be replaced every 3 days.
MiniMed requires one Energizer AAA alkaline battery. An estimated replacement time
of 8.5 days was assumed.
The Animas Vibe operates on one AA lithium battery. The expected battery lifetime is 5
weeks (35 days) when used with CGM and 8 weeks when used without CGM.
We assumed the same percentage of increase in battery lifetime for MiniMed when used
without CGM.
The MiniLink transmitter is replaced each year and the sensors every 6 days.
The G4 Platinum is replaced every 6 months and the sensors every 7 days.
Stand-alone insulin pumps
The assumptions made for integrated insulin pumps are also valid for stand-alone insulin
pumps.
Stand-alone continuous glucose monitoring
Transmitter and sensor costs and usage for the Dexcom G4 and the Medtronic Guardian
were assumed to be the same as for integrated systems. This was mentioned by the
companies.
For the Abbott Freestyle Navigator sensor costs and usage were assumed to be the same
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14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
as reported in the updated CG15.3
Blood glucose tests
For the base case we assumed on average 4 blood glucose tests per day for both SMBG
and CGM.
In the sensitivity analysis, we followed the approach in the updated CG153 and
considered 2 tests per day (for calibration) for CGM and 4 tests per day for SMBG since
this is considered as current practice. Moreover, in their base analysis 8 tests per day for
SMBG was the most cost-effective strategy.
We also explored a scenario based on the observational study by Lynch et al 2012134
which reports an average number of 4.35 blood glucose tests per day for CGM and 7.11
for SMBG.
We assumed that blood glucose meters are supplied free of charge.
Insulin
We assumed the same type and amount of short-acting insulin for both integrated and
stand-alone insulin pumps. This was based on expert opinion.
For the base case we assumed 48 units per day of short-acting for insulin pumps. This
was based on Bergenstal et al.37 and the updated CG15,3 and it was validated by clinical
experts.
Based on clinical opinion we assumed that patients on MDI would use a regimen with
basal (long-acting) insulin once or twice daily, and bolus (short-acting) insulin with
meals, three times per day.
The updated CG153 concluded that it is likely that insulin detemir twice daily is the most
cost effective long-acting insulin regimen for people with type 1 diabetes. Therefore, we
assumed this for the base case.
Based on clinical opinion we also assumed that the amount of daily insulin would split
50:50 between basal and bolus.
For the base case we assumed 48 units per day for MDI as in the updated CG15.3
In an additional scenario we assumed 48 units per day of short-acting for pumps as in
the base case and 55 units per day (14% increase as reported in Cummins et al. 201078)
for MDI.
Multiple daily injections
The unit cost of the needles was assumed to be £0.11 as in the updated CG15.3
The annual cost of needles per patient was then calculated based on a frequency of 5
injections per day (long-acting twice daily and short-acting insulin three times per day).
Outpatient care
We assumed that in the first year during the pump initiation there were 7 appointments
and 3 group sessions of 45 minutes each with diabetic specialist nurses in a 6 month
period.
After the pump initiation period, but still during the first year, we assumed 2
appointments of 45 minutes with a consultant and 2 appointments of 45 minutes with a
diabetic specialized nurse.
Each subsequent year we assumed 2 appointments of 45 minutes with a consultant and 2
appointments of 45 minutes with a diabetic specialized nurse.
For patients on MDI we assumed 2 appointments of 45 minutes with a consultant and 2
appointments of 45 minutes with a diabetic specialized nurse every year.
HbA1c tests
We assumed that on average this test would be performed 3 times a year.
The cost of the test will depend on the hospital, lab, etc. where the test would be
performed. Based on the average of three hospital prices we assumed £3.14 as the
average price for an HbA1c test.
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Treatment effects
33. Treatment effects are estimated as the mean reduction from the baseline value from our
systematic review. This reduction is assumed to occur up to 12 months. After this,
annual progression occurs. In the base case we followed the CG15 update,3 which chose
a type 1 diabetes trial, DCCT (annual progression of 0.045%) for the base case and no
progression in sensitivity analysis.
34. In the absence of data treatment effects of integrated CSII+CGM and non-integrated
CSII+CGM were assumed to be identical.
Disease natural history
35. The probability of death from severe hypoglycaemic event was assumed to be zero for
the base case.3 Other values were explored in separate scenarios.
5.6
Results of cost-effectiveness analyses
5.6.1 Base case results
The base case results from the full incremental analysis reported as cost per QALY gained
(ICER) per technology for type 1 diabetes adult patients are summarised in Table 48.
Table 48: Base case model results (all technologies) probabilistic simulation
QALYs
Cost
Incr. QALY Incr. Cost
MDI+SMBG
11.4146 £64,563
CSII+SMBG
11.9756 £90,436
0.561
£25,873
MiniMed Veo system
12.0412
£138,357
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
12.0604
£146,476
12.0604
£147,150
0.0849
£56,039
ICER
£46,123
Extendedly
dominated† by
CSII+CGM
stand-alone
£660,376
dominated by
CSII+CGM
stand-alone
† An extendedly dominated strategy has an ICER higher than that of the next most effective strategy.
Superseded –
see Erratum
First note that since the same treatment effects were assumed for CSII+CGM stand-alone and
integrated, the latter is dominated (effectiveness is the same as in the stand-alone technology
but the integrated technology is more expensive as can be seen in Table 38). As expected
MDI+SMBG is the cheapest treatment but also the one providing the lowest amount of
QALYs. The ICER of CSII+SMBG compared to MDI+SMBG is £46,123. MiniMed
Paradigm Veo is extendedly dominated by CSII+CGM stand-alone. Essentially this means
that in a full incremental analysis, where all the interventions and comparators are considered,
CSII+CGM is better value than MiniMed Veo. This is because from our systematic review
the decrease on HbA1c with respect to baseline was highest for CSII+CGM stand-alone, and
this relatively small decrease in HbA1c leads to a decrease in the number of complications
that occur over life time to such an extent that it compensates for the higher number of
hypoglycaemic events. In any case, the ICER of CSII+CGM stand-alone compared to
CSII+SMBG is £660,376. Thus, given the common threshold ICER of £30,000, it is clear that
CSII+CGM stand-alone is not cost-effective.
Alternatively, we present in Table 49 the base case ICERs for the two interventions against
every comparator. Integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone.
Note that when the MiniMed Veo system is compared to CSII+CGM stand-alone the ICER
obtained is high (£422,849) but that this comes from both negative incremental QALYs and
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incremental costs, i.e. the ICER is in the south-west quadrant of the cost-effectiveness plane.
In this case, the cost savings outweighs the loss in QALYs and therefore the MiniMed Veo
system is cost-effective compared to CSII+CGM stand-alone. This might not be immediately
apparent when looking at the full incremental results in Table 48 because there MiniMed Veo
is in position of extended dominance. The lowest ICERs are obtained when the interventions
are compared to MDI+SMBG, but these are above £100,000 in the north-east quadrant of the
cost-effectiveness plane. When the interventions are compared to CSII+SMBG the highest
ICERs are obtained (around £700,000 in the north-east quadrant of the cost-effectiveness
plane). Thus, given the common threshold ICER of £30,000 the interventions are not costeffective.
Table 49: Base case model results (intervention versus comparator only) probabilistic
simulation
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6266
£73,794
£117,769
MiniMed Veo system
CSII+SMBG
0.0656
£47,921
£730,501
MiniMed Veo system
CSII+CGM stand-alone
-0.0192
-£8,119
£422,849
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
£82,587
£127,883
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0849
£56,713
£668,789
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£674
undefined
In the deterministic simulation the cost-effectiveness results are very similar. These are shown
in Table 24. Although overall cost and QALY estimates are higher than in the probabilistic
simulation, the ICERs and the main conclusions from Table 50 are similar to the ones from
Table 48.
Superseded –
see Erratum
Table 50: Base case model results (all technologies) deterministic simulation
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
12.1450 £66,585
CSII+SMBG
12.7258 £93,433
0.5808
£26,847
£46,225
Extendedly dominated
MiniMed Veo system 12.8087 £143,309
by CSII+CGM standalone
CSII+CGM stand12.8223 £151,671
0.0965
£58,238
£603,495
alone
Integrated
Dominated by
12.8223 £152,372
CSII+CGM (Vibe)
CSII+CGM stand-alone
The base case ICERs for the two interventions against every comparator in the deterministic
simulation are shown in Table 51. These are similar to those in Table 49 and so are the
conclusions.
Table 51: Base case model results (intervention versus comparator only) deterministic
simulation
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6637
£76,723
£115,600
MiniMed Veo system
CSII+SMBG
0.0829
£49,876
£601,639
MiniMed Veo system
CSII+CGM stand-alone
-0.0136
-£8,363
£614,910
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6773
£85,787
£126,660
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0965
£58,939
£610,772
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£701
undefined
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When we looked at the break-down of the total costs, we observed that treatment costs always
represent the largest proportion of the total costs, independently of the treatment chosen. In
Figure 11, the treatment costs constitute 79% of the total direct costs for the MiniMed
Paradigm Veo system, and integrated and stand-alone CSII+CGM. For CSII+SMBG
treatment costs represent 66% of the total costs and for MDI+SMBG this is 45%. In each
treatment, foot ulcer/amputation/neuropathy cost category is the second largest, and eye
diseases and renal diseases are the third and fourth largest cost categories. MDI+SMBG has
higher complication (CVD, ulcer, eye disease, etc.) incidences, whereas for the other four
treatments these incidences are comparable. Lifetime hypoglycaemia events were reported the
least for the MiniMed Paradigm Veo system (0.622 severe hypoglycaemic events per patient),
and the highest for MDI+SMBG (5.412 severe hypoglycaemic event per patient).
Superseded –
see Erratum
Figure 11: Breakdown of costs per treatment
5.6.2 Results of the probabilistic sensitivity analyses
Statistical uncertainties in the model were investigated in the PSA. Since we compared five
treatments simultaneously, the scatter plot of the PSA outcomes in the cost-effectiveness (CE)
plane was not very informative (Figure 12). Nevertheless, we can observe a clear positive
correlation between costs and QALYs and that the treatments including CGM are similarly
scattered, showing that they are more expensive but also providing more QALYs.
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Figure 12: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
patients
Superseded –
see Erratum
The cost-effectiveness acceptability curves (CEACs) for each treatment are shown in Figure
13. These confirmed that only the treatments including SMBG are those considered costeffective. At ceiling ratio values lower than £46,123 MDI+SMBG was the treatment with the
highest probability of being cost-effective. When that threshold is exceeded then
CSII+SMBG was the treatment with the highest probability of being cost-effective. Note that
for all the three treatments including CGM the cost-effectiveness probability was zero for all
the ceiling ratios considered in the analysis. This is to be expected as the difference in costs
between CGM-treatments and SMBG-treatments was too large to outweigh the additional
QALYs gained by using CGM.
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Figure 13: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes patients
5.6.2.1 MDI non-suitable subgroup
As mentioned in Chapter 2.3 insulin pumps are recommended for people with type 1 diabetes
for whom MDI is not suitable. Therefore, we may question to what extent insulin pumps
(especially modern pumps such as the integrated systems) and MDI are used in comparable
populations. This seems a reasonable question in light of the lack of studies found in our
systematic review comparing these two treatments. When MDI+SMBG is not considered in
the analysis, the ICERs from the full incremental analysis are the same as those reported in
Table 48, but excluding the first row. It appears that CSII+SMBG is the strategy most likely
to be cost-effective, independently of the ceiling ratio value (up to 100,000/QALY), which
can be seen from Figure 14.
Superseded –
see Erratum
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Figure 14: Cost-effectiveness acceptability curves for all non-MDI treatments in type 1
diabetes patients
5.6.2.2 CGM-indicated/SMBG non-suitable subgroup
In the analysis for the CGM-indicated/SMBG non-suitable subgroup, we excluded SMBGbased treatment options from the analysis on the presumption that the most relevant
population is those who find it difficult to perform SMBG often or adequately enough. In this
situation integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone as shown in
Table 48. The only relevant comparison is then MiniMed Veo system versus CSII+CGM
stand-alone. The ICER is £422,849 (in the south-west quadrant of the cost-effectiveness
plane) as shown in Table 49. The corresponding acceptability curves are shown in Figure 15.
We can observe that MiniMed Veo is the CGM-treatment most likely to be cost-effective for
all the ceiling ratios considered in the analysis. However, as the ceiling ratio increases the
CEACs for MiniMed Paradigm Veo and CSII+CGM stand-alone seem to converge. As
expected, the CEAC for integrated CSII+CGM was always zero for all the ceiling ratios
considered in the analysis, since this was dominated by the stand-alone combination of
CSII+CGM.
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Figure 15: Cost-effectiveness acceptability curves for CGM treatments in type 1 diabetes
patients
5.6.3 Results of scenario analyses
In the scenarios presented below only the ICERs from the full incremental analysis are
discussed. The ICERs for the two interventions against every comparator are shown in
Appendix 8.
Superseded
see Erratum
–
5.6.3.1 Baseline population characteristics
In the scenario analysis, where the baseline population characteristics are updated as in the
updated CG15,3 the main results are comparable to the base case results as can be seen in
Table 52.
Table 52: Model results (all technologies), scenario with different baseline population
characteristics
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
9.6117
£68,049
CSII+SMBG
10.0991
£91,189
0.4874
£23,140
£47,476
Extendedly
dominated by
MiniMed Veo system
10.1474
£132,149
CSII+CGM
stand-alone
CSII+CGM stand-alone
10.164
£139,157
0.0649
£47,967
£738,593
dominated by
Integrated CSII+CGM
10.164
£139,733
CSII+CGM
(Vibe)
stand-alone
MDI+SMBG is the intervention with minimum costs and QALYs gained. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERs of £47,476/QALY and
£738,593/QALY, respectively. Thus, given the common threshold ICER of £30,000 they are
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not cost-effective. MiniMed Veo and integrated CSII+CGM are extendedly dominated and
dominated, respectively, by CSII+CGM stand-alone.
5.6.3.2 Number of blood glucose tests per day
All the scenarios listed in Table 44 gave similar results. Compared to the base case, costs
decreased in the scenarios for treatments that require less than four blood glucose tests per
day and increased otherwise. Since all results were similar, we only present in Table 53 the
full incremental cost-effectiveness results of the scenario with two blood glucose tests per day
for CGM-containing treatments and eight blood glucose tests per day for SMBG. These eight
tests per day for SMBG represent the most cost-effective frequency as was shown in the
updated CG15.3
Table 53: Model results (all technologies), scenario with two (CGM) versus eight (SMBG)
blood glucose testing per day
Incr.
QALYs
Cost
Incr. Cost
ICER
QALY
MDI+SMBG
11.4146
£71,973
CSII+SMBG
11.9756
£98,034
0.561
£26,061
£46,459
Extendedly
dominated by
MiniMed Veo system
12.0412
£138,357
CSII+CGM
stand-alone
CSII+CGM stand-alone
12.0604
£146,476
0.0849
£48,441
£570,844
Integrated CSII+CGM
dominated by
(Vibe)
12.0604
£147,150
CSII+CGM
stand-alone
Superseded
see Erratum
–
MDI+SMBG is the intervention with minimum costs and gain in QALYs. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERS of £47,476/QALY and
£738,593/QALY, respectively. Therefore, given the common threshold ICER of £30,000 they
are not cost-effective. MiniMed Veo and integrated CSII+CGM are extendedly dominated
and dominated, respectively, by CSII+CGM stand-alone.
5.6.3.3 Amount of insulin per day
In this scenario the costs in MDI+SMBG increased but this had a very small impact on the
cost-effectiveness results since all QALYs and the costs of the other treatments remained
unchanged. Since the main conclusions of the cost-effectiveness analyses were the same in
this scenario as in the base case, we do not present the results in a separate table for this
scenario here but in Appendix 8.
5.6.3.4 HbA1c progression
In this scenario no HbA1c progression after year one was assumed for each treatment. Table
54 summarises the model results.
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Table 54: Model results (all technologies), scenario with no HbA1c progression
Incr.
QALYs
Cost
Incr. Cost
QALY
MDI+SMBG
11.8715
£62,127
CSII+SMBG
12.4558
£88,663
0.5843
£26,536
MiniMed Veo system
12.5228
£137,739
0.0669
£49,076
CSII+CGM stand-alone
12.5398
£146,076
0.0840
£57,414
Integrated CSII+CGM
(Vibe)
12.5398
£146,767
0
£690
ICER
£45,413
Extendedly
dominated
by
CSII+CGM
stand-alone
£683,889
Dominated
by
CSII+CGM
stand-alone
MDI+SMBG is the intervention with minimum costs and QALYs gained. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERS of £45,413/QALY and
£683,889/QALY, respectively. Therefore, they are not cost-effective given the common
threshold ICER of £30,000. The MiniMed Veo system and integrated CSII+CGM (Vibe) are
extendedly dominated and dominated, respectively, by CSII+CGM stand-alone.
Superseded –
see Erratum
5.6.3.5 Treatment effects part-I: HbA1c change in the first year
In this scenario analysis we assumed that the baseline HbA1c value is stabilised for one year
and that it does not change in any of the treatments (i.e. 0% change in HbA1c level in the first
year). The model results for this scenario can be seen in Table 55.
Table 55: Cost-effectiveness results when no treatment effect (in terms of HbA1c change) in
the first year is assumed (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
Dominated
CSII+CGM stand12.0006 £146,632
by
alone
MDI+SMBG
Dominated
Integrated CSII+CGM
12.0006 £147,304
by
(Vibe)
MDI+SMBG
MDI+SMBG
12.0016 £60,539
CSII+SMBG
12.0160 £90,178
0.0144
£29,638
£2,057,175
MiniMed Veo system
12.0260 £138,538
0.0099
£48,360
£4,871,356
The QALY expectations for all treatments are very similar. The minor differences in QALYs
can be explained due to the differences in severe hypoglycaemic episode rates. Note that
although the rate of severe hypoglycaemic events for MDI+SMBG was estimated higher than
the rate for integrated CSII+CGM in Chapter 5.3.4, MDI+SMBG resulted in a slightly higher
gain in QALYs which can be due to randomness. CSII+CGM systems were dominated by
MDI+SMBG. Furthermore, CSII+SMBG and the MiniMed Veo system are on the efficient
frontier but with extremely high ICER values. As can be seen in the resulting CEACs in
Figure 16, MDI+SMBG was the most cost-effective treatment for all the values of the ceiling
ratio considered in the analysis.
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Figure 16: Cost-effectiveness acceptability curves for all treatments when there is no HbA1c
treatment effect
Superseded –
see Erratum
5.6.3.6 Treatment effects part-II: severe hypoglycaemic event rates
When we used different RR (0.125, 0.25, 0.5 and 1) for the severe hypoglycaemic episode
rates for MiniMed Veo system, the results did not deviate significantly from the base case. In
all of the scenarios, MDI+SMBG was the cheapest intervention, MiniMed Veo system was
extendedly dominated by CSII+CGM stand-alone and integrated CSII+CGM was dominated.
Table 56 shows the results for the most extreme scenario which is obtained when RR=0.125.
For this RR, the different rates per 100 patient years can be seen in Table 46.
Table 56: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (all technologies)
Hypo MiniMed Veo
Incr.
QALYs
Cost
Incr. Cost
ICER
system RR=0.125
QALY
MDI+SMBG
11.4120
£64,323
CSII+SMBG
11.9597
£91,195
0.5477
£26,871
£49,059
Extendedly
dominated
MiniMed Veo system
12.0453
£138,333
by
CSII+CGM
stand-alone
CSII+CGM stand-alone
12.0604
£146,476
0.1007
£55,281
£549,080
Dominated
Integrated CSII+CGM
by
12.0604
£147,150
(Vibe)
CSII+CGM
stand-alone
5.6.3.7 Non-zero death probability due to severe hypoglycemia
In this scenario we assumed a mortality due to severe hypoglycaemia equal to 4.9%, as
derived from Ben-Ami et al 1999.136 The model results can be seen in Table 57.
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Table 57: Cost-effectiveness results mortality due to severe hypoglycaemia scenario (all
technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.1041
£61,924
Dominated
CSII+CGM stand-alone
11.7701
£142,215
by
CSII+SMBG
Dominated
Integrated CSII+CGM
11.7701
£142,872
by
(Vibe)
CSII+SMBG
CSII+SMBG
11.8781
£89,475
0.774
£27,551
£35,596
MiniMed Veo system
12.0071
£137,801
0.129
£8,326
£374,531
Superseded –
see Erratum
In this scenario both integrated and stand-alone CSII+CGM were dominated by CSII+SMBG.
The ICER of CSII+SMBG compared to MDI+SMBG was £35,596 and the ICER of MiniMed
Veo compared to CSII+SMBG was £374,531. Thus, they are not cost-effective given the
common threshold ICER of £30,000. Both CE-plane scatter plot and CEACs are similar to
those in the base case scenario and therefore they are not shown here. When only the CGM
treatments were considered we observed that the probability of being cost-effective for
MiniMed Paradigm Veo was equal to 1 for almost all the values of the ceiling ratio
considered in the analysis. This can be seen in Figure 17.
Figure 17: Cost-effectiveness acceptability curves for CGM treatments only nonzero
mortality due to severe hypoglycaemia scenario
5.6.3.8 QALY estimation method
In this scenario we assumed the minimum approach as an alternative QALY estimation
method, where the minimum of the multiple health state utility values is applied for patients
having a history of multiple events. The results of this scenario can be seen in Table 58.
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Table 58: Cost-effectiveness results minimum QALY estimation method scenario (all
technologies)
QALYs
Cost
Incr. QALY
Incr. Cost
ICER
MDI+SMBG
12.1327
£64,563
CSII+SMBG
12.5861
£90,436
0.4534
£25,873
£57,062
MiniMed Veo
12.6408
£138,357
0.0546
£47,920
£876,987
system
CSII+CGM stand12.6462
£146,476
0.0601
£56,039
£932,305
alone
Dominated
Integrated
by
12.6462
£147,150
0
£673
CSII+CGM (Vibe)
CSII+CGM
stand-alone
Superseded –
see Erratum
Results are similar to the base case scenario but here MiniMed Paradigm Veo is not
extendedly dominated by CSII+CGM stand-alone. All the ICERs are larger than £50,000; and
therefore the different treatments are not cost-effective given the common threshold ICER of
£30,000.
5.6.3.9 Different time horizon
In this scenario we assumed a four year time horizon, which corresponds to the average
lifetime of an insulin pump. The results can be seen in Table 59.
Table 59: Four year time horizon scenario (all technologies)
QALYs
Cost
Incr. QALY
2.7718
£7,437
MDI+SMBG
CSII+CGM stand2.7882
£24,803
alone
Integrated
2.7886
£24,939
CSII+CGM (Vibe)
CSII+SMBG
2.7906
£13,365
0.0188
MiniMed
2.7928
£23,144
0.0022
Paradigm Veo
Incr. Cost
ICER
£5,927
Dominated by
CSII+SMBG
Dominated by
CSII+SMBG
£314,826
£9,778
£4,461,063
We observed that both stand-alone and integrated CSII+CGM are dominated by
CSII+SMBG. Although MiniMed Paradigm Veo is the treatment with the highest amount of
QALYs gained, its high cost when compared with CSII+SMBG does not outweigh the gain in
QALYs and results in an ICER equal to £4,461,063. Therefore, also in this scenario it is very
unlikely that MiniMed Paradigm Veo is chosen as cost-effective as it is illustrated by the
corresponding CEACs in Figure 18.
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Figure 18: Cost-effectiveness acceptability curves for all treatments four year time horizon
scenario
Superseded –
see Erratum
When only the CGM treatments are considered we observed that MiniMed Paradigm Veo is
clearly the treatment with the highest probability of being cost-effective as shown in Figure
19.
Figure 19: Cost-effectiveness acceptability curves for CGM treatments only; four year time
horizon scenario
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5.6.3.10 Fear of hypoglycaemia unawareness
Table 60 shows the results obtained when the utility increment from Kamble et al 201267
(0.0329) was used to represent the reduced fear of hypoglycaemia. We applied this utility
increment throughout the remaining lifetimes of patients using integrated devices (the
MiniMed Paradigm Veo system and integrated CSII+CGM). This benefit is not applied to
non-integrated devices (CSII+CGM stand-alone, CSII+SMBG and MDI+SMBG), as these
non-integrated devices do not give a warning nor activate/stop releasing of insulin
automatically based on low blood glucose levels.
Table 60: Cost-effectiveness results fear of hypoglycaemia scenario (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146
£64,563
CSII+SMBG
11.9756
£90,436
0.5610
£25,873
£46,123
Extendedly
dominated
CSII+CGM stand-alone 12.0604
£146,476
by MiniMed
Veo system
MiniMed Veo system
12.6224
£138,357
0.6468
£47,920
£74,088
Integrated CSII+CGM
12.6429
£147,150
0.0205
£8,792
£428,595
(Vibe)
Superseded –
see Erratum
The main difference with respect to the base case scenario is that here CSII+CGM standalone is extendedly dominated by MiniMed Paradigm Veo, which has an ICER compared to
CSII+SMBG equal to £74,088. Moreover, integrated CSII+CGM is no longer dominated by
the corresponding stand-alone combination, as the utility increment for the integrated system
led to a larger number of QALYs accumulated compared to the non-intergrated options.
Nevertheless, the ICER of integrated CSII+CGM compared to MiniMed Paradigm Veo is still
very large (£428,595).
The scatter plot of the PSA outcomes in the CE plane is very similar to the one in the base
case scenario and therefore we decided not to show it here. The CEACs for each treatment are
shown in Figure 20. We observed that compared to the base case scenario, the probability of
being cost-effective for CSII+SMBG starts decreasing at approximately £55,000. As the
ceiling ratio increases the probability of being cost-effective for MiniMed Paradigm Veo and
integrated CSII+CGM also increases. At ceiling ratio values larger than (approximately)
£75,000 MiniMed Paradigm Veo was the treatment with the highest probability of being costeffective, followed by integrated CSII+CGM at ceiling ratio values larger than
(approximately) £90,000. Note that for CSII+CGM stand-alone the cost-effectiveness
probability was zero for all the ceiling ratios considered in the analysis.
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Figure 20: Cost-effectiveness acceptability curves for reduced fear of hypoglycaemia scenario
Superseded –
see Erratum
When only the CGM treatments were considered we observed similar CEACs (Figure 21) as
in the base case (Figure 14) but in this scenario the role of integrated and stand-alone
CSII+CGM was interchanged in the CEAC.
Figure 21: Cost-effectiveness acceptability curves for CGM treatments only fear of
hypoglycaemia scenario
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5.6.3.11 Cost of stand-alone insulin pump and continuous glucose monitoring device
In this scenario we assumed that the yearly cost of stand-alone CSII+CGM was estimated as
the average costs of the different stand-alone devices shown in Table 32 and Table 33 but
without the weighting for market share from White et al 2013.114, 115 Therefore, in this
scenario the estimated yearly cost of the stand-alone CSII+CGM was £5,460.19. The results
of this scenario can be seen in Table 61.
Table 61: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (all technologies)
Incr.
QALYs
Cost
Incr. Cost
ICER
QALY
MDI+SMBG
11.4146
£64,564
CSII+SMBG
11.9756
£92,272
0.5610
£27,708
£49,395
MiniMed Veo system
Extendedly
12.0412
£138,358
dominated
Integrated CSII+CGM
12.0604
£147,150
0.0849
£54,878
£646,692
(Vibe)
CSII+CGM stand12.0604
£150,063
0
£2,912
Dominated
alone
Superseded –
see Erratum
The main difference with respect to the base case scenario was that as expected stand-alone
CSII+CGM became more expensive than integrated CSII+CGM (Vibe). Since both
technologies are assumed to have the same efficacy, integrated CSII+CGM (Vibe) dominated
stand-alone CSII+CGM. The CEACs for each treatment are shown in Figure 22. These are
very similar to those in the base case scenario. The increase in cost of CSII+CGM stand-alone
had almost no impact on the cost-effectiveness probability since MDI+SMBG and
CSII+SMBG are the only strategies that are considered cost-effective.
Figure 22: Cost-effectiveness acceptability curves cost of stand-alone CSII+CGM without
market share scenario
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When only the CGM treatments were considered we observed similar CEACs (Figure 23) as
in the base case (Figure 15) but as expected in this scenario the role of integrated CSII+CGM
(Vibe) and stand-alone was interchanged in the CEAC.
Figure 23: Cost-effectiveness acceptability curves for CGM treatments only cost of standalone CSII+CGM without market share scenario
5.7
Extension of the health economic analysis for children and adolescent patients
Besides the clinical effectiveness limitations regarding evidence for children and adolescent
patients mentioned in Chapter 4.2.3, the model employed to conduct the cost-effectiveness
analyses, the IMS CDM, is not suitable to model long-term outcomes for children/adolescent
populations, mostly because the background risk adjustment/risk factor progression equations
are all based on adult populations.
Based on these limitations it was deemed that there are too many crucial parameters with
essentially no evidence specifically for these subgroups. This makes the reliability and
validity of the results of conducting an economic evaluation for children and adolescents in
this DAP questionable. An overview of these parameters and reasons for the extreme
uncertainty related to children and young adolescent patients is given below.
We also review the latest NICE guidelines in order to summarise how they have modelled
children and further emphasise the limitation in terms of lack of evidence.
5.7.1 Parameters subject to extreme uncertainty in the clinical effectiveness evidence for
children and adolescent patients
These are all parameters for the treatment effect on both HbA1c and hypoglycaemic event
rate for all six treatments, i.e. essentially 12 different parameters.
For the MiniMed Veo system our systematic review only identified one study in children.
That is Ly et al 2013.38 This study includes patients between 4 and 50 years old, 70% of
whom are children (4-18y). However, data by age group are not reported separately;
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therefore, we could only use the data for the total population and assume that it would apply
to children.
Our clinical experts advised us not to use this study as a study in children for two main
reasons: (1) children behave differently to adults; therefore, results for children are not the
same as for adults; and (2) pre-teen children behave differently to teenagers; therefore, the age
group 4-12 years is different from 12-18 years (also because the influence of parents in
younger children needs to be taken into account). Indeed this further subdivision of children
essentially implies a doubling of the number of parameters for which there is no evidence of
treatment effect.
The only reason we presented the data from this study in Chapter 4 (clinical effectiveness), is
because without it there is no evidence at all to inform the effectiveness of MiniMed Veo in
children. Therefore, as far as MiniMed Veo is concerned (and the assessment of severe
hypoglycaemic events), we have data from only one study which does not properly apply to
children.
In addition, we found two trials presenting evidence for the integrated CSII+CGM system
versus CSII+SMBG4 and versus MDI+SMBG,10 respectively, and three trials comparing
CSII+SMBG versus MDI+SMBG.45-47
However, the studies differed in terms of age groups included (12-17y, 7-18y, 8-14y, 8-18y,
and 8-21y), whether patients had pump experience or not, baseline HbA1c (8% to 11.5%),
follow-up (3, 6, and 12m), different hypoglycaemic status at baseline (in one study patients
with hypoglycaemia unawareness were excluded; another study only included patients with
impaired awareness of hypoglycaemia; other studies had no exclusions or no information),
and country (Israel, USA, and USA & Canada). None of the studies were performed in the
UK. Therefore, there is considerable heterogeneity between the studies, which makes any
pooling of results invalid.
5.7.2 Parameters for disease progression and treatment within the IMS CDM for
children and adolescent patients
Several additional modelling uncertainties for using the IMS CDM for children and
adolescents have been identified. Indeed the CDM structure is limited in that it lacks crucial
parameters to inform the long-term effect of hypoglycaemia. These uncertainties have been
summarized in Table 62, along with those in terms of treatment effect on HbA1c and
hypoglycaemic event rate.
Table 62: Uncertainties regarding modelling children and adolescent population with the IMS CDM
Category of
Parameter
Possibility to include
Impact on CE
parameter
it in current version
results
of IMS CDM
Treatment
Long-term consequences of
No. The model
Long-term costs
related adverse
hypoglycaemia in young children
structure is fixed.
and QALYs
events
are not included in the model.
associated to
these
“Rapid growth and development of
complications
the brain occurs from birth to 3
would change.
years, continuing to 7 years of age.
There are thus greater concerns
It is not possible
about the consequences of
to predict in
hypoglycaemia in the young as it is
which direction
more likely that hypoglycaemia
the CE results
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Category of
parameter
Costs
Utilities
Parameter
occurring early in life, has longterm adverse effects. Cognitive
deficits, particularly in visuospatial tasks and lower I.Q. scores
have been reported in children who
develop diabetes before 5 years of
age as compared to their siblings.
In children who develop diabetes
after 5 years, this impairment has
not been found”.137
1. Disease management costs:
whether disease management is the
same for children and adults is
uncertain. Some additional disease
management categories can be
relevant for children/adolescents
such as screening/management of
eating disorders and anxiety.
2. Blood glucose tests costs:
frequency of blood glucose tests
differs for adults and children.
3. Insulin costs: amount of insulin
differs for adults and children.
4. Outpatient care related costs:
unclear how these costs would
change for children. We anticipate
additional costs associated with
special training for parents.
5. HbA1c tests: unclear how these
costs would change for children.
It is uncertain how the different
complications can affect quality of
life in children compared to adults.
If this would be different then at
least two different utility values
would be needed for each
complication.
We anticipate that utilities
associated with severe
hypoglycaemic events (including
the fear of experiencing it) may be
different, in particular for younger
children as hypoglycaemic events
Possibility to include
it in current version
of IMS CDM
Impact on CE
results
would change.
Partially (except for
categories that only
apply to children if
any). These costs
could be averaged
(together with the costs
for the adult
population) over the
simulation time
horizon.
No. The model only
accepts one value per
health state as input.
Note also that
consequences of
hypoglycaemic events
in young children are
not modelled.
1, 2 & 5: No
change in base
case incremental
results, as these
costs are the
same for all
treatments
(unless there are
categories that
only apply to
children).
3: Results would
be more
favourable to
CSII
technologies as
the difference in
insulin costs with
respect to MDI
technologies
would increase.
4: It is not
possible to
predict in which
direction the CE
results would
change.
It is not possible
to predict in
which direction
the CE results
would change.
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Category of
parameter
Treatment
effects –
reduction in
baseline HbA1c
level in the first
12 months
Parameter
can cause serious long-term
adverse events (e.g. brain damage).
In the IMS CDM the change in
HbA1c level is assumed to occur
within the first 12 months.
It is uncertain whether this is also
applicable for children. It may take
longer to observe the treatment
benefits in children.
The rate of severe hypoglycaemic
events differs between children and
adults.138
Treatment
effects – rate per
100 patient
years of severe
hypoglycaemic
episodes
HbA1c
Annual HbA1c progression in
progression after children and adults is different.138
year 1
Progression in children has been
reported in the literature.139
Disease
management
parameters
It is uncertain whether these
parameters are the same for adults
and children. If this would be
different then at least two values
would be needed for each
parameter.
Disease natural
It is uncertain whether these
history
parameters are the same for adults
parameters
and children. If this would be
different then at least two values
would be needed for each
parameter.
Transition
All these probabilities/equations
probabilities/risk are based on adult data. Therefore,
equations
it is uncertain to what extent these
parameters are appropriate to
model children populations. We
anticipate that e.g. risk reduction
for MI or for nephropathy for %1
reduction in HbA1c or 10mmHg
reduction in SBP would be
different for children/younger
patients than adults due to
accumulation of the depreciation in
disease duration.
Possibility to include
it in current version
of IMS CDM
Impact on CE
results
Partially. The change
in HbA1c can be an
input in the model
regardless of the age.
However extending the
treatment effect
beyond 12 months is
not possible.
No. The model only
accepts one value as
input which is carried
over the simulation
time horizon.
It is not possible
to predict in
which direction
the CE results
would change.
Yes. This can be
modelled for example
as in the updated
CG15 for children.3
It is not possible
to predict in
which direction
the CE results
would change.
It is not possible
to predict in
which direction
the CE results
would change.
No. The model only
accepts one value as
input.
It is not possible
to predict in
which direction
the CE results
would change.
No. The model only
accepts one value as
input.
It is not possible
to predict in
which direction
the CE results
would change.
No. The model only
accepts one value as
input.
It is not possible
to predict in
which direction
the CE results
would change.
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5.7.3 Health economic analyses in T1DM for children and adolescent patients in other
NICE guidelines/assessment reports
CG15 (2004): Type 1 Diabetes: Diagnosis and Management of T1DM in Children and Young
People
This guideline was developed for the diagnosis and management of T1DM in adults and
children/younger patients. In this guideline, no economic analysis is carried out in the
corresponding part for children and younger patients.140 No explicit reasons for not
conducting such economic analyses were mentioned in the guideline. In the introduction of
the guideline it is stated that the “purpose of the economic input to the guideline was to
inform the guideline development group (GDG) of potential economic issues that needed to
be considered, to review the economic literature, and to carry out economic analyses agreed
with the GDG where appropriate data were available”. Moreover, it “was agreed that
economic models using data from the literature review should be considered where guideline
recommendations had major resource implications, or represented a change in policy or where
clinical effectiveness data from well conducted studies were available”.
TA151 (2011): Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for
diabetes: updating review
No economic analysis is conducted for children in this assessment, because in the report, it
was stated that “the IMS CDM, the online accessible software used in the economic analysis
for adults, was not designed to run with children and not appropriate to simulate the long term
outcomes of children, therefore the results of cost-effectiveness of CSII for children/younger
adults have not been modelled”.16
CG15, Update (2015)-DRAFT: Diabetes in children and young people (update)
This guideline is in its draft version and is focused on children and younger patients with
T1DM as well as with T2DM.
In this guideline two cost-effectiveness analyses for T1DM are conducted using the IMS
CDM. The first analysis compares MDI (4 or more injections of insulin per day, matching
insulin to food – also known as basal-bolus regimen) with mixed insulin injections (less than
four injections of insulin per day and no matching insulin to food). The second analysis is a
“what if” analysis where the intervention effects are based on an observational study and
explores possible cost-effectiveness of different frequencies of capillary blood glucose
monitoring.
For these analyses a newly diagnosed cohort (therefore a disease duration of zero years) with
a baseline age of 12 years and an average baseline HbA1c value of 11.4% is used. Among the
physical risk factors only HbA1c progression is tailored by the GDG (based on clinical
advice) to represent progression in children. However, we anticipate that other risk factors
and the risk adjustments for the children/younger patients should also be adjusted: e.g. risk
reduction for MI or for nephropathy for %1 reduction in HbA1c or 10mmHg reduction in
SBP would be different for children/younger patients than adults due to accumulation of the
depreciation in disease duration. In conclusion, some input parameters of the IMS CDM (like
baseline HbA1c value and HbA1c progression) were changed to adapt them to the children
population but there are many other parameters that cannot be adjusted (see Table 62). Note
that it is not possible to predict to what extent these non-adjusted parameters would affect the
cost-effectiveness results, which makes using the IMS CDM in these analyses for
children/younger population questionable. No explicit discussion regarding the use of the
IMS CDM in children/adolescents was given in the draft guideline.
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Finally, note that in this draft guideline it was mentioned that regarding the use of CGM as a
glucose monitoring strategy, the clinical evidence was not sufficiently robust to support a
recommendation for routine use and therefore modelling was not used to aid
recommendations.3 In that sense the conclusions from the draft guideline on the lack of
clinical evidence are similar to those in our report, which are summarised in Chapter 5.7.1.
5.7.4
Conclusion
The limited clinical effectiveness evidence (as discussed in Chapters 4.2.3 and 5.7.1), the
limitations of the model (summarised in Table 62) and the approaches followed in previous
NICE clinical guidelines and assessment reports support our conclusion that it is not possible
to conduct a reliable and valid economic evaluation for children/adolescent populations using
the IMS CDM.
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6
DISCUSSION
6.1
6.1.1
Statement of principal findings
Clinical effectiveness
Nineteen trials were included, 12 reported data for adults, six reported data for children and
one trial reported data for pregnant women. Four trials were in mixed populations (adults and
children); two of these reported data separately for adults and children and are included in
both the 12 trials for adults and six trials for children. Two trials did not report data separately
for adults and children (O’Connell 2009 and RealTrend). Therefore, the results from these
trials were not used in the main analyses.
Twelve studies were included in the analyses for adults. The main conclusion from these trials
is that the MiniMed Paradigm Veo system reduces hypoglycaemic events in adults in
comparison with the integrated CSII+CGM system, without any differences in other
outcomes, including change in HbA1c. Nocturnal hypoglycemic events occurred 31.8% less
frequently in the Minimed Veo group than in the integrated CSII+CGM group (1.5±1.0 vs.
2.2±1.3 per patient week, P<0.001). Similarly, the Minimed Veo group had significantly
lower weekly rates of combined daytime and night-time events than the integrated
CSII+CGM group (P<0.001). Indirect evidence seems to suggest that that there are no
significant differences between the MiniMed Paradigm Veo system and CSII+SMBG and
MDI+SMBG in ‘change in HbA1c’ at three months follow-up. However, if all studies are
combined (combining different follow-up times and including mixed populations), the
MiniMed Paradigm Veo system is significantly better than MDI+SMBG in terms of HbA1c.
For the integrated CSII+CGM system (MiniMed Paradigm REAL-Time 722 System) versus
other treatments results showed a significant effect in favour of the integrated CSII+CGM
system in comparison with MDI+SMBG for HbA1c, but not when compared with
CSII+SMBG; and a significant effect in favour of the integrated CSII+CGM system in
comparison with MDI+SMBG and with CSII+SMBG for quality of life.
When comparing CSII versus MDI, only one of the six trials showed a significant difference
between CSII+SMBG and MDI+SMBG in terms of Change in HbA1c. DeVries et al (2002)
found a significant difference in favour of CSII+CGM: at 16 weeks mean HbA1c was 0.84%
(95% CI: -1.31, -0.36) lower in the CSII+SMBG group compared with the MDI+SMBG
group. No differences were found in any trial for the number of severe hypoglycaemic events.
Six studies were included in the analyses for children. None of the studies in children made a
direct comparison between the MiniMed Paradigm Veo system and the integrated CSII+CGM
system. An indirect comparison was possible, using data at six months follow-up from Ly et
al. 2013 and Hirsch 2008, but only for HbA1c, which showed no significant difference
between groups.
One study compared the MiniMed Paradigm Veo system with CSII+SMBG. The only
significant difference between treatment groups was the rate of moderate and severe
hypoglycaemic events, which favoured the MiniMed Paradigm Veo system.
One study compared the integrated CSII+CGM system with CSII+SMBG, this trial found no
significant difference in HbA1c scores between groups. One study compared the integrated
CSII+CGM system with MDI+SMBG, this trial showed a significant difference in HbA1c
change scores in favour of the integrated CSII+CGM system, but no significant difference in
the number of children achieving HbA1c ≤7%. Hyperglycaemic AUC was significantly lower
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in the integrated CSII+CGM group, but hypoglycaemic AUC showed no significant
difference. Other outcomes showed no significant differences between groups.
For pregnant women we found only one trial comparing CSII+SMBG with MDI+SMBG
which is not relevant to the decision problem.
6.1.2 Cost-effectiveness
We assessed the cost-effectiveness of the MiniMed Paradigm Veo system and the Vibe and
G4 PLATINUM CGM system compared with stand-alone CSII+CGM, CSII+SMBG,
MDI+CGM, and MDI+SMBG for the management of type 1 diabetes in adults.
Besides the literature limitations regarding the population subgroups of interest (i.e. children
and pregnant women) mentioned above, the model employed to conduct the costeffectiveness analyses, the IMS CDM, is not suitable to model long-term outcomes for
children/adolescent and pregnant women populations, because the background risk
adjustment/ risk factor progression equations are all based on adult populations.
The comparator MDI+CGM was not included in the cost-effectiveness analyses since no
evidence was found in the systematic review. Moreover, in the absence of data on comparing
the clinical effectiveness of integrated CSII+CGM systems against stand-alone CSII+CGM
systems, we assumed in our analyses that both technologies would be equally effective, which
seems to be plausible. The immediate consequence of this assumption is that stand-alone
CSII+CGM systems dominated the integrated CSII+CGM systems since the stand-alone
system was cheaper, according to our estimated cost, whilst being equally effective.
Superseded
see Erratum
Overall, the cost-effectiveness results suggested that the technologies using SMBG (either
with CSII or MDI) are more likely to be cost-effective since the higher quality of life
provided by the technologies using CGM did not outweigh the increased costs. This is in line
with the findings in the currently updated T1DM guideline3 where CGM was compared to
several SMBG setups and it was found to be not cost-effective. In particular, the base case
results showed that MDI+SMBG was the cheapest treatment but also the one providing the
lowest amount of QALYs. The ICER of CSII+SMBG compared to MDI+SMBG was
£46,123. MiniMed Paradigm Veo was extendedly dominated by CSII+CGM stand-alone.
This was mainly because from our systematic review the decrease on HbA1c with respect to
baseline was highest for integrated CSII+CGM, and this relatively small decrease in HbA1c
leads to a decrease in the number of complications that occur over life time to such an extent
that it compensates for the higher number of severe hypoglycaemic events. In any case, the
ICER of CSII+CGM stand-alone compared to CSII+SMBG was £660,376. Thus, given the
common threshold ICER of £30,000, it is clear that CSII+CGM stand-alone would not be
cost-effective.
We also considered two additional base case analyses. Since insulin pumps are recommended
for people with type 1 diabetes for whom MDI is not suitable, we excluded the MDIcontaining technology from the analysis. We observed that CSII+SMBG was the strategy
most likely to be cost-effective, with a cost-effectiveness probability almost equal to 1 for all
the ceiling ratios considered in the analysis. Afterwards, we also excluded SMBG treatments
from the analysis in order to capture the effect of the LGS function of the MiniMed Paradigm
Veo which is expected to have influence on reducing the number of severe hypoglycaemic
events, and thus on the number of QALYs gained. In this situation the only relevant
comparison is MiniMed Veo versus CSII+CGM stand-alone, since the Vibe and G4
PLATINUM CGM system was dominated by the stand-alone combination of CSII+CGM.The
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corresponding results showed that when the MiniMed Veo system is compared to CSII+CGM
stand-alone the ICER obtained is high (£422,849). However, this comes from both negative
incremental QALYs and incremental costs, i.e. the ICER is in the south-west quadrant of the
cost-effectiveness plane. In this case, the higher the ICER the better i.e. any cost saving could
be used on other patients in order to generate QALYs that could ‘outweighs’ the loss in
QALYs. Therefore, at a ceiling ratio of £30,000 per QALY, the MiniMed Veo system would
be cost-effective compared to CSII+CGM stand-alone. This can be seen in the corresponding
CEACs since MiniMed Paradigm Veo is the CGM-treatment most likely to be cost-effective
for all the ceiling ratios considered in the analysis. However, as the ceiling ratio increases the
CEACs for MiniMed Paradigm Veo and CSII+CGM stand-alone seem to converge. As
expected, the CEAC for the Vibe and G4 PLATINUM CGM system was always zero for all
the ceiling ratios considered in the analysis.
The results of the different scenario analyses did not differ much from the base case results.
The scenario that was most favourable to MiniMed Paradigm Veo was the one that
considered an additional utility decrement associated to reducing the fear of hypoglycaemia.
In that scenario the ICER of MiniMed Paradigm Veo compared to CSII+SMBG was equal to
£74,088 (the lowest found in all analyses). However, given the common threshold ICER of
£30,000, MiniMed Paradigm Veo would not be considered cost-effective. For the Vibe and
G4 PLATINUM CGM system, when it was not (extendedly) dominated by other strategies,
the lowest ICER obtained was £428,595 when compared to MiniMed Paradigm Veo. This
also occurred in the scenario where a utility increment associated with reducing the fear of
hypoglycaemia was considered.
6.2
Strengths and limitations of assessment
6.2.1 Clinical effectiveness
Overall, the evidence seems to suggest that the MiniMed Paradigm Veo system reduces
hypoglycaemic events in comparison with other treatments, without any differences in other
outcomes, including change in HbA1c. In addition we found significant results in favour of
the integrated CSII+CGM system in comparison with MDI+SMBG for HbA1c and quality of
life. However, the evidence base was poor. The quality of included studies was generally low
and often there was only one study to compare treatments in a specific population and at a
specific follow-up time. Especially, the evidence for the two interventions of interest was
limited, with only one study comparing the MiniMed Paradigm Veo system with an
integrated CSII+CGM system and one study in a mixed population comparing the MiniMed
Paradigm Veo system with CSII+SMBG. In addition, although several studies included the
integrated CSII+CGM system as a treatment arm, it is important to note that none of these
studies looked at the Vibe and G4 PLATINUM CGM system; in the included studies, the
integrated CSII+CGM system was always a MiniMed Paradigm pump with integrated CGM
system (MiniMed Paradigm REAL-Time 722 System). This also means that all studies
assessing the effectiveness of the integrated CSII+CGM system were performed in the USA.
Overall, only three out of the 19 included studies included patients from the UK, and only one
of these was completely performed in the UK (Thomas 2007). Interactions between patients
and health care providers may show considerable differences in different countries, which
will affect patients’ behaviour and therefore the effectiveness of insulin pumps and monitors.
Therefore, the results from the included studies may not be representative for the UK
situation.
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Unfortunately, many studies had to be excluded because they compared CSII versus MDI
(without specifying the type of monitoring) or CGM versus SMBG (without specifying the
type of insulin delivery). Two studies with 2x2 factorial design including CSII+CGM,
CSII+SMBG, MDI+CGM and MDI+SMBG, had to be excluded because results were only
reported for CSII versus MDI, and CGM versus SMBG. One of these studies was in children
(Mauras et al 2012141) and one was in adults (Little et al 2014142 (HypoCOMPaSS trial)).
These studies were excluded because they could not be classified as one of the relevant
comparators defined by NICE and they could not be compared with the MiniMed Paradigm
Veo system or an integrated CSII+CGM system.
In addition, we had problems differentiating interventions as CSII+CGM or integrated
CSII+CGM systems. The interventions were often poorly described, making it difficult to be
sure which type of intervention was used. Sometimes researchers made no difference between
these two types of treatments, by providing patients in one and the same treatment arm with
stand-alone CSII+CGM and integrated CSII+CGM systems (see Beck et al 2009143).
Four of the included studies were in mixed populations (Ly 2013: 65 children/30 adults; range
4-50 years; O’Connell 2009: 32 children/30 adults; range 13-40 years; RealTrend: 51
children/81 adults; range 2-65 years; Hirsch: 40 children/98 adults; range 12-72 years).
Advice from clinical experts was not to combine results from adults with children and vice
versa. Therefore, these studies were in first instance excluded from our analyses. Only where
results were reported separately for adults and children were results included in the analyses
and where there was no data without using the study, as in the case with Ly 2013, which was
used as a study in children to make a comparison between the MiniMed Paradigm Veo system
and other treatments.
As reported in the protocol and in the methods chapter of this report, there is a problem with
the comparability of populations in studies evaluating insulin pumps and MDI. NICE
recommended CSII ‘as a treatment option for adults and children 12 years and over, who
suffer disabling hypoglycaemia (including anxiety about hypoglycaemia) when attempting to
achieve HbA1c below 7.5%, or who have HbA1c persistently above 8.5%, while on multiple
daily injection therapy (MDIT). CSII is also recommended for children under 12 years of age
for whom MDIT is considered impractical.’16 In other words, insulin pumps are
recommended for people with type 1 diabetes for whom MDI is not suitable. Therefore, it was
anticipated that it will be problematic to find studies comparing insulin pumps (especially
modern pumps such as the integrated systems) with MDI in comparable populations.
Most studies comparing CSII with MDI show no difference in HbA1c levels. One trial found
a significant difference in change in HbA1c levels at follow-up (DeVries 2002); that was a
trial in which patients with persistent poor control, defined as a mean of all HbA1c levels
≥8.5 in the last six months before the trial, were included. Partly based on this trial, NICE
concluded that CSII would most likely be cost-effective in patients with poorly controlled
diabetes. Our current systematic review shows that nothing has changed in the evidence base
for CSII versus MDI. The trial by DeVries et al 2002 is still the only trial with significant
differences in HbA1c levels at follow-up when comparing CSII+SMBG with MDI+SMBG.
This highlights the problem with identifying the correct population for the comparisons
between the interventions relevant for this appraisal. For the comparison between the
MiniMed Paradigm Veo system and the integrated CSII+CGM system, we have included a
general population of type 1 diabetes patients. However, if we compare these interventions
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with CSII+SMBG and MDI+SMBG in general populations, we will obscure differences that
exist between CSII and MDI in diabetes patients with poor control at baseline.
For the comparison between CSII and MDI it is important to differentiate between
populations with good HbA1c control at baseline and populations with poor control.
However, when we compare the MiniMed Paradigm Veo system with the integrated
CSII+CGM system and with CSII+SMBG, all patients are using a pump; and in most studies
comparing different types of pumps, patients have been using pumps for more than six
months. In these studies, baseline HbA1c levels will be relatively low because of long term
pump use. Therefore, it is difficult to assess how comparable those patients are to patients in
trials comparing pump with MDI.
Given these problems due to heterogeneity between trial populations in RCTs, we did not
consider to include any further observational studies as these problems would be even more
serious when comparing results from observational studies.
For pregnant women we found no studies looking at the MiniMed Paradigm Veo system or
the integrated CSII+CGM system.
6.2.2 Cost-effectiveness
An important strength of the current cost-effectiveness evaluation is that we used a wellvalidated diabetes model that has been used for many assessments, including submissions for
NICE.3, 16, 79-82 In particular it was used to assess the cost effectiveness of CSII against MDI
for type 1 diabetes patients in an HTA report from 201078 and in the current update of the
Clinical Guideline on type 1 diabetes (CG15).3 Since 1999, it has participated in Mount Hood
conferences, during which health economic models on diabetes are compared against each
other in terms of their structure, performance and validity.83-85 Two major validation papers
for the IMS CDM have been published to date.1, 2 The latest one, from 2014, is the basis for
the technical model description provided in this report. This is consistent with the latest
version of the model, which is numbered 8.5. Given the degree of validation of the model,
and in order to be in line with the currently updated T1DM guideline,3 from where we
sourced many input parameters, for this evaluation it was believed important not to use an
alternative model or develop a de novo cost-effectiveness model. The most recent unit cost
data were obtained. This included detailed data on equipment costs obtained from the
companies.
Although many of our input parameters are the same as for the updated CG15, we add to
those analyses by considering interventions that were not assessed in the updated CG15.3 We
have also run a large variety of scenarios and performed PSA for all of them.
A major limitation of the model is that the IMS CDM is not appropriate for the health
economic outcomes for pediatric/adolescent populations. This was reported in the HTA of
CSII against MDI for type 1 diabetes patients from 201078 and confirmed by the model
developers who also mentioned that the model is not appropriate for pregnant women either.
Therefore, these two subgroup populations were not included in the cost-effectiveness
analyses.
Another limitation is that not all input parameters can be included in a PSA because of the
technical constraints of the IMS CDM. We consider that the most important parameter that
was not included in the PSA is the rate of severe hypoglycaemic events as this is expected to
be one of the key drivers of the model results, especially for the MiniMed Paradigm Veo. As
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a consequence, the uncertainty around the ICERs is currently somewhat underestimated.
However, the ICERs themselves are not influenced by this limitation.
Another major limitation is the lack of comparability of treatments and clinical trials to
estimate the treatment effect for CSII+CGM stand-alone. In the current analysis we had to
assume equal effectiveness to integrated CSII+CGM, thus assuring that CSII+CGM standalone would always dominate integrated CSII+CGM. Moreover, it is difficult to determine to
what extent the effect of the LGS function of the MiniMed Paradigm Veo was captured in the
model results. Moreover, we found no reliable data on minor hypoglycaemic events and
diabetic ketoacidosis events. The impact of these parameters on the cost-effectiveness results
is hard to predict but we expect them to have less impact than the other treatment effect
parameters (reduction in HbA1c level and rate of severe hypoglycaemic events).
Finally, information was limited for the estimation of the cost of the stand-alone insulin
pump. Although we do not expect a large difference in our estimated costs it may have a
major implication for the comparison of stand-alone CSII+CGM versus the the integrated
Vibe and G4 PLATINUM CGM system as both are equally effective. Thus, depending on the
price, one of the two options will dominate the other.
6.3
Uncertainties
6.3.1 Clinical effectiveness
The main uncertainties regarding clinical effectiveness are the general lack of data (especially
for children and pregnant women) and the poor quality of the available data. In addition, there
were problems differentiating interventions (in particular the integrated CSII+CGM system
and the CSII+CGM (stand-alone)) and interpreting results from mixed populations (adults and
children).
Due to inherit differences in patient characteristics at baseline it is difficult to compare
MDI+SMBG with any of the other interventions in this assessment.
6.3.2 Cost-effectiveness
The uncertainties described for the clinical effectiveness carry over into the assessment of the
cost-effectiveness. In addition, it is uncertain how realistic it is to assume a continuous
increasing HbA1c over the first year of treatment. It seems likely that in clinical practice
efforts will be made to keep the HbA1c as low as possible, so periods of increase maybe
followed by decreases again. It is unclear at this moment what in the long run will be the most
realistic scenario.
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7
7.1
CONCLUSIONS
Implications for service provision
Overall, the evidence seems to suggest that the MiniMed Paradigm Veo system reduces
hypoglycaemic events in comparison with other treatments, without any differences in other
outcomes, including change in HbA1c. In addition we found significant results in favour of
the integrated CSII+CGM system in comparison with MDI+SMBG for HbA1c and quality of
life. However, the evidence base was poor. The quality of included studies was generally low
and often there was only one study to compare treatments in a specific population and at a
specific follow-up time. Especially, the evidence for the two interventions of interest was
limited, with only one study comparing the MiniMed Paradigm Veo system with an
integrated CSII+CGM system and one study in a mixed population comparing the MiniMed
Paradigm Veo system with CSII+SMBG.
Cost-effectiveness analyses indicated that MDI+SMBG is the option most likely to be costeffective, given the current threshold of £30,000 per QALY gained, whereas integrated
CSII+CGM systems and MiniMed Paradigm Veo are dominated and extendedly dominated,
respectively, by CSII+CGM stand-alone. Scenario analyses, used to assess the potential
impact of changing various input parameters, did not alter these conclusions. No costeffectiveness modelling was conducted for children and pregnant women.
7.2
Suggested research priorities
In adults, a trial comparing the MiniMed Paradigm Veo system with CSII+SMBG is
warranted. Similarly a trial comparing the integrated CSII+CGM system with CSII+SMBG is
warranted.
In children, a trial comparing the MiniMed Paradigm Veo system with the integrated
CSII+CGM system is warranted. Similarly a trial comparing the integrated CSII+CGM
system with CSII+SMBG is warranted.
For pregnant women, trials comparing the MiniMed Paradigm Veo system and the integrated
CSII+CGM system with other interventions are warranted.
Future trials should include longer term follow-up and include EQ-5D at various time points
with a view to informing improved cost-effectiveness modelling.
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8
REFERENCES
[1] Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, et al. Validation of
the CORE Diabetes Model against epidemiological and clinical studies. Curr Med Res Opin
2004;20 Suppl 1:S27-S40.
[2] McEwan P, Foos V, Palmer JL, Lamotte M, Lloyd A, Grant D. Validation of the IMS
CORE Diabetes Model. Value Health 2014;17(6):714-24.
[3] National Institute for Health and Care Excellence. Type 1 Diabetes (update). [Internet].
London: National Institute for Health and Care Excellence, 2015 [accessed 15.1.15].
Available from: http://www.nice.org.uk/guidance/indevelopment/gid-cgwaver122/documents
[4] Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J, et al. Sensoraugmented insulin pump therapy: results of the first randomized treat-to-target study.
Diabetes Technol Ther 2008;10(5):377-83.
[5] O'Connell MA, Donath S, O'Neal DN, Colman PG, Ambler GR, Jones TW, et al.
Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a
randomised controlled trial. Diabetologia 2009;52(7):1250-7.
[6] Raccah D, Sulmont V, Reznik Y, Guerci B, Renard E, Hanaire H, et al. Incremental value
of continuous glucose monitoring when starting pump therapy in patients with poorly
controlled type 1 diabetes: the RealTrend study. Diabetes Care 2009;32(12):2245-50.
[7] Hermanides J, Nørgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, et al. Sensoraugmented pump therapy lowers HbA(1c) in suboptimally controlled type 1 diabetes; a
randomized controlled trial. Diabet Med 2011;28(10):1158-67.
[8] Lee SW, Sweeney T, Clausen D, Kolbach C, Hassen A, Firek A, et al. Combined insulin
pump therapy with real-time continuous glucose monitoring significantly improves glycemic
control compared to multiple daily injection therapy in pump naïve patients with type 1
diabetes; single center pilot study experience. J Diabetes Sci Technol 2007;1(3):400-4.
[9] Peyrot M, Rubin RR. Patient-reported outcomes for an integrated real-time continuous
glucose monitoring/insulin pump system. Diabetes Technol Ther 2009;11(1):57-62.
[10] Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, et al.
Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.[Erratum appears
in N Engl J Med. 2010 Sep 9;363(11):1092]. N Engl J Med 2010;363(4):311-20.
[11] National Institute for Health and Clinical Excellence. Type 1 diabetes: diagnosis and
management of type 1 diabetes in adults. Final scope [Internet]. London: National Institute
for Health and Clinical Excellence, 2012 [accessed 31.7.14] Available from:
http://www.nice.org.uk/guidance/gid-cgwaver122/resources/type-1-diabetes-update-finalscope2
[12] NHS Choices. Diabetes [Internet]. NHS Choices, 2012 [accessed 31.7.14]. Available
from: http://www.nhs.uk/Conditions/Diabetes/Pages/Diabetes.aspx
[13] The Association of Public Health Observatories (APHO). Diabetes prevalence model
[Internet]. The Association of Public Health Observatories (APHO), 2010 [accessed 31.7.14].
Available from: http://www.yhpho.org.uk/default.aspx?RID=81090
123
CONFIDENTIAL UNTIL PUBLISHED
[14] National Institute for Health and Care Excellence. Clinical Knowledge Summaries.
Diabetes - type 1 [Internet]. National Institute for Health and Care Excellence, 2012 [accessed
31.7.14]. Available from: http://cks.nice.org.uk/diabetes-type-1
[15] National Institute for Health and Clinical Excellence. Type 2 diabetes: management of
type 2 diabetes in adults. Final scope [Internet]. London: National Institute for Health and
Clinical
Excellence,
2012
[accessed
31.7.14]
Available
from:
http://www.nice.org.uk/guidance/gid-cgwave0612/resources/type-2-diabetes-final-scope2
[16] National Institute for Health and Clinical Excellence. Continuous subcutaneous insulin
infusion for the treatment of diabetes mellitus. NICE technology appraisal guidance 151
[Internet]. London: National Institute for Health and Clinical Excellence, 2008 [accessed
8.7.14] Available from: http://www.nice.org.uk/Guidance/TA151
[17] The Diabetes Control and Complications Trial Research Group. The effect of intensive
treatment of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-86.
[18] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837-53.
[19] Scottish Study Group for the Care of the Young with Diabetes. A longitudinal
observational study of insulin therapy and glycaemic control in Scottish children with Type 1
diabetes: DIABAUD 3. Diabet Med 2006;23(11):1216-21.
[20] National Paediatric Diabetes Audit Project Board, Royal College of Paediatrics and
Child Health, The Healthcare Quality Improvement Partnership (HQIP). National Paediatric
Diabetes Audit Report 2011-12. Care processes and outcomes [Internet]. London: Royal
College of Paediatrics and Child Health, 2013 [accessed 31.7.14] Available from:
http://www.rcpch.ac.uk/child-health/standards-care/clinical-audit-and-qualityimprovement/national-paediatric-diabetes-au-1
[21] Heller S. Sudden death and hypoglycaemia. Diabetic Hypoglycemia 2008;1(2):2-7.
[22] Barnard K, Thomas S, Royle P, Noyes K, Waugh N. Fear of hypoglycaemia in parents of
young children with type 1 diabetes: a systematic review. BMC Pediatr 2010;10:50.
[23] DAFNE Study Group. Training in flexible, intensive insulin management to enable
dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE)
randomised controlled trial. BMJ 2002;325(7367):746.
[24] Markowitz JT, Pratt K, Aggarwal J, Volkening LK, Laffel LM. Psychosocial correlates
of continuous glucose monitoring use in youth and adults with type 1 diabetes and parents of
youth. Diabetes Technol Ther 2012;14(6):523-6.
[25] Barnard KD, Wysocki T, Allen JM, Elleri D, Thabit H, Leelarathna L, et al. Closing the
loop overnight at home setting: psychosocial impact for adolescents with type 1 diabetes and
their parents. BMJ Open Diab Res Care 2014;2:e000025.
[26] Choudhary P, Shin J, Wang Y, Evans ML, Hammond PJ, Kerr D, et al. Insulin pump
therapy with automated insulin suspension in response to hypoglycemia: reduction in
nocturnal hypoglycemia in those at greatest risk. Diabetes Care 2011;34(9):2023-5.
124
CONFIDENTIAL UNTIL PUBLISHED
[27] Choudhary P. Insulin pump therapy with automated insulin suspension: toward freedom
from nocturnal hypoglycemia. JAMA 2013;310(12):1235-6.
[28] Mensh BD, Wisniewski NA, Neil BM, Burnett DR. Susceptibility of interstitial
continuous glucose monitor performance to sleeping position. J Diabetes Sci Technol
2013;7(4):863-70.
[29] Didangelos T, Iliadis F. Insulin pump therapy in adults. Diabetes Res Clin Pract 2011;93
Suppl 1:S109-13.
[30] Centre for Reviews and Dissemination. Systematic Reviews: CRD’s guidance for
undertaking reviews in health care [Internet]. York: University of York, 2009 [accessed
8.7.14] Available from: http://www.york.ac.uk/inst/crd/SysRev/!SSL!/WebHelp/SysRev3.htm
[31] National Institute for Health and Clinical Excellence. Diagnostics Assessment
Programme manual [Internet]. Manchester: National Institute for Health and Clinical
Excellence,
2011
[accessed
8.7.14]
Available
from:
http://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-diagnosticsguidance/Diagnostics-assessment-programme-manual.pdf
[32] Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions
[Internet]. Version 5.1.0 [updated March 2011]: The Cochrane Collaboration, 2011 [accessed
8.7.14]. Available from: http://www.cochrane-handbook.org/
[33] Canadian Agency for Drugs and Technologies in Health. CADTH peer review checklist
for search strategies [Internet]. Ottawa: CADTH, 2013 [accessed 8.7.14] Available from:
http://www.cadth.ca/en/resources/finding-evidence-is
[34] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
1986;7(3):177-88.
[35] Song F, Loke YK, Walsh T, Glenny A, Eastwood AJ, Altman DG. Methodological
problems in the use of indirect comparisons for evaluating healthcare interventions: survey of
published systematic reviews. BMJ 2009;338:b1147.
[36] Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect
treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol
1997;50(6):683-91.
[37] Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et al.
Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med
2013;369(3):224-32.
[38] Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW. Effect of sensoraugmented insulin pump therapy and automated insulin suspension vs standard insulin pump
therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA
2013;310(12):1240-7.
[39] Bolli GB, Kerr D, Thomas R, Torlone E, Sola-Gazagnes A, Vitacolonna E, et al.
Comparison of a multiple daily insulin injection regimen (basal once-daily glargine plus
mealtime lispro) and continuous subcutaneous insulin infusion (lispro) in type 1 diabetes: a
randomized open parallel multicenter study.[Erratum appears in Diabetes Care. 2009
Oct;32(10):1944]. Diabetes Care 2009;32(7):1170-6.
125
CONFIDENTIAL UNTIL PUBLISHED
[40] DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ, Dutch Insulin Pump Study
Group. A randomized trial of continuous subcutaneous insulin infusion and intensive
injection therapy in type 1 diabetes for patients with long-standing poor glycemic control.
Diabetes Care 2002;25(11):2074-80.
[41] Nosadini R, Velussi M, Fioretto P, Doria A, Avogaro A, Trevisan R, et al. Frequency of
hypoglycaemic and hyperglycaemic-ketotic episodes during conventional and subcutaneous
continuous insulin infusion therapy in IDDM. Diabetes Nutr Metab 1988;1(4):289-96.
[42] Brinchmann-Hansen O, Dahl-Jorgensen K, Hanssen KF, Sandvik L. Effects of
intensified insulin treatment on various lesions of diabetic retinopathy. Am J Ophthalmol
1985;100(5):644-53.
[43] Thomas RM, Aldibbiat A, Griffin W, Cox MAA, Leech NJ, Shaw JAM. A randomized
pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous
hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone. Diabet
Med 2007;24(7):778-83.
[44] Tsui E, Barnie A, Ross S, Parkes R, Zinman B. Intensive insulin therapy with insulin
lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily
insulin injection. Diabetes Care 2001;24(10):1722-7.
[45] Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, et al.
Comparison of continuous subcutaneous insulin infusion and multiple daily injection
regimens in children with type 1 diabetes: a randomized open crossover trial. Pediatrics
2003;112(3 Pt 1):559-64.
[46] Thrailkill KM, Moreau CS, Swearingen C, Rettiganti M, Edwards K, Morales AE, et al.
Insulin pump therapy started at the time of diagnosis: effects on glycemic control and
pancreatic beta-cell function in type 1 diabetes. Diabetes Technol Ther 2011;13(10):1023-30.
[47] Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WV. A
randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin
infusion with multiple daily injections using insulin glargine. Diabetes Care
2004;27(7):1554-8.
[48] Nosari I, Maglio ML, Lepore G, Cortinovis F, Pagani G. Is continuous subcutaneous
insulin infusion more effective than intensive conventional insulin therapy in the treatment of
pregnant diabetic women? Diabetes Nutr Metab 1993;6(1):33-7.
[49] Lawson ML, Bradley B, McAssey K, Clarson C, Kirsch SE, Mahmud FH, et al. The
JDRF CCTN CGM TIME Trial: Timing of Initiation of continuous glucose Monitoring in
Established pediatric type 1 diabetes: study protocol, recruitment and baseline characteristics.
BMC Pediatr 2014;14:183.
[50] Troub T, Shin J, Oroszlan G. The ASPIRE-2 study of automatic insulin suspension:
Design, methods, and interim baseline characteristics. Paper presented at 12th Annual
Diabetes Technology Meeting; 8-10 Nov 2012; Bethesda: USA. J Diabetes Sci Technol
2013;7(1):A135.
[51] Blair J. Randomised controlled trial of continuous subcutaneous insulin infusion
compared to multiple daily injection regimens in children and young people at diagnosis of
type I diabetes mellitus. HTA - 08/14/39. (Project record) [Internet]. 2010 [accessed 5.9.14].
Available from: http://www.nets.nihr.ac.uk/projects/hta/081439
126
CONFIDENTIAL UNTIL PUBLISHED
[52] Assistance Publique - Hôpitaux de Paris. Study of insulin therapy augmented by real
time sensor in type 1 children and adolescents (START-IN!). In: ClinicalTrials.gov [Internet].
Bethesda (MD): National Library of Medicine (US). 2009-2012 [cited 2014 Sep 5]. Available
from: http://ClinicalTrials.gov/show/NCT00949221 NLM Identifier: NCT00949221
[53] Steen Andersen, Steno Diabetes Center, Medtronic. Effect of CSII and CGM on
progression of late diabetic complications. In: ClinicalTrials.gov [Internet]. Bethesda (MD):
National Library of Medicine (US). 2011- [cited 2014 Sep 5]. Available from:
http://ClinicalTrials.gov/show/NCT01454700 NLM Identifier: NCT01454700
[54] Medtronic Diabetes. Threshold suspend in pediatrics at home. In: ClinicalTrials.gov
[Internet]. Bethesda (MD): National Library of Medicine (US). 2014- [cited 2014 Sep 5].
Available
from:
http://ClinicalTrials.gov/show/NCT02120794
NLM
Identifier:
NCT02120794
[55] Vastra Gotaland Region, DexCom Inc. CGM treatment in patients with type 1 diabetes
treated with insulin injections. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National
Library of Medicine (US). 2014- [cited 2014 Sep 5]. Available from:
http://ClinicalTrials.gov/show/NCT02092051 NLM Identifier: NCT02092051.
[56] University of British Columbia. Comparison of insulin pump and MDI for pregestational
diabetes during pregnancy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library
of
Medicine
(US).
2014[cited
2014
Sep
5].
Available
from:
http://ClinicalTrials.gov/show/NCT02064023 NLM Identifier: NCT02064023.
[57] Sheffield Teaching Hospitals NHS Foundation Trust, Cambridge University Hospitals
NHS Foundation Trust, Dumfries & Galloway NHS, NHS Lothian, NHS Greater Glasgow
and Clyde, Harrogate & District NHS Foundation Trust, et al. The REPOSE (Relative
Effectiveness of Pumps Over MDI and Structured Education) trial. In: ClinicalTrials.gov
[Internet]. Bethesda (MD): National Library of Medicine (US). 2011- [cited 2014 Sep 5].
Available
from:
http://ClinicalTrials.gov/show/NCT01616784
NLM
Identifier:
NCT01616784.
[58] Seattle Children's Hospital, The Gerber Foundation, Medtronic. The effectiveness of
continuous glucose monitoring in diabetes treatment for infants and young children. In:
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2008-2014
[cited 2014 Sep 5]. Available from: http://ClinicalTrials.gov/show/NCT00875290 NLM
Identifier: NCT00875290.
[59] Nemours Children's Clinic. Insulin pump therapy in adolescents with newly diagnosed
type 1 diabetes (T1D). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of
Medicine
(US).
2005[cited
2014
Sep
5].
Available
from:
http://ClinicalTrials.gov/show/NCT00357890 NLM Identifier: NCT00357890.
[60] Addenbrooke's NHS Trust. A randomised controlled study of continuous subcutaneous
insulin infusion (CSII) therapy compared to conventional bolus insulin treatment in preschool
aged children with Type 1 diabetes. EUCTR2005-004526-72-GB. In: EU Clinical Trials
Register (EUCTR) [Internet]. London: European Medicines Agency (EMA). 2006 [accessed
5.9.14].
Available
from:
https://www.clinicaltrialsregister.eu/ctrsearch/search?query=eudract_number:2005-004526-72
[61] Medtronic Australasia. Does real-time patient analysis of continuous glucose monitor
data improve glycaemic control in patients with Type 1 diabetes on insulin pump therapy?
ACTRN12606000049572. In: Australian and New Zealand Clinical Trials Registry (ACTRN)
127
CONFIDENTIAL UNTIL PUBLISHED
[Internet]. Sydney: National Health and Medical Research Council (Australia). 2006
[accessed 5.9.14]. Available from: http://www.anzctr.org.au/ACTRN12606000049572.aspx
[62] Juvenile Diabetes Research Foundation. Predictive Low Glucose Management (PLGM)
trial: comparing insulin pump therapy with predictive low glucose suspend feature versus
standard sensor augmented pump therapy in patients with type 1 diabetes.
ACTRN12614000510640. In: Australian and New Zealand Clinical Trials Registry
(ACTRN) [Internet]. Sydney: National Health and Medical Research Council (Australia).
2014
[accessed
5.9.14].
Available
from:
http://www.anzctr.org.au/ACTRN12614000510640.aspx
[63] The Royal Children's Hospital Melbourne. A randomized controlled trial comparing the
impact of continuous subcutaneous insulin infusion (CSII) therapy and multiple daily
injection (MDI) regimens upon indices of behaviour, cognition and glycaemia in children and
adolescents with type 1 diabetes. ACTRN12610000605099. In: Australian and New Zealand
Clinical Trials Registry (ACTRN) [Internet]. Sydney: National Health and Medical Research
Council
(Australia).
2010
[accessed
5.9.14].
Available
from:
http://www.anzctr.org.au/ACTRN12610000605099.aspx
[64] Royal Children's Hospital, Murdoch Children's Research Institute, Roche Australia Pty
Ltd. Integrated blood glucose monitoring with insulin pumps versus standard method - a
randomised crossover trial. ACTRN12611000142932. In: Australian and New Zealand
Clinical Trials Registry (ACTRN) [Internet]. Sydney: National Health and Medical Research
Council
(Australia).
2011
[accessed
5.9.14].
Available
from:
http://www.anzctr.org.au/ACTRN12611000142932.aspx
[65] Alder Hey Children's NHS Foundation Trust. SCIPI-subcutaneous insulin: pumps or
injections. ISRCTN29255275. In: ISRCTN Registry [Internet]: Springer. 2010 [accessed
5.9.14]. Available from: http://isrctn.org/ISRCTN29255275
[66] University of Schleswig-Holstein. Psychosocial issues in insulin pump therapy in
children with type 1 DM. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library
of
Medicine
(US).
2011-2013
[cited
2014
Sep
5].
Available
from:
http://clinicaltrials.gov/show/NCT01338922 NLM Identifier: NCT01338922.
[67] Kamble S, Schulman KA, Reed SD. Cost-effectiveness of sensor-augmented pump
therapy in adults with type 1 diabetes in the United States. Value Health 2012;15(5):632-8.
[68] Ly TT, Brnabic AJM, Eggleston A, Kolivos A, McBride ME, Schrover R, et al. A costeffectiveness analysis of sensor-augmented insulin pump therapy and automated insulin
suspension versus standard pump therapy for hypoglycemic unaware patients with type 1
diabetes. Value Health 2014;17(5):561-9.
[69] Kamble S, Perry BM, Shafiroff J, Schulman KA, Reed SD. The cost-effectiveness of
initiating sensor-augmented pump therapy versus multiple daily injections of insulin in adults
with type 1 diabetes: evaluating a technology in evolution. Paper presented at 16th Annual
International Meeting of the International Society for Pharmacoeconomics and Outcomes
Research, ISPOR 2011; 21-25 May 2011; Baltimore: USA. Value Health 2011;14(3):A82.
[70] Gomez A, Alfonso-Cristancho R, Prieto-Salamanca D, Valencia JE, Lynch P, Roze S.
Clinical impact of sensor-augmented insulin pump (SAP) therapy in type 1 diabetes long-term
related complications in Colombia. Paper presented at 7th International Conference on
Advanced Technologies and Treatments for Diabetes, ATTD; 5-8 Feb 2014; Vienna: Austria.
Diabetes Technol Ther 2014;16:A67-A68.
128
CONFIDENTIAL UNTIL PUBLISHED
[71] Gomez A, Alfonso-Cristancho R, Prieto-Salamanca D, Valencia JE, Lynch P, Roze S.
Health economic benefits of sensor augmented insulin pump therapy in Colombia. Paper
presented at ISPOR 4th Latin America Conference; 12-14 Sep 2013; Buenos Aires:
Argentina. Value Health 2013;16(7):A690.
[72] Lindholm Olinder A, Hanas R, Heintz E, Jacobson S, Johansson UB, Olsson PO, et al.
CGM and SAP are valuable tools in the treatment of diabetes: a Swedish health technology
assessment. Paper presented at 7th International Conference on Advanced Technologies and
Treatments for Diabetes; 5-8 Feb 2014; Vienna: Austria. Diabetes Technol Ther
2014;16:A74.
[73] Roze S, Payet V, Debroucker F, de Portu S, Cucherat M. Projection of long term health
economic benefits of sensor augmented pump (SAP) versus pump therapy alone (CSII) in
uncontrolled type 1 diabetes in France. Paper presented at ISPOR 17th Annual European
Congress; 8-12 Nov 2014; Amsterdam: The Netherlands. Value Health 2014;17(7):A348.
[74] Roze S, Cook M, Jethwa M, de Portu S. Projection of long term health-economic
benefits of sensor augmented pump (SAP) versus pump therapy alone (CSII) in type 1
diabetes, a UK perspective. Paper presented at ISPOR 17th Annual European Congress; 8-12
Nov 2014; Amsterdam: The Netherlands. Value Health 2014;17(7):A348.
[75] Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic
submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ
1996;313(7052):275-83.
[76] Beaudet A, Clegg J, Thuresson PO, Lloyd A, McEwan P. Review of utility values for
economic modeling in type 2 diabetes. Value Health 2014;17(4):462-70.
[77] Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, et al. The CORE
Diabetes Model: projecting long-term clinical outcomes, costs and cost-effectiveness of
interventions in diabetes mellitus (types 1 and 2) to support clinical and reimbursement
decision-making. Curr Med Res Opin 2004;20 Suppl 1:S5-26.
[78] Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, et al. Clinical
effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes:
systematic review and economic evaluation. Health Technol Assess 2010;14(11):iii-iv, xi-xvi,
1-181.
[79] National Institute for Health and Care Excellence. Dapagliflozin in combination therapy
for treating type 2 diabetes. NICE technology appraisal guidance 288 [Internet]. London:
National Institute for Health and Care Excellence, 2013 [accessed 26.1.15] Available from:
http://www.nice.org.uk/Guidance/TA288
[80] National Institute for Health and Care Excellence. Liraglutide for the treatment of type 2
diabetes mellitus. NICE technology appraisal guidance 203 [Internet]. London: National
Institute for Health and Care Excellence, 2014 [accessed 26.1.15] Available from:
http://www.nice.org.uk/Guidance/TA203
[81] National Institute for Health and Care Excellence. Exenatide prolonged-release
suspension for injection in combination with oral antidiabetic therapy for the treatment of
type 2 diabetes. NICE technology appraisal guidance 248 [Internet]. London: National
Institute for Health and Care Excellence, 2014 [accessed 26.1.15] Available from:
http://www.nice.org.uk/Guidance/TA248
129
CONFIDENTIAL UNTIL PUBLISHED
[82] National Institute for Health and Care Excellence. Canagliflozin in combination therapy
for treating type 2 diabetes. NICE technology appraisal guidance 315 [Internet]. London:
National Institute for Health and Care Excellence, 2014 [accessed 26.1.15] Available from:
http://www.nice.org.uk/Guidance/TA315
[83] The Mount Hood 4 Modeling Group. Computer modeling of diabetes and its
complications: a report on the Fourth Mount Hood Challenge Meeting. Diabetes Care
2007;30(6):1638-46.
[84] Brown JB, Palmer AJ, Bisgaard P, Chan W, Pedula K, Russell A. The Mt. Hood
challenge: cross-testing two diabetes simulation models. Diabetes Res Clin Pract 2000;50
Suppl 3:S57-64.
[85] Palmer AJ, Mount Hood 5 Modeling Group, Clarke P, Gray A, Leal J, Lloyd A, et al.
Computer modeling of diabetes and its complications: a report on the Fifth Mount Hood
challenge meeting. Value Health 2013;16(4):670-85.
[86] Clarke PM, Gray AM, Briggs A, Farmer AJ, Fenn P, Stevens RJ, et al. A model to
estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom
Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68). Diabetologia
2004;47(10):1747-59.
[87] The absence of a glycemic threshold for the development of long-term complications: the
perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45(10):1289-98.
[88] D’Agostino RB, Russell MW, Huse DM, Ellison RC, Silbershatz H, Wilson PW, et al.
Primary and subsequent coronary risk appraisal: new results from the Framingham study. Am
Heart J 2000;139(2 Pt 1):272-81.
[89] World Health Organization. WHO Mortality Database [Internet]. Geneva: World Health
Organization,
2014
[accessed
26.1.15].
Available
from:
http://www.who.int/healthinfo/mortality_data/en/
[90] National Institute for Health and Care Excellence. Type 1 diabetes management of type 1
diabetes in adults. NICE guideline. Draft for consultation, December 2014. [Internet].
London: National Institute for Health and Care Excellence, 2014 [accessed 15.1.15] Available
from: http://www.nice.org.uk/guidance/gid-cgwaver122/documents/type-1-diabetes-updatedraft-nice-guideline2
[91] National Clinical Guideline Centre. Type 1 diabetes in adults. Type 1 diabetes: diagnosis
and management of type 1 diabetes in adults. Clinical guideline. Methods, evidence and
recommendations. Draft for consultation, December 2014. Commissioned by the National
Institute for Health and Care Excellence. [Internet]. London: National Clinical Guideline
Centre, 2014 [accessed 15.1.15] Available from: http://www.nice.org.uk/guidance/gidcgwaver122/documents/type-1-diabetes-update-draft-guideline2
[92] Health and Social Care Information Centre. National Diabetes Audit 2011–2012. Report
1: care processes and treatment targets. Findings about the quality of care for people with
diabetes in England and Wales. Report for the audit period 2011-2012. [Internet]. London:
Health and Social Care Information Centre, 2013 [accessed 15.1.15] Available from:
https://catalogue.ic.nhs.uk/publications/clinical/diabetes/nati-diab-audi-11-12/nati-diab-audi11-12-care-proc-rep.pdf
[93] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B, Cleary PA, Backlund
130
CONFIDENTIAL UNTIL PUBLISHED
J-YC, Genuth S, et al. Modern-day clinical course of type 1 diabetes mellitus after 30 years'
duration: the diabetes control and complications trial/epidemiology of diabetes interventions
and complications and Pittsburgh epidemiology of diabetes complications experience (19832005). Arch Intern Med 2009;169(14):1307-16.
[94] Office for National Statistics. Opinions and lifestyle survey, smoking habits amongst
adults, 2012. [Internet]. London: Office for National Statistics, 2013 [accessed 16.1.15]
Available from: http://www.ons.gov.uk/ons/dcp171776_328041.pdf
[95] World Health Organization. Global status report on alcohol and health. [Internet].
Geneva, Switzerland: World Health Organization, 2011 [accessed 16.1.15] Available from:
http://www.who.int/substance_abuse/publications/global_alcohol_report/msbgsruprofiles.pdf
?ua=1
[96] The Health and Social Care Information Centre. Health survey for England, 2011.
Volume 1: health, social care and lifestyles: cardiovascular disease. [Internet]. Leeds: The
Health and Social Care Information Centre, 2011 [accessed 16.1.15] Available from:
http://www.hscic.gov.uk/catalogue/PUB09300/HSE2011-Ch2-CVD.pdf
[97] Hopkins D, Lawrence I, Mansell P, Thompson G, Amiel S, Campbell M, et al. Improved
biomedical and psychological outcomes 1 year after structured education in flexible insulin
therapy for people with type 1 diabetes: the U.K. DAFNE experience. Diabetes Care
2012;35(8):1638-42.
[98] Personal Social Services Research Unit. Unit costs of health and social care [Internet].
Canterbury: University of Kent, 2014 [accessed 13.1.15] Available from:
http://www.pssru.ac.uk/project-pages/unit-costs/2014/index.php
[99] NHS Business Services Authority, NHS England and Wales. NHS electronic drug tariff.
November 2014. [Internet]. Newcastle upon Tyne: NHS Business Services Authority, 2014
[accessed 27.11.14] Available from: http://www.ppa.org.uk/edt/November_2014/mindex.htm
[100] Lamb EJ, MacKenzie F, Stevens PE. How should proteinuria be detected and
measured? Ann Clin Biochem 2009;46(Pt 3):205-17.
[101] Department of Health. NHS reference costs 2012-2013 [Internet]. London: Department
of
Health,
2013
[accessed
7.10.14]
Available
from:
https://www.gov.uk/government/publications/nhs-reference-costs-2012-to-2013
[102] National Institute for Health and Care Excellence. Lipid modification: cardiovascular
risk assessment and the modification of blood lipids for the primary and secondary prevention
of cardiovascular disease. NICE clinical guideline 181. [Internet]. London: National Institute
for Health and Care Excellence, 2014 [accessed 16.1.15] Available from:
http://guidance.nice.org.uk/CG181
[103] National Clinical Guideline Centre. Lipid modification: cardiovascular risk assessment
and the modification of blood lipids for the primary and secondary prevention of
cardiovascular disease. Clinical guideline. Methods, evidence and recommendations. July
2014. Commissioned by the National Institute for Health and Care Excellence. [Internet].
London: National Clinical Guideline Centre, 2014 [accessed 16.1.15] Available from:
http://www.nice.org.uk/guidance/cg181/evidence/cg181-lipid-modification-update-fullguideline3
[104] National Institute for Health and Clinical Excellence. Peritoneal dialysis. Peritoneal
dialysis in the treatment of stage 5 chronic kidney disease. NICE clinical guideline 125.
131
CONFIDENTIAL UNTIL PUBLISHED
[Internet]. London: National Institute for Health and Clinical Excellence, 2011 [accessed
16.1.15] Available from: http://guidance.nice.org.uk/CG125
[105] National Institute for Health and Care Excellence. Glaucoma: diagnosis and
management of chronic open angle glaucoma and ocular hypertension. NICE clinical
guideline 85. [Internet]. London: National Institute for Health and Care Excellence, 2009
[accessed 16.1.15] Available from: http://guidance.nice.org.uk/CG85
[106] National Collaborating Centre for Acute Care. Glaucoma: diagnosis and management
of chronic open angle glaucoma and ocular hypertension. Methods, evidence and
recommendations. April 2009. Commissioned by the National Institute for Health and Care
Excellence. [Internet]. London: National Collaborating Centre for Acute Care, 2009
[accessed 16.1.15] Available from: http://www.nice.org.uk/guidance/cg85/resources/cg85glaucoma-full-guideline2
[107] MIMMS. Duloxetine. MIMMS Online. [Internet]. 2014 [accessed 16.1.15]. Available
from: http://www.mims.co.uk/
[108] National Institute for Health and Care Excellence. Neuropathic pain: the
pharmacological management of neuropathic pain in adults in non-specialist settings. NICE
clinical guideline 96. [Internet]. London: National Institute for Health and Care Excellence,
2010 [accessed 16.1.15] Available from: http://www.nice.org.uk/guidance/cg96
[109] National Institute for Health and Clinical Excellence. Lower limb peripheral arterial
disease: diagnosis and management. NICE clinical guideline 147. [Internet]. London:
National Institute for Health and Clinical Excellence, 2012 [accessed 16.1.15] Available
from: http://guidance.nice.org.uk/CG147
[110] National Clinical Guideline Centre. Lower limb peripheral arterial disease: diagnosis
and management. NICE clinical guideline. Methods, evidence and recommendations.
Stakeholder consultation draft. 09 March 2012. Commissioned by the National Institute for
Health and Clinical Excellence. [Internet]. London: National Clinical Guideline Centre, 2012
[accessed 16.1.15] Available from: http://www.nice.org.uk/guidance/cg147/documents/lowerlimb-peripheral-arterial-disease-guideline-review-full-guideline2
[111] Havas S. Educational guidelines for achieving tight control and minimizing
complications of type 1 diabetes. Am Fam Physician 1999;60(7):1985-92.
[112] Kerr M, Insight Health Economics. Foot care for people with diabetes: the economic
case for change. [Internet]. London: NHS Diabetes, 2012 [accessed 16.1.15] Available from:
http://www.diabetes.org.uk/Documents/nhs-diabetes/footcare/footcare-for-people-withdiabetes.pdf
[113] London New Drugs Group. Comparative table of insulin pumps [Internet]. London:
UKMi,
2013
[accessed
13.1.15]
Available
from:
www.medicinesresources.nhs.uk/GetDocument.aspx?pageId=784787
[114] White HD, Goenka N, Furlong NJ, Saunders S, Morrison G, Langridge P, et al. The
U.K. service level audit of insulin pump therapy in adults. Diabet Med 2014;31(4):412-8.
[115] Diabetes UK, Juvenile Diabetes Research Foundation (JDFR), Association of British
Clinical Diabetologists. The United Kingdom insulin pump audit-service level data.
[Internet]. London: Diabetes UK, 2013 [accessed 16.1.15] Available from:
http://www.diabetes.org.uk/Documents/News/The_United_Kingdom_Insulin_Pump_Audit_
May_2013.pdf
132
CONFIDENTIAL UNTIL PUBLISHED
[116] Health and Social Care Information Centre. Prescription Cost Analysis - England, 2012
[NS]. [Internet]. Leeds: Health and Social Care Information Centre, 2013 [accessed 6.1.15]
Available from: http://www.hscic.gov.uk/catalogue/PUB10610
[117] Monitor, NHS England. National tariff payment system 2014/15. Statutory guidance
[Internet].
GOV.UK,
2013
[accessed
21.1.15].
Available
from:
https://www.gov.uk/government/publications/national-tariff-payment-system-2014-to-2015
[118] Ara R, Brazier J. Comparing EQ-5D scores for comorbid health conditions estimated
using 5 different methods. Med Care 2012;50(5):452-9.
[119] Clarke P, Gray A, Holman R. Estimating utility values for health states of type 2
diabetic patients using the EQ-5D (UKPDS 62). Med Decis Making 2002;22(4):340-9.
[120] Currie CJ, Morgan CL, Poole CD, Sharplin P, Lammert M, McEwan P. Multivariate
models of health-related utility and the fear of hypoglycaemia in people with diabetes. Curr
Med Res Opin 2006;22(8):1523-34.
[121] Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of
life: a population study. Diabetes Care 2004;27(5):1066-70.
[122] Minshall ME, Oglesby AK, Wintle ME, Valentine WJ, Roze S, Palmer AJ. Estimating
the long-term cost-effectiveness of exenatide in the United States: an adjunctive treatment for
type 2 diabetes mellitus. Value Health 2008;11(1):22-33.
[123] Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller
ME, Byington RP, Goff DC, Jr., Bigger JT, et al. Effects of intensive glucose lowering in type
2 diabetes. N Engl J Med 2008;358(24):2545-59.
[124] Siegmund T, Weber S, Blankenfeld H, Oeffner A, Schumm-Draeger PM. Comparison
of insulin glargine versus NPH insulin in people with Type 2 diabetes mellitus under
outpatient-clinic conditions for 18 months using a basal-bolus regimen with a rapid-acting
insulin analogue as mealtime insulin. Exp Clin Endocrinol Diabetes 2007;115(6):349-53.
[125] McMullin J, Brozek J, Jaeschke R, Hamielec C, Dhingra V, Rocker G, et al. Glycemic
control in the ICU: a multicenter survey. Intensive Care Med 2004;30(5):798-803.
[126] Lyon KC. The case for evidence in wound care: investigating advanced treatment
modalities in healing chronic diabetic lower extremity wounds. J Wound Ostomy Continence
Nurs 2008;35(6):585-90.
[127] Jones LE, Doebbeling CC. Depression screening disparities among veterans with
diabetes compared with the general veteran population. Diabetes Care 2007;30(9):2216-21.
[128] O'Meara S, Cullum N, Majid M, Sheldon T. Systematic reviews of wound care
management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health
Technol Assess 2000;4(21):1-237.
[129] Kantor J, Margolis DJ. Treatment options for diabetic neuropathic foot ulcers: a costeffectiveness analysis. Dermatol Surg 2001;27(4):347-51.
[130] Lopez-Bastida J, Cabrera-Lopez F, Serrano-Aguilar P. Sensitivity and specificity of
digital retinal imaging for screening diabetic retinopathy. Diabet Med 2007;24(4):403-7.
133
CONFIDENTIAL UNTIL PUBLISHED
[131] Cortes-Sanabria L, Martinez-Ramirez HR, Hernandez JL, Rojas-Campos E, CanalesMunoz JL, Cueto-Manzano AM. Utility of the Dipstick Micraltest II in the screening of
microalbuminuria of diabetes mellitus type 2 and essential hypertension. Rev Invest Clin
2006;58(3):190-7.
[132] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and
Complications Study Research Group, Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary
P, et al. Long-term effect of diabetes and its treatment on cognitive function. [Erratum in N
Engl J Med. 2009 Nov 5;361(19):1914]. N Engl J Med 2007;356(18):1842-52.
[133] Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control
and Complications Trial Research Group. Diabetes 1997;46(2):271-86.
[134] Lynch P, Attvall S, Persson S, Barsoe C, Gerdtham U. Routine use of personal
continuous glucose monitoring system with insulin pump in Sweden. Paper presented at 48th
Annual Meeting of the European Association for the Study of Diabetes, EASD; 1-5 Oct 2012;
Berlin: Germany. Diabetologia 2012;55:S432.
[135] Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Ganes T, Kierulf P, Smeland
E, et al. Effect of near normoglycaemia for two years on progression of early diabetic
retinopathy, nephropathy, and neuropathy: the Oslo study. BMJ 1986;293(6556):1195-9.
[136] Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y. Drug-induced hypoglycemic
coma in 102 diabetic patients. Arch Intern Med 1999;159(3):281-4.
[137] Couper JJ, Jones TW, Donaghue KC, Clarke CF, Thomsett MJ, Silink M. The Diabetes
Control and Complications Trial. Implications for children and adolescents. Australasian
Paediatric Endocrine Group. Med J Aust 1995;162(7):369-72.
[138] Effect of intensive diabetes treatment on the development and progression of long-term
complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and
Complications Trial. Diabetes Control and Complications Trial Research Group. J Pediatr
1994;125(2):177-88.
[139] Pinhas-Hamiel O, Hamiel U, Boyko V, Graph-Barel C, Reichman B, Lerner-Geva L.
Trajectories of HbA1c levels in children and youth with type 1 diabetes. PLoS One
2014;9(10):e109109.
[140] National Institute for Health and Care Excellence. Type 1 diabetes: diagnosis and
management of type 1 diabetes in children, young people and adults. NICE clinical guideline
15 [Internet]. London: National Institute for Health and Care Excellence, 2004 [accessed
31.7.14] Available from: http://www.nice.org.uk/Guidance/CG15
[141] Mauras N, Beck R, Xing DY, Ruedy K, Buckingham B, Tansey M, et al. A randomized
clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in
the management of type 1 diabetes in young children aged 4 to <10 years. Diabetes Care
2012;35(2):204-10.
[142] Little SA, Leelarathna L, Walkinshaw E, Tan HK, Chapple O, Lubina-Solomon A, et
al. Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 × 2
factorial randomized controlled trial comparing insulin pump with multiple daily injections
and continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes Care
2014;37(8):2114-22.
134
CONFIDENTIAL UNTIL PUBLISHED
[143] Beck RW. The effect of continuous glucose monitoring in well-controlled type 1
diabetes. Diabetes Care 2009;32(8):1378-83.
[144] Stevens RJ, Kothari V, Adler AI, Stratton IM. The UKPDS risk engine: a model for the
risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci (lond)
2001;101(6):671-9.
[145] Kannel WB, D’Agostino RB, Silbershatz H, Belanger AJ, Wilson PW, Levy D. Profile
for estimating risk of heart failure. Arch Intern Med 1999;159(11):1197-204.
[146] Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, et al. UKPDS 60:
risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine.
Stroke 2002;33(7):1776-81.
[147] Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk
profile from the Framingham study. Stroke 1991;22:312-18.
[148] Murabito JM, D’Agostino RB, Silbershatz H, Wilson WF. Intermittent claudication. A
risk profile from The Framingham Heart Study. Circulation 1997;96(1):44-9.
[149] Janghorbani MB, Jones RB, Allison SP. Incidence of and risk factors for cataract
among diabetes clinic attenders. Ophthalmic Epidemiol 2000;7(1):13-25.
[150] Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO.
Survival and recurrence after first cerebral infarction: a population- based study in Rochester,
Minnesota, 1975 through 1989. Neurology 1998;50(1):208-16.
[151] Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al.
Comparison of mortality in all patients on dialysis, patients on dialysis awaiting
transplantation, and recipients of a first cadaveric transplant. N Engl J Med
1999;341(23):1725-30.
[152] Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic
Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in
persons with type 1 diabetes. Ophthalmology 2009;116(3):497-503.
[153] Rosolowsky ET, Skupien J, Smiles AM, Niewczas M, Roshan B, Stanton R, et al. Risk
for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol
2011;22(3):545-53.
[154] Grauslund J, Green A, Sjolie AK. Cataract surgery in a population-based cohort of
patients with type 1 diabetes: long-term incidence and risk factors. Acta Ophthalmol (Copenh)
2011;89(1):25-9.
[155] Lind M, Bounias I, Olsson M, Gudbjornsdottir S, Svensson AM, Rosengren A.
Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an
observational study. Lancet 2011;378(9786):140-6.
[156] Morioka T, Emoto M, Tabata T, Shoji T, Tahara H, Kishimoto H, et al. Glycemic
control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care
2001;24(5):909-13.
[157] Wiesbauer F, Heinze G, Regele H, Horl WH, Schernthaner GH, Schwarz C, et al.
Glucose control is associated with patient survival in diabetic patients after renal
transplantation. Transplantation 2010;89(5):612-9.
135
CONFIDENTIAL UNTIL PUBLISHED
[158] Monami M, Vivarelli M, Desideri CM, Colombi C, Marchionni N, Mannucci E. Pulse
pressure and prediction of incident foot ulcers in type 2 diabetes. Diabetes Care
2009;32(5):897-9.
[159] Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association
of systolic blood pressure with macrovascular and microvascular complications of type 2
diabetes (UKPDS 36): prospective observational study. BMJ 2000;321(7258):412-9.
[160] D'Agostino RB, Russell MW, Huse DM, Ellison RC, Silbershatz H, Wilson PW, et al.
Primary and subsequent coronary risk appraisal: new results from the Framingham study. Am
Heart J 2000;139(2 Pt 1):272-81.
[161] Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R,
Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular
disease: collaborative meta-analysis of individual participant data from randomised trials.
Lancet 2009;373(9678):1849-60.
[162] Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The
benefits of statins in people without established cardiovascular disease but with
cardiovascular risk factors: metaanalysis of randomised controlled trials. BMJ
2009;338:b2376.
[163] Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet 2002;360(9346):1623-30.
[164] Effects of ramipril on cardiovascular and microvascular outcomes in people with
diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes
Prevention Evaluation Study Investigators. Lancet 2000;355(9200):253-9.
[165] Sonke GS, Beaglehole R, Stewart AW, Jackson R, Stewart FM. Sex differences in case
fatality before and after admission to hospital after acute cardiac events: analysis of
community based coronary heart disease register. BMJ 1996;313(7061):853-5.
[166] Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al.
Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in
diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1
year. J Am Coll Cardiol 1995;26(1):57-65.
[167] Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of
antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged
antiplatelet therapy in various categories of patients. [Erratum in BMJ 1994 Jun
11;308(6943):1540]. BMJ 1994;308(6921):81-106.
[168] Stenestrand U, Wallentin L, Swedish Register of Cardiac Intensive Care (RIKS-HIA).
Early statin treatment following acute myocardial infarction and 1-year survival. JAMA
2001;285(4):430-6.
[169] Briel M, Schwartz GG, Thompson PL, de Lemos JA, Blazing MA, van Es GA, et al.
Effects of early treatment with statins on short-term clinical outcomes in acute coronary
syndromes: a meta-analysis of randomized controlled trials. JAMA 2006;295(17):2046-56.
[170] Gustafsson I, Torp-Pedersen C, Køber L, Gustafsson F, Hildebrandt P. Effect of the
angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic
136
CONFIDENTIAL UNTIL PUBLISHED
patients with left ventricular dysfunction after acute myocardial infarction. Trace Study
Group. J Am Coll Cardiol 1999;34(1):83-9.
[171] Amarenco P, Bogousslavsky J, Callahan A, 3rd, Goldstein LB, Hennerici M, Rudolph
AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med
2006;355(6):549-59.
[172] PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6,105 individuals with previous stroke or transient
ischaemic attack. [Erratum in Lancet 2002 Jun 15;359(9323):2120; Lancet 2001 Nov
3;358(9292):1556]. Lancet 2001;358(9287):1033-41.
[173] Eriksson SE, Olsson JE. Survival and recurrent strokes in patients with different
subtypes of stroke: a fourteen-year follow-up study. Cerebrovasc Dis 2001;12(3):171-80.
[174] Manktelow BN, Potter JF. Interventions in the management of serum lipids for
preventing stroke recurrence. Cochrane Database of Systematic Reviews 2009, Issue 3. Art.
No.: CD002091. DOI: 10.1002/14651858.CD002091.pub2.
[175] Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute
ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.:
CD000029. DOI: 10.1002/14651858.CD000029.pub2.
[176] Chitravas N, Dewey HM, Nicol MB, Harding DL, Pearce DC, Thrift AG. Is prestroke
use of angiotensin-converting enzyme inhibitors associated with better outcome? Neurology
2007;68(20):1687-93.
[177] Asberg S, Henriksson KM, Farahmand B, Asplund K, Norrving B, Appelros P, et al.
Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529
patients in the Swedish Stroke Register. Stroke 2010;41(7):1338-42.
[178] Ascenção R, Fortuna P, Reis I, Carneiro AV. Drug therapy for chronic heart failure due
to left ventricular systolic dysfunction: a review. III. Angiotensin-converting enzyme
inhibitors. Rev Port Cardiol 2008;27(9):1169-87.
[179] Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of
congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88(1):107-15.
[180] Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, et
al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1
diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in InsulinDependent Diabetes Mellitus. Lancet 1998;351(9095):28-31.
[181] Penno G, Chaturvedi N, Talmud PJ, Cotroneo P, Manto A, Nannipieri M, et al. Effect
of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease
and the influence of ACE inhibition in IDDM patients: findings from the EUCLID
Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM. Diabetes
1998;47(9):1507-11.
[182] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. The Collaborative Study Group. [Erratum in N
Engl J Med 1993 Jan 13;330(2):152]. N Engl J Med 1993;329(20):1456-62.
137
CONFIDENTIAL UNTIL PUBLISHED
[183] MacIsaac RJ, Lee LY, McNeil KJ, Tsalamandris C, Jerums G. Influence of age on the
presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Intern Med J
2002;32(8):379-85.
[184] Persson U, Willis M, Odegaard K, Apelqvist J. The cost-effectiveness of treating
diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an
application using Swedish cost data. Value Health 2000;3 Suppl 1:39-46.
[185] Borkosky SL, Roukis TS. Incidence of re-amputation following partial first ray
amputation associated with diabetes mellitus and peripheral sensory neuropathy: a systematic
review. Diabet Foot Ankle 2012;3.
[186] Ragnarson Tennvall G, Apelqvist J. Prevention of diabetes-related foot ulcers and
amputations: a cost-utility analysis based on Markov model simulations. Diabetologia
2001;44(11):2077-87.
[187] Egede LE, Nietert PJ, Zheng D. Depression and all-cause and coronary heart disease
mortality among adults with and without diabetes. Diabetes Care 2005;28(6):1339-45.
[188] Yoshida S, Hirai M, Suzuki S, Awata S, Oka Y. Neuropathy is associated with
depression independently of health-related quality of life in Japanese patients with diabetes.
Psychiatry Clin Neurosci 2009;63(1):65-72.
[189] Whyte EM, Mulsant BH, Vanderbilt J, Dodge HH, Ganguli M. Depression after stroke:
a prospective epidemiological study. J Am Geriatr Soc 2004;52(5):774-8.
[190] U.S. Renal Data System. USRDS 2010 annual data report: atlas of chronic kidney
disease and end-stage renal disease in the United States [Internet]. Bethesda, MD: National
Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2010
[accessed 13.1.15] Available from: http://www.usrds.org/atlas10.aspx
[191] Golden SH, Lazo M, Carnethon M, Bertoni AG, Schreiner PJ, Diez Roux AV, et al.
Examining a bidirectional association between depressive symptoms and diabetes. JAMA
2008;299(23):2751-9.
[192] Valenstein M, Vijan S, Zeber JE, Boehm K, Buttar A. The cost-utility of screening for
depression in primary care. Ann Intern Med 2001;134(5):345-60.
[193] Bagust A, Beale S. Modelling EuroQol health-related utility values for diabetic
complications from CODE-2 data. Health Econ 2005;14(3):217-30.
[194] Herlitz J, Bång A, Karlson BW. Mortality, place and mode of death and reinfarction
during a period of 5 years after acute myocardial infarction in diabetic and non-diabetic
patients. Cardiology 1996;87(5):423-8.
138
CONFIDENTIAL UNTIL PUBLISHED
APPENDICES
Appendix 1: Literature search strategies
Clinical effectiveness searches
Embase (OvidSP): 1974-2014/week 34
Searched 5.9.14
1 insulin dependent diabetes mellitus/ (78607)
2 exp diabetic ketoacidosis/ (7787)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (49088)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (29355)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (217259)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (20038)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(14231)
8 hypoglycemia/ or hyperglycemia/ (108615)
9 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (104051)
10
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (126603)
11 or/1-10 (436900)
12 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (598)
13 SAPT.ti,ab,ot,hw. (114)
14 (minimed or paradigmveo).ti,ab,ot,hw,dm,dv. (727)
15 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot,dm,dv. (127)
16 (veo adj3 pump$).ti,ab,ot,hw,dm,dv. (38)
17 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw,dm,dv. (25)
18 (g4 adj3 platinum).ti,ab,ot,hw,dm,dv. (27)
19 dexcom.ti,ab,ot,hw,dm,dv. (298)
20 or/12-19 (1674)
21 11 and 20 (1105)
22 insulin pump/ (3425)
23 insulin infusion/ (5096)
24 artificial pancreas/ (1433)
25 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (17265)
26 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (3171)
27 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (4218)
28 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (2050)
29
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (1941)
30 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw,dm,dv. (529)
31
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(39256)
32 or/22-31 (62055)
33 insulin/ and exp injection/ (3392)
34 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (1188)
35 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (561)
36 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (9358)
37 MDI.ti,ab,hw,ot. (3791)
38 (injection adj3 therapy).ti,ab,ot,hw. (4157)
39
((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot.
(1491)
139
CONFIDENTIAL UNTIL PUBLISHED
40 (short acting adj3 insulin).ti,ab,hw,ot. (1038)
41 (rapid acting adj3 insulin).ti,ab,hw,ot. (864)
42 or/33-41 (22079)
43 32 or 42 (81787)
44
crossover-procedure/ or double-blind procedure/ or randomized controlled trial/ or
single-blind procedure/ (397683)
45
(random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or
(doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).ti,ab,ot,hw.
(1636591)
46 44 or 45 (1636591)
47 11 and 43 and 46 (3628)
48 21 or 47 (4491)
49 animal/ (1574788)
50 animal experiment/ (1795287)
51
(rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or
pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow
or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5694449)
52 or/49-51 (5694449)
53 exp human/ (15050997)
54 human experiment/ (328369)
55 53 or 54 (15052426)
56 52 not (52 and 55) (4552229)
57 (letter or editorial or note).pt. (1874995)
58 48 not (56 or 57) (4185)
Trials filter based on terms suggested by the Cochrane Handbook:
Lefebvre C, Manheimer E, Glanville J. Chapter 6: searching for studies. 6.3.2.2. What is in
The Cochrane Central Register of Controlled Trials (CENTRAL) from EMBASE? In:
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org
dv
dm
Device Trade Name
Device Manufacturer
MEDLINE (OvidSP): 1946-2014/Aug week 4
Searched 5.9.14
1 Diabetes Mellitus, Type 1/ (62323)
2 Diabetic Ketoacidosis/ (5178)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (69580)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (20273)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (30469)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (13085)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(9331)
8 Hyperglycemia/ (20833)
9 Hypoglycemia/ (21743)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (72656)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (94623)
12 or/1-11 (245714)
140
CONFIDENTIAL UNTIL PUBLISHED
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (312)
14 SAPT.ti,ab,ot,hw. (93)
15 (minimed or paradigmveo).ti,ab,ot,hw. (197)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (34)
17 (veo adj3 pump$).ti,ab,ot,hw. (5)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (7)
19 (g4 adj3 platinum).ti,ab,ot,hw. (3)
20 dexcom.ti,ab,ot,hw. (44)
21 or/13-20 (645)
22 12 and 21 (297)
23 Insulin Infusion Systems/ (3988)
24 Pancreas, Artificial/ (402)
25 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (11972)
26 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (1810)
27 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (2474)
28 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (1203)
29
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (1310)
30 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw. (150)
31
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(32573)
32 or/23-31 (47787)
33 Insulin/ and Injections, Subcutaneous/ (2134)
34 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (624)
35 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (452)
36 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (6795)
37 MDI.ti,ab,hw,ot. (2372)
38 (injection adj3 therapy).ti,ab,ot,hw. (2858)
39
((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot.
(1015)
40 (short acting adj3 insulin).ti,ab,hw,ot. (466)
41 (rapid acting adj3 insulin).ti,ab,hw,ot. (468)
42 or/33-41 (15196)
43 32 or 42 (61325)
44 randomized controlled trial.pt. (387461)
45 controlled clinical trial.pt. (89748)
46 randomized.ab. (283558)
47 placebo.ab. (150467)
48 randomly.ab. (200457)
49 trial.ab. (294684)
50 groups.ab. (1279172)
51 or/44-50 (1878983)
52 exp Animals/ not (exp Animals/ and Humans/) (4007023)
53 51 not 52 (1535840)
54 12 and 43 and 53 (2750)
55 22 not 52 (291)
56 54 or 55 (2966)
Based on Trials filter:
Lefebvre C, Manheimer E, Glanville J. Chapter 6: searching for studies. Box 6.4.c: Cochrane
Highly sensitive search strategy for identifying randomized controlled trials in Medline:
Sensitivity-maximizing version (2008 version); OVID format. In: Higgins JPT, Green S
(editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochranehandbook.org
141
CONFIDENTIAL UNTIL PUBLISHED
MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily Update
(OvidSP): September 4, 2014
Searched 5.9.14
1 Diabetes Mellitus, Type 1/ (36)
2 Diabetic Ketoacidosis/ (3)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (2614)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (1105)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (701)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (884)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(430)
8 Hyperglycemia/ (20)
9 Hypoglycemia/ (10)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (5462)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (7457)
12 or/1-11 (14909)
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (59)
14 SAPT.ti,ab,ot,hw. (83)
15 (minimed or paradigmveo).ti,ab,ot,hw. (13)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (4)
17 (veo adj3 pump$).ti,ab,ot,hw. (1)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (0)
19 (g4 adj3 platinum).ti,ab,ot,hw. (3)
20 dexcom.ti,ab,ot,hw. (7)
21 or/13-20 (164)
22 12 and 21 (40)
23 Insulin Infusion Systems/ (2)
24 Pancreas, Artificial/ (2)
25 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (504)
26 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (189)
27 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (172)
28 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (61)
29
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (343)
30 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw. (16)
31
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(4137)
32 or/23-31 (5154)
33 Insulin/ and Injections, Subcutaneous/ (3)
34 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (66)
35 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (9)
36 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (492)
37 MDI.ti,ab,hw,ot. (161)
38 (injection adj3 therapy).ti,ab,ot,hw. (206)
39 ((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot. (51)
40 (short acting adj3 insulin).ti,ab,hw,ot. (29)
41 (rapid acting adj3 insulin).ti,ab,hw,ot. (59)
42 or/33-41 (937)
43 32 or 42 (6014)
142
CONFIDENTIAL UNTIL PUBLISHED
44
45
46
47
48
49
50
51
52
53
54
55
56
randomized controlled trial.pt. (809)
controlled clinical trial.pt. (53)
randomized.ab. (24330)
placebo.ab. (8979)
randomly.ab. (21647)
trial.ab. (25986)
groups.ab. (122705)
or/44-50 (163158)
exp Animals/ not (exp Animals/ and Humans/) (1565)
51 not 52 (162926)
12 and 43 and 53 (178)
22 not 52 (40)
54 or 55 (203)
Based on Trials filter:
Lefebvre C, Manheimer E, Glanville J. Chapter 6: searching for studies. Box 6.4.c: Cochrane
Highly sensitive search strategy for identifying randomized controlled trials in Medline:
Sensitivity-maximizing version (2008 version); OVID format. In: Higgins JPT, Green S
(editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochranehandbook.org
PubMed (NLM): up to 2014/9/5
http://www.ncbi.nlm.nih.gov/pubmed/
Searched 5.9.14
#63
Search (#61 and #62) 99
#62
Search (pubstatusaheadofprint OR publisher[sb] OR pubmednotmedline[sb])
1815003
#61
Search (#57 not #60) 1862
#60
Search ((#58 not (#58 and #59)))
2730690
#59
Search human*[tiab] 2017079
#58
Search (rat[tiab] or rats[tiab] or mouse[tiab] or mice[tiab] or murine[tiab] or
rodent[tiab] or rodents[tiab] or hamster[tiab] or hamsters[tiab] or pig[tiab] or
pigs[tiab] or porcine[tiab] or rabbit[tiab] or rabbits[tiab] or animal[tiab] or
animals[tiab] or dogs[tiab] or dog[tiab] or cats[tiab] or cow[tiab] or bovine[tiab] or
sheep[tiab] or ovine[tiab] or monkey[tiab] or monkeys[tiab])
3335539
#57
Search (#30 or #56)
1967
#56
Search (#20 and #54 and #55) 1778
#55
Search (#38 or #46)
19531
#54
Search (#47 or #48 or #49 or #50 or #51 or #52 or #53) 2074509
#53
Search groups [tiab]
1413274
#52
Search trial [tiab]
369610
#51
Search randomly [tiab] 219790
#50
Search placebo [tiab] 160018
#49
Search randomized [tiab]
324067
#48
Search controlled clinical trial [pt]
87768
#47
Search randomized controlled trial [pt] 371691
#46
Search (#39 or #40 or #41 or #42 or #43 or #44 or #45) 9426
#45
Search ("short acting insulin"[tiab] OR "rapid acting insulin"[tiab])
810
#44
Search (basal*[tiab] AND bolus[tiab] AND (injection*[tiab] OR regime*[tiab] OR
routine*[tiab] OR system*[tiab]))
1549
#43
Search "injection therapy"[tiab] 2098
#42
Search MDI[tiab]
2524
143
CONFIDENTIAL UNTIL PUBLISHED
#41
#40
#39
#38
#37
#36
#35
#34
#33
#32
#31
#30
#29
#28
#27
#26
#25
#23
#22
#21
#20
#19
#18
Search "multiple injection"[tiab] or "multiple injections"[tiab] or "multiple
insulin"[tiab] or "multiple regime"[tiab] or "multiple regimes"[tiab] or "multiple
routine"[tiab] or "multiple routines"[tiab]
2414
Search "multiple dose injection"[tiab] or "multiple dose injections"[tiab] or "multiple
dose insulin"[tiab] or "multiple dose regime"[tiab] or "multiple dose regimes"[tiab] or
"multiple dose routine"[tiab] or "multiple dose routines"[tiab]
48
Search "multiple daily injection"[tiab] or "multiple daily injections"[tiab] or "multiple
daily insulin"[tiab] or "multiple daily regime"[tiab] or "multiple daily regimes"[tiab]
or "multiple daily routine"[tiab] or "multiple daily routines"[tiab] 603
Search (#31 or #32 or #33 or #34 or #35 or #36 or #37) 10964
Search "integrated system"[tiab] or "integrated systems"[tiab] "integrated
device"[tiab] or "integrated devices"[tiab] or "dual system"[tiab] or "dual
systems"[tiab] or "dual device"[tiab] or "dual devices"[tiab] or "combined
system"[tiab] or "combined systems"[tiab] or "combined device"[tiab] or "combined
devices"[tiab] or "unified system"[tiab] or "unified systems"[tiab] or "unified
device"[tiab] or "unified devices"[tiab] 1317
Search (accu-chek[tiab] or cellnovo[tiab] or "dana diabecare"[tiab] or omnipod[tiab])
159
Search "closed loop pump"[tiab] or "closed loop pumps"[tiab] or "closed loop
delivery"[tiab] or "closed loop infusion"[tiab] or "closed loop infusions"[tiab] or
"closed loop therapy"[tiab] or "closed loop treatment"[tiab] or "closed loop
treatments"[tiab] or "closed loop system"[tiab] or "closed loop systems"[tiab]
812
Search "artificial pancreas"[tiab] or "artificial beta cell"[tiab]
822
Search "subcutaneous insulin"[tiab] or CSII[tiab]
2385
Search "pump therapy"[tiab] or "pump therapies"[tiab] or "pump treatment"[tiab] or
"pump treatments"[tiab] 920
Search "insulin pump"[tiab] or "insulin pumps"[tiab] or "insulin infusion"[tiab] or
"insulin infuse"[tiab] or "insulin infused"[tiab] or "insulin deliver"[tiab] or "insulin
delivery"[tiab] 7485
Search (#20 and #29) 273
Search (#21 or #22 or #23 or #25 or #26 or #27 or #28) 928
Search dexcom 54
Search (animas or vibe) AND (pump* or infus* or system*)
81
Search "veo pump" or "veo pumps"
15
Search (paradigm* AND (veo or pump*))
350
Search minimed or paradigmveo216
Search SAPT[tiab]
184
Search "sensor augmented"[tiab] or "sensor augment"[tiab] or "sensor pump"[tiab] or
"pump sensor"[tiab] or "sensor pumps"[tiab]
91
Search (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13
or #14 or #15 or #16 or #17 or #18 or #19)
126788
Search "high glycohemoglobin"[tiab] or "higher glycohemoglobin"[tiab] or "low
glycohemoglobin"[tiab] or "lower glycohemoglobin"[tiab] or "increase
glycohemoglobin"[tiab] or "increased glycohemoglobin"[tiab] or "increases
glycohemoglobin"[tiab]
or
"decrease
glycohemoglobin"[tiab]
or
"decreasedcglycohemoglobin"[tiab] or "decreases glycohemoglobin"[tiab] or
"deficient glycohemoglobin"[tiab] or "sufficient glycohemoglobin"[tiab] or
"insufficient glycohemoglobin"[tiab] or "reduce glycohemoglobin"[tiab] or "reduced
glycohemoglobin"[tiab] or "glycohemoglobin reduction"[tiab] or "fallen
glycohemoglobin"[tiab] or "falling glycohemoglobin"[tiab] or "glycohemoglobin
threshold"[tiab] or "safe glycohemoglobin"[tiab] 17
Search "high haemoglobin"[tiab] or "higher haemoglobin"[tiab] or "low
haemoglobin"[tiab] or "lower haemoglobin"[tiab] or "increase haemoglobin"[tiab] or
"increased haemoglobin"[tiab] or "increases haemoglobin"[tiab] or "decrease
haemoglobin"[tiab]
or
"decreasedchaemoglobin"[tiab]
or
"decreases
144
CONFIDENTIAL UNTIL PUBLISHED
#17
#16
#15
#14
#13
#12
#11
haemoglobin"[tiab]
or
"deficient
haemoglobin"[tiab]
or
"sufficient
haemoglobin"[tiab]
or
"insufficient
haemoglobin"[tiab]
or
"reduce
haemoglobin"[tiab] or "reduced haemoglobin"[tiab] or "haemoglobin reduction"[tiab]
or "fallen haemoglobin"[tiab] or "falling haemoglobin"[tiab] or "haemoglobin
threshold"[tiab] or "safe haemoglobin"[tiab]
1110
Search "high hemoglobin"[tiab] or "higher hemoglobin"[tiab] or "low
hemoglobin"[tiab] or "lower hemoglobin"[tiab] or "increase hemoglobin"[tiab] or
"increased hemoglobin"[tiab] or "increases hemoglobin"[tiab] or "decrease
hemoglobin"[tiab] or "decreasedchemoglobin"[tiab] or "decreases hemoglobin"[tiab]
or "deficient hemoglobin"[tiab] or "sufficient hemoglobin"[tiab] or "insufficient
hemoglobin"[tiab] or "reduce hemoglobin"[tiab] or "reduced hemoglobin"[tiab] or
"hemoglobin reduction"[tiab] or "fallen hemoglobin"[tiab] or "falling
hemoglobin"[tiab] or "hemoglobin threshold"[tiab] or "safe hemoglobin"[tiab]
3476
Search "high a1c"[tiab] or "higher a1c"[tiab] or "low a1c"[tiab] or "lower a1c"[tiab]
or "increase a1c"[tiab] or "increased a1c"[tiab] or "increases a1c"[tiab] or "decrease
a1c"[tiab] or "decreasedca1c"[tiab] or "decreases a1c"[tiab] or "deficient a1c"[tiab] or
"sufficient a1c"[tiab] or "insufficient a1c"[tiab] or "reduce a1c"[tiab] or "reduced
a1c"[tiab] or "a1c reduction"[tiab] or "fallen a1c"[tiab] or "falling a1c"[tiab] or "a1c
threshold"[tiab] or "safe a1c"[tiab]
291
Search (("high hba1"[tiab] or "higher hba1"[tiab] or "low hba1"[tiab] or "lower
hba1"[tiab] or "increase hba1"[tiab] or "increased hba1"[tiab] or "increases
hba1"[tiab] or "decrease hba1"[tiab] or "decreasedchba1"[tiab] or "decreases
hba1"[tiab] or "deficient hba1"[tiab] or "sufficient hba1"[tiab] or "insufficient
hba1"[tiab] or "reduce hba1"[tiab] or "reduced hba1"[tiab] or "hba1 reduction"[tiab]
or "fallen hba1"[tiab] or "falling hba1"[tiab] or "hba1 threshold"[tiab] or "safe
hba1"[tiab])) 76
Search "high hb a1"[tiab] or "higher hb a1"[tiab] or "low hb a1"[tiab] or "lower hb
a1"[tiab] or "increase hb a1"[tiab] or "increased hb a1"[tiab] or "increases hb
a1"[tiab] or "decrease hb a1"[tiab] or "decreasedchb a1"[tiab] or "decreases hb
a1"[tiab] or "deficient hb a1"[tiab] or "sufficient hb a1"[tiab] or "insufficient hb
a1"[tiab] or "reduce hb a1"[tiab] or "reduced hb a1"[tiab] or "hb a1 reduction"[tiab]
or "fallen hb a1"[tiab] or "falling hb a1"[tiab] or "hb a1 threshold"[tiab] or "safe hb
a1"[tiab]
0
Search "high hba1c"[tiab] or "higher hba1c"[tiab] or "low hba1c"[tiab] or "lower
hba1c"[tiab] or "increase hba1c"[tiab] or "increased hba1c"[tiab] or "increases
hba1c"[tiab] or "decrease hba1c"[tiab] or "decreasedchba1c"[tiab] or "decreases
hba1c"[tiab] or "deficient hba1c"[tiab] or "sufficient hba1c"[tiab] or "insufficient
hba1c"[tiab] or "reduce hba1c"[tiab] or "reduced hba1c"[tiab] or "hba1c
reduction"[tiab] or "fallen hba1c"[tiab] or "falling hba1c"[tiab] or "hba1c
threshold"[tiab] or "safe hba1c"[tiab] 1271
Search "high sugar"[tiab] or "higher sugar"[tiab] or "low sugar"[tiab] or "lower
sugar"[tiab] or "increase sugar"[tiab] or "increased sugar"[tiab] or "increases
sugar"[tiab] or "decrease sugar"[tiab] or "decreasedcsugar"[tiab] or "decreases
sugar"[tiab] or "deficient sugar"[tiab] or "sufficient sugar"[tiab] or "insufficient
sugar"[tiab] or "reduce sugar"[tiab] or "reduced sugar"[tiab] or "sugar
reduction"[tiab] or "fallen sugar"[tiab] or "falling sugar"[tiab] or "sugar
threshold"[tiab] or "safe sugar"[tiab]
1539
Search ("high glucose"[tiab] or "higher glucose"[tiab] or "low glucose"[tiab] or
"lower glucose"[tiab] or "increase glucose"[tiab] or "increased glucose"[tiab] or
"increases glucose"[tiab] or "decrease glucose"[tiab] or "decreasedcglucose"[tiab] or
"decreases glucose"[tiab] or "deficient glucose"[tiab] or "sufficient glucose"[tiab] or
"insufficient glucose"[tiab] or "reduce glucose"[tiab] or "reduced glucose"[tiab] or
"glucose reduction"[tiab] or "fallen glucose"[tiab] or "falling glucose"[tiab] or
"glucose threshold"[tiab] or "safe glucose"[tiab]) 16645
145
CONFIDENTIAL UNTIL PUBLISHED
#10
#9
#8
#7
#6
#5
#4
#3
#2
#1
Search (hyperglycemia[tiab] or hypoglycaemia[tiab] or hyperglycemic[tiab] or
hypoglycaemic[tiab]) 44267
Search ketoacidosis[tiab] or acidoketosis[tiab] or "keto acidosis"[tiab] or
ketoacidemia[tiab] or ketosis[tiab]
7293
Search dm1[tiab] or "dm 1"[tiab] or t1dm[tiab] or "t1 dm"[tiab] or t1d[tiab] or
iddm[tiab]
13131
Search "insulin dependent"[tiab] or insulindepend*[tiab] 27550
Search "brittle diabetic"[tiab] or "diabetic juvenile"[tiab] or "diabetic pediatric"[tiab]
or "diabetic paediatric"[tiab] or "diabetic early"[tiab] or "diabetic labile"[tiab] or
"diabetic acidosis"[tiab] or "diabetic sudden onset"[tiab] 348
Search "diabetic brittle"[tiab] or "juvenile diabetic"[tiab] or "pediatric diabetic"[tiab]
or "paediatric diabetic"[tiab] or "early diabetic"[tiab] or "labile diabetic"[tiab] or
"acidosis diabetic"[tiab] or "sudden onset diabetic"[tiab] 1122
Search "brittle diabetes"[tiab] or "diabetes juvenile"[tiab] or "diabetes pediatric"[tiab]
or "diabetes paediatric"[tiab] or "diabetes early"[tiab] or "diabetes ketosis"[tiab] or
"diabetes labile"[tiab] or "diabetes acidosis"[tiab] or "diabetes sudden onset"[tiab]
264
Search "diabetes brittle"[tiab] or "juvenile diabetes"[tiab] or "pediatric diabetes"[tiab]
or "paediatric diabetes"[tiab] or "early diabetes"[tiab] or "ketosis diabetes"[tiab] or
"labile diabetes"[tiab] or "acidosis diabetes"[tiab] or "sudden onset diabetes"[tiab]
2238
Search "diabetic type 1"[tiab] OR "type 1 diabetic"[tiab] OR "diabetic type i"[tiab]
OR "type i diabetic"[tiab] OR "diabetic type1"[tiab] OR "type1 diabetic"[tiab] OR
"diabetic typei"[tiab] OR "typei diabetic"[tiab] 6044
Search (("diabetes type 1"[tiab] OR "type 1 diabetes"[tiab] OR "diabetes type i"[tiab]
OR "type i diabetes"[tiab] OR "diabetes type1"[tiab] OR "type1 diabetes"[tiab] OR
"diabetes typei"[tiab] OR "typei diabetes"[tiab])) 28884
Cochrane Database of Systematic Reviews (CDSR) (Wiley). Issue 9 of 12: September
2014
Cochrane Central Register of Controlled Trials (Central) (Wiley). Issue 8 of 12: August
2014
Database of Abstracts of Reviews of Effects (DARE) (Wiley). Issue 3 of 4: July 2014
Health Technology Assessment Database (HTA) (Wiley). ). Issue 3 of 4: July 2014
Searched 5.9.14
#1
MeSH descriptor: [Diabetes Mellitus, Type 1] this term only
#2
MeSH descriptor: [Diabetic Ketoacidosis] this term only
#3
(diabet* near/3 (typ* next 1 or typ* next i or type1 or typei or typ* next
one)):ti,ab,kw
#4
(diabet* near/3 (britt* or juvenil* or pediatric or paediatric or early or keto* or labil*
or acidos* or autoimmun* or auto next immun* or sudden next onset)):ti,ab,kw
#5
((insulin* near/2 depend*) or insulindepend*):ti,ab,kw
#6
(dm1 or dm next 1 or dmt1 or dm next t1 or t1dm or t1 next dm or t1d or
iddm):ti,ab,kw
#7
(ketoacidosis or acidoketosis or keto next acidosis or ketoacidemia or
ketosis):ti,ab,kw
#8
MeSH descriptor: [Hyperglycemia] this term only
#9
MeSH descriptor: [Hypoglycemia] this term only
#10
(hyperglyc?em* or hypoglyc?em*):ti,ab,kw
#11
((high or higher or low or lower or increas* or decreas* or deficien* or sufficien* or
insufficien* or reduce* or reduction* or fluctuat* or fallen or falling or threshold or safe)
near/3 (glucose* or sugar* or hba1c or hb next a1 or hba1 or a1c or h?emoglob* or
glycoh?emoglob*)):ti,ab,kw
#12
#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
146
CONFIDENTIAL UNTIL PUBLISHED
#13
(sensor* near/3 (augment* or pump*))
#14
SAPT:ti,ab,kw
#15
minimed or paradigmveo
#16
(paradigm* near/3 (veo or pump*))
#17
(veo near/3 pump*)
#18
((animas or vibe) near/3 (pump* or infus* or system*))
#19
dexcom
#20
#13 or #14 or #15 or #16 or #17 or #18 or #19
#21
MeSH descriptor: [Insulin Infusion Systems] this term only
#22
MeSH descriptor: [Pancreas, Artificial] this term only
#23
(insulin* near/3 (pump* or infus* or deliver* or catheter*)):ti,ab,kw
#24
(pump* near/2 (therap* or treatment*)):ti,ab,kw
#25
((subcutaneous near/2 insulin*) or CSII):ti,ab,kw
#26
(artificial near/3 (pancreas or beta next cell*)):ti,ab,kw
#27
(closed next loop near/3 (pump* or deliver* or infus* or therap* or treatment* or
system*)):ti,ab,kw
#28
accu-chek or cellnovo or dana next diabecare or omnipod
#29
((integrat* or dual or combined or unified) near/3 (system* or device*)):ti,ab,kw
#30
#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29
#31
MeSH descriptor: [Insulin] this term only
#32
MeSH descriptor: [Injections, Subcutaneous] this term only
#33
#31 and #32
#34
"multiple daily" near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#35
"multiple dose" near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#36
multiple near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#37
MDI:ti,ab,kw
#38
injection near/3 therapy:ti,ab,kw
#39
(basal* and bolus) near/3 (inject* or regime* or routine* or system*):ti,ab,kw
#40
("short acting" near/3 insulin) or ("rapid acting" near/3 insulin):ti,ab,kw
#41
#34 or #35 or #36 or #37 or #38 or #39 or #40
#42
#12 and (#20 or #30 or #41)
CDSR
DARE
CENTRAL
HTA
14
25
1910
19
Science Citation Index Expanded (Web of Science): 1988-2014/08/29
Searched 5.9.14
# 40
# 39
4,012 #38 not #39
3,123,359
TS=(rat or rats or mouse or mice or murine or hamster or hamsters or
animal or animals or dogs or dog or pig or pigs or cats or bovine or cow or sheep or
ovine or porcine or monkey)
# 38
5,027 #37 OR #18
# 37
4,914 #36 AND #33 AND #8
# 36
4,219,275
#35 OR #34
# 35
4,185,460
TS=((clinic* SAME trial*) OR (placebo* OR random* OR control*
OR prospectiv*))
# 34
194,182
TS=((singl* or doubl* or trebl* or tripl*) SAME (blind* or mask*))
# 33
126,955
#32 OR #26
# 32
11,323 #31 OR #30 OR #29 OR #28 OR #27
# 31
837
TS=("short acting" NEAR/3 insulin) or TS=("rapid acting" NEAR/3 insulin)
# 30
5,207 TS=(injection NEAR/3 therapy)
# 29
4,652 TS=MDI
147
CONFIDENTIAL UNTIL PUBLISHED
# 28
332
TS=("multiple dose" NEAR/3 (inject* or insulin* or regime* or routine*))
# 27
774
TS=("multiple daily" NEAR/3 (inject* or insulin* or regime* or routine*))
# 26
116,578
#19 or #20 or #21 or #22 or #23 or #24 or #25
# 25
91,258 TS=((integrat* or dual or combined or unified) NEAR/3 (system* or
device*))
# 24
165
TS=(accu-chek or cellnovo or "dana diabecare" or omnipod)
# 23
11,130 TS=("closed loop" NEAR/3 (pump* or deliver* or infus* or therap* or
treatment* or system*))
# 22
851
TS=(artificial NEAR/3 (pancreas or "beta cell*"))
# 21
3,017 TS=((subcutaneous NEAR/2 insulin*) or CSII)
# 20
3,696 TS=(pump* NEAR/2 (therap* or treatment*))
# 19
10,301 TS=(insulin* NEAR/3 (pump* or infus* or deliver* or catheter*))
# 18
260
#8 and #17
# 17
1,375 #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16
# 16
38
TS=dexcom
# 15
7
TS=(g4 NEAR/3 platinum)
# 14
13
TS=((animas or vibe) NEAR/3 (pump* or infus* or system*))
# 13
4
TS=(veo NEAR/3 pump*)
# 12
38
TS=(paradigm* NEAR/3 (veo or pump*))
# 11
154
TS=(minimed or paradigmveo)
# 10
396
TS=SAPT
#9
765
TS=(sensor* NEAR/3 (augment* or pump*))
#8
226,312
#1 or #2 or #3 or #4 or #5 or #6 or #7
#7
109,659
TS=((high or higher or low or lower or increas* or decreas* or
deficien* or sufficien* or insufficien* or reduce* or reduction* or fluctuat* or fallen
or falling or threshold or safe) NEAR/3 (glucose* or sugar* or hba1c or "hb a1" or
hba1 or a1c or hemoglob* or glycohemoglob* or haemoglob* or glycohaemoglob*))
#6
68,183 TS=(hyperglycem* or hypoglycem* or hyperglycaem* or hypoglycaem*)
#5
5,944 TS=(ketoacidosis or acidoketosis or "keto acidosis" or ketoacidemia or
ketosis)
#4
17,145 TS=(dm1 or "dm 1" or dmt1 or "dm t1" or t1dm or "t1 dm" or t1d or iddm)
#3
25,575 TS=((insulin* NEAR/2 depend*) or insulindepend*)
#2
17,654 TS=(diabet* NEAR/3 (britt* or juvenil* or pediatric or paediatric or early or
keto* or labil* or acidos* or autoimmun* or "auto immun*" or "sudden onset"))
#1
40,584 TS=(diabet* NEAR/3 ("typ* 1" or "typ* i" or type1 or typei or "typ* one"))
Latin American and Caribbean Health Sciences (LILACS) (Internet): 1982-2014/09/05
http://lilacs.bvsalud.org/en/
Searched 5.9.14
((MH:C18.452.394.750.124 or MH:C18.452.076.176.652.500 or MH:C18.452.394.952 or
MH:C18.452.394.984 or "diabetes type 1" or "diabetes type i" or "diabetes type1" or
"diabetes typei" or "diabetes type one" or "type 1 diabetes" or "type I diabetes" or "type1
diabetes" or "typei diabetes" or "type one diabetes" or "diabetes tipo 1" or "diabetes tipo i" or
"diabetes tipo1" or "diabetes tipoi" or "tipo 1 diabetes" or "tipo I diabetes" or "tipo1 diabetes"
or "tipoi diabetes" or "brittle diabetes" or "juvenile diabetes" or "pediatric diabetes" or
"paediatric diabetes" or "early diabetes" or "labile diabetes" or "autoimmune diabetes" or
"auto immune diabetes" or "sudden onset diabetes" or "diabetes autoimune" or "diabetes
inestable" or "diabetes instável" or "insulin dependent" or insulindependent or "insulin
dependiente" or insulinodependiente or "insulin dependente" or insulinodependente or dm1 or
"dm 1" or dmt1 or "dm t1" or t1dm or "t1 dm" or t1d or iddm or dmid or ketoacidosis or
acidoketosis or "keto acidosis" or ketoacidemia or ketosis or cetoacidosis or cetoacidose or
hyperglycem$ or hyperglycaem$ or hiperglucem$ or hiperglicem$ or hypoglycem$ or
hypoglycaem$ or hipoglucem$ or hipoglicem$) AND (MH:E02.319.300.508 or "insulin
148
CONFIDENTIAL UNTIL PUBLISHED
pump" or "insulin pumps" or "insulin infusion" or "insulin infusions" or "insulin delivery" or
"insulin catheter" or "insulin catheters" or "pump therapy" or "pump therapies" or "pump
treatment" or "pump treatments" or "insulina sistemas" or "sistemas insulina" or "insulina
infusion" or "infusion insulina" or "insulina infusions" or "infusion insulinas" or "infusão de
insulina" or "subcutaneous insulin" or CSII or "artificial pancreas" or "artificial beta cell" or
"célula beta artificial" or "páncreas endocrino artificial" or "integrated system" or "integrated
systems" or "integrated devices" or "dual system" or "dual systems" or "dual devices" or
"combined system" or "combined systems" or "combined devices" or "unified system" or
"unified systems" or "unified devices" or (MH: D06.472.699.587.200.500.625 and MH;
E02.319.267.530.620) or "multiple daily injection" or "multiple daily injections" or "multiple
daily insulin" or "multiple dose injection" or "multiple dose injections" or "multiple injection"
or "multiple injections" or MDI or "injection therapy" or "inyecciones terapia" or "injeções
terapia" or "short acting insulin" or "rapid acting insulin")) or ("sensor augmented pump" or
"sensor augmented pumps" or "sensor augmented insulin" or SAPT or minimed or
paradigmveo or "paradigm veo" or "paradigm pump" or "veo pump" or "veo pumps" or
"animas pump" or "animas pumps" "animas system" or "vibe pump" or "vibe pumps" or "vibe
system" or dexcom)
Retrieved 58
NIHR Project Portfolio and NIHR Journals Library (Internet): up to 2014/9/5
Searched 5.9.14
http://www.nets.nihr.ac.uk/projects/
and
http://www.journalslibrary.nihr.ac.uk/
Search terms
Project Portfolio
Journals Library
"sensor augmented pump"
0
0
"sensor augmented pumps"
0
0
"sensor augmented insulin"
0
0
SAPT
0
0
minimed
1
6
paradigmveo
0
0
"paradigm veo"
0
0
"veo pump"
0
0
"veo pumps"
0
0
animas
0
4
vibe
0
0
dexcom
0
1
"insulin pump"
5
14
"insulin pumps"
5
12
"continuous subcutaneous insulin infusion"
4
17*
[Journals Library limit: ICD-10; E10-E14
Diabetes mellitus*]
"artificial pancreas"
0
2
"multiple daily injection"
3
7
"multiple daily injections"
3
11
Total
21 (14 dups)
72 (47 dups)
Final Total
93 (61 dups)
32
PROSPERO (Internet): Up to 2014/9/5
Searched 5.9.14
http://www.crd.york.ac.uk/prospero/
Search; Combine phrase/terms with ‘OR’; five search boxes ‘in ‘All fields’
149
CONFIDENTIAL UNTIL PUBLISHED
Terms searched
sensor augmented pump* OR sensor augmented insulin* OR
SAPT OR minimed OR paradigmveo
paradigm veo OR veo pump* OR animas OR vibe OR
dexcom
insulin pump* OR insulin infusion* OR insulin therapy OR
subcutaneous insulin OR csii
artificial pancreas
multiple daily injection* OR multiple daily insulin*
MDI [Review title]
Total
Total after dedup
Records
2
0
14 (1 dup)
0
1
0
17 (2 duplicates)
15
US Food & Drug Administration (FDA) (Internet): up to 2014/9/5
http://www.fda.gov/
Searched 5.9.14
Medical Devices
Search terms
Records
minimed
6
animas
5
Vibe
0
"g4 platinum"
3
"multiple daily injection"
0
"multiple daily injections"
0
"multiple daily insulin"
1
Total
15
Includes links to approval/summary of safety & effectiveness
Medicines and Healthcare Products Regulatory Agency (MHRA) (Internet): up to
2014/9/5
www.mhra.gov.uk
Searched 5.9.14
Search terms
Records
minimed
7
Animas + insulin + pump
16
Animas + vibe
5
"g4 platinum"
2
"multiple daily injection"
0
"multiple daily injections"
0
"multiple daily insulin"
0
Total
30*
*Results almost entirely FSNs (Field Safety Notices)
NIH Clinicaltrials.gov (Internet): up to 2014/9/2
Searched 2.9.14
http://clinicaltrials.gov/ct2/search/advanced
Advanced search option
Results
Search terms: ("sensor augmented pump" OR "sensor augmented
insulin" OR SAPT OR minimed or paradigmveo OR paradigm*
OR veo OR animas OR vibe OR dexcom OR "G4 platinum")
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
84
150
CONFIDENTIAL UNTIL PUBLISHED
Hypoglycemia
Search terms: "insulin pump" OR "insulin pumps" OR "insulin
infusion" OR "insulin delivery" OR "pump therapy" OR
"subcutaneous insulin" OR CSII OR "artificial pancreas" OR
"artificial beta cell"
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
Hypoglycemia
Search terms: "closed loop" OR accu-chek OR cellnovo OR "dana
diabecare" OR omnipod
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
Hypoglycemia
Search terms: "integrated system" OR "integrated device" OR
"integrated systems" OR "integrated devices" OR "dual system"
OR "dual device" OR "dual systems" OR "dual devices" OR
"combined system" OR "combined device" OR "combined
systems" OR "combined devices"
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
Hypoglycemia
Search terms: "multiple daily injection" OR "multiple daily
injections" OR "multiple daily insulin" OR "multiple dose
injection" OR "multiple dose injections"
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
Hypoglycemia
Search terms: MDI OR "multiple dose insulin" OR "multiple
injection" OR "multiple injections" OR "multiple insulin" OR
"injection therapy"
Conditions: Type 1 Diabetes Mellitus OR Hyperglycemia OR
Hypoglycemia
Total
Total after dedup
454
136
1
42
46
763
496
metaRegister of Controlled Trials (mRCT) (Internet): up to 2014/9/5
Searched 5.9.14
http://www.controlled-trials.com/
NIH Clinical Trials register option not ticked as already searched separately.
Results
("sensor augmented pump" OR "sensor augmented insulin" OR
SAPT OR minimed or paradigmveo OR paradigm* OR veo OR
animas OR vibe OR dexcom OR "G4 platinum") AND (Diabetes
OR Hyperglycemia OR Hypoglycemia)
("insulin pump" OR "insulin pumps" OR "insulin infusion" OR
"insulin delivery" OR "pump therapy" OR "subcutaneous insulin"
OR CSII OR "artificial pancreas" OR "artificial beta cell") AND
(Diabetes OR Hyperglycemia OR Hypoglycemia)
("closed loop" OR accu-chek OR cellnovo OR "dana diabecare"
OR omnipod) AND (Diabetes OR Hyperglycemia OR
Hypoglycemia)
("integrated system" OR "integrated device" OR "integrated
systems" OR "integrated devices") AND (Diabetes OR
Hyperglycemia OR Hypoglycemia)
("dual system" OR "dual device" OR "dual systems" OR "dual
devices" OR "combined system" OR "combined device" OR
2
4
0
0
0
151
CONFIDENTIAL UNTIL PUBLISHED
"combined systems" OR "combined devices") AND (Diabetes OR
Hyperglycemia OR Hypoglycemia)
("multiple daily injection" OR "multiple daily injections" OR 0
"multiple daily insulin" OR "multiple dose injection" OR
"multiple dose injections") AND (Diabetes OR Hyperglycemia
OR Hypoglycemia)
(MDI OR "multiple dose insulin" OR "multiple injection" OR 3
"multiple injections" OR "multiple insulin" OR "injection
therapy") AND (Diabetes OR Hyperglycemia OR Hypoglycemia)
Total
9
Total after dedup
7
WHO International Clinical Trials Register Portfolio (ICTRP) (Internet): up to 2014/9/5
Searched 5.9.14
http://www.who.int/ictrp/en/
Standard search option.
Results
sensor augmented pump* OR SAPT OR minimed OR
paradigmveo OR paradigm veo OR animas vibe OR dexcom OR
G4 platinum
type 1 diabetes mellitus AND insulin pump* OR insulin infusion*
OR pump therapy OR subcutaneous insulin* OR CSII OR
artificial pancreas
type 1 diabetes mellitus AND closed loop* OR accu-chek OR
cellnovo OR dana diabecare OR omnipod
type 1 diabetes mellitus AND integrated system* OR integrated
device* OR dual system* OR dual device*
type 1 diabetes mellitus AND multiple daily injection* OR
multiple dose injection* OR multiple daily insulin* OR multiple
injection*
type 1 diabetes mellitus AND MDI OR multiple insulin OR
injection therapy
Total
70 for 65 trials
Total after dedup
475
317 for 297 trials
115 for 115 trials
1
75 for 50 trials
95 for 78 trials
606
Diabetes UK Professional Conference (Internet)
http://www.diabetes.org.uk/diabetes-uk-professional-conference/
Searched 10.9.14
Abstracts were not available from the Diabetes UK website; proceedings are published in
Diabetic Medicine. It was not possible to search the proceedings from the Diabetic Medicine
search screen. Available PDFs were scanned for 2014 and 2013. Previous conference
proceedings were only available for purchase online, so could not be scanned.
Abstracts of the Diabetes UK Professional Conference 2014, Arena and Convention Centre,
Liverpool, UK, 5-7 March 2014. Diabet Med. 2014;31 Suppl 1:1-184. doi:
10.1111/dme.12377_1.
http://onlinelibrary.wiley.com/doi/10.1111/dme.2014.31.issue-s1/issuetoc
Basic and clinical science posters
Clinical care and other categories posters
Hypoglycaemia
152
CONFIDENTIAL UNTIL PUBLISHED
Children, young people and emerging adulthood
Abstracts of the Diabetes UK Professional Conference 2013. Manchester, United Kingdom.
March 13-15, 2013. Diabet Med. 2013;30 Suppl 1:1-213, E1-10. doi: 10.1111/dme.12090_1.
http://onlinelibrary.wiley.com/doi/10.1111/dme.2013.30.issue-s1/issuetoc
Basic and clinical science posters
Clinical care and other categories posters
Abstracts of Diabetes UK Professional Conference 2012. Glasgow, Scotland, United
Kingdom. March 7-9, 2012. Diabet Med. 2012;29 Suppl 1:1-187. doi: 10.1111/j.14645491.2011.03554_1.x.
http://onlinelibrary.wiley.com/doi/10.1111/dme.2012.29.issue-s1/issuetoc
Not available online. Purchase access only
Abstracts of Diabetes UK Annual Professional Conference 2011. London, United Kingdom.
March 30-April 1, 2011.Diabet Med. 2011;28 Suppl 1:1-214. doi: 10.1111/j.14645491.2011.03232_1.x.
http://onlinelibrary.wiley.com/doi/10.1111/dme.2012.29.issue-s1/issuetoc
Not available online. Purchase access only
Abstracts of Diabetes UK Annual Professional Conference. Liverpool, United Kingdom.
March 3-5, 2010. Diabet Med. 2010;27 Suppl 1:1-188. doi: 10.1111/j.14645491.2009.02935.x.
http://onlinelibrary.wiley.com/doi/10.1111/dme.2010.27.issue-s1/issuetoc
Not available online. Purchase access only
Terms scanned
sensor augmented
SAPT
minimed
paradigmveo
paradigm veo
animas
dexcom
Total
Abstracts identified
2014 = 0
2013 = 1
2014 = 0
2013 = 0
2014 = 0
2013 = 0
2014 = 0
2013 = 0
2014 = 0
2013 = 0
2014 = 0
2013 = 0
2014 = 0
2013 = 0
1
European Association for the Study of Diabetes (EASD) Annual meeting
http://www.easd.org
Searched 10.9.14
Advanced Search
Session type = ALL Keyword = ALL
Searched in Presentation Title and Abstract body
153
CONFIDENTIAL UNTIL PUBLISHED
2014 Meeting in September:
50th EASD Annual Meeting. 15-19 September 2014, Vienna, Austria.
49th EASD Annual Meeting. 23-27 September 2013, Barcelona, Spain
http://www.abstractsonline.com/plan/start.aspx?mkey={7E87E03A-5554-4497-B24598ADF263043C}
48th EASD Annual Meeting. 1-5 October 2012, Berlin, Germany
http://www.abstractsonline.com/plan/ViewSession.aspx?mID=1668&skey=8e40db00-2d4840da-891e-e4c9db8d9378&mKey={2DBFCAF7-1539-42D5-8DDA-0A94ABB089E8}
47th EASD Annual Meeting. 12-16 September 2011, Lisbon, Portugal
http://www.abstractsonline.com/plan/start.aspx?mkey={BAFB2746-B0DD-4110-8588E385FAF957B7}
46th EASD Meeting. 20-24 September 2010, Stockholm, Sweden
http://www.abstractsonline.com/plan/AdvancedSearch.aspx?mkey={10A86782-07E4-4A2D9100-F660E5D752A9}
45th EASD Meeting. 29 September-2 October 2009, Vienna, Austria
http://www.abstractsonline.com/plan/start.aspx?mkey={B3E385FB-2CC7-4F7C-87662F743C19F069}
Terms
"sensor augmented pump"
"sensor augmented pumps"
SAPT
minimed
paradigmveo
"paradigm veo"
Hits in Title
2013 = 0
2012 = 0
2011 = 1
2010 = 0
2009 = 1
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
Hits in Abstract Body
2013 = 0
2012 = 1
2011 = 0
2010 = 2
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2013 = 5
2012 = 5
2011 = 2
2010 = 5
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2013 = 0
2012 = 0
2011 = 2
2010 = 0
154
CONFIDENTIAL UNTIL PUBLISHED
"veo pump"
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
animas
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
vibe
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2009 = 0
dexcom
2013 = 0
2012 = 1
2011 = 0
2010 = 0
2009 = 0
"insulin pump"
2013 = 7
2012 = 8
2011 = 8
2010 = 5
2009 = 3
"insulin pumps"
2013 = 4
2012 = 0
2011 = 0
2010 = 0
2009 = 2
"continuous
subcutaneous 2013 = 3
insulin infusion"
2012 = 1
2011 = 4
2010 = 7
2009 = 6
CSII
2013 = 3
2012 = 2
2011 = 2
2010 = 3
2009 = 4
"artificial pancreas"
2013 = 2
2012 = 3
2011 = 0
2010 = 0
2009 = 0
"multiple daily injection"
2013 = 1
2012 = 0
2011 = 0
2010 = 4
2009 = 0
"multiple daily injections"
2013 = 0
2012 = 0
2011 = 0
2010 = 2
2013 = 0
2012 = 0
2011 = 0
2010 = 0
2013 = 0
2012 = 1
2011 = 2
2010 = 3
2013 = 0
2012 = 0
2011 = 1
2010 = 0
2013 = 4
2012 = 7
2011 = 1
2010 = 2
2013 = 18
2012 = 20
2011 = 18
2010 = 16
2013 = 8
2012 = 6
2011 = 6
2010 = 5
2013 = 8
2012 = 8
2011 = 11
2010 = 13
2013 = 15
2012 = 23
2011 = 17
2010 = 20
2013 = 5
2012 = 7
2011 = 3
2010 = 1
2013 = 6
2012 = 1
2011 = 2
2010 = 6
2013 = 7
2012 = 2
2011 = 6
2010 = 7
155
CONFIDENTIAL UNTIL PUBLISHED
MDI
Total
Total
2009 = 3
2013 = 0
2013 = 13
2012 = 2
2012 = 12
2011 = 1
2011 = 8
2010 = 0
2010 = 13
2009 = 1
94
354
448
196 after removal of duplicates
American Diabetes Association (ADA) Scientific Sessions
www.diabetes.org/
Searched 10.9.14
74th American Diabetes Association Scientific Sessions. 13-17 June 2014, San Francisco, CA
http://www.abstractsonline.com/plan/start.aspx?mkey={40FC5C61-819A-4D1B-AABA3705F7D0EA76}
73rd American Diabetes Association Scientific Sessions. 21-25 June 2013, Chicago, IL
http://www.abstractsonline.com/plan/start.aspx?mkey={89918D6D-3018-4EA9-9D4F711F98A7AE5D}
72nd American Diabetes Association Scientific Sessions. 8-12 June 2012, Philadelphia, PA
http://www.abstractsonline.com/plan/start.aspx?mkey={0F70410F-8DF3-49F5-A63D3165359F5371}
Terms
"sensor augmented pump"
"sensor augmented pumps"
SAPT
minimed
paradigmveo
"paradigm veo"
"veo pump"
animas
vibe
Hits in Abstract Title
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 2
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
2014 = 0
2013 = 0
2012 = 0
156
CONFIDENTIAL UNTIL PUBLISHED
dexcom
2014 = 1
2013 = 0
2012 = 1
"insulin pump"
2014 = 16
2013 = 7
2012 = 12
"insulin pumps"
2014 = 6
2013 = 0
2012 = 1
"continuous subcutaneous insulin 2014 = 5
infusion"
2013 = 6
2012 = 3
CSII
2014 = 8
2013 = 7
2012 = 5
"artificial pancreas"
2014 = 13
2013 = 7
2012 = 4
"multiple daily injection"
2014 = 1
2013 = 0
2012 = 0
"multiple daily injections"
2014 = 1
2013 = 0
2012 = 0
MDI
2014 = 2
2013 = 6
2012 = 1
Total
115
91 after removal of duplicates
Cost-effectiveness searches
NHS Economic Evaluation Database (NHS EED) (Wiley Online Library). Issue 3 of 4:
July 2014
Searched 5.9.14
#1
MeSH descriptor: [Diabetes Mellitus, Type 1] this term only
#2
MeSH descriptor: [Diabetic Ketoacidosis] this term only
#3
(diabet* near/3 (typ* next 1 or typ* next i or type1 or typei or typ* next
one)):ti,ab,kw
#4
(diabet* near/3 (britt* or juvenil* or pediatric or paediatric or early or keto* or labil*
or acidos* or autoimmun* or auto next immun* or sudden next onset)):ti,ab,kw
#5
((insulin* near/2 depend*) or insulindepend*):ti,ab,kw
#6
(dm1 or dm next 1 or dmt1 or dm next t1 or t1dm or t1 next dm or t1d or
iddm):ti,ab,kw
#7
(ketoacidosis or acidoketosis or keto next acidosis or ketoacidemia or
ketosis):ti,ab,kw
#8
MeSH descriptor: [Hyperglycemia] this term only
#9
MeSH descriptor: [Hypoglycemia] this term only
#10
(hyperglyc?em* or hypoglyc?em*):ti,ab,kw
#11
((high or higher or low or lower or increas* or decreas* or deficien* or sufficien* or
insufficien* or reduce* or reduction* or fluctuat* or fallen or falling or threshold or safe)
near/3 (glucose* or sugar* or hba1c or hb next a1 or hba1 or a1c or h?emoglob* or
glycoh?emoglob*)):ti,ab,kw
157
CONFIDENTIAL UNTIL PUBLISHED
#12
#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13
(sensor* near/3 (augment* or pump*))
#14
SAPT:ti,ab,kw
#15
minimed or paradigmveo
#16
(paradigm* near/3 (veo or pump*))
#17
(veo near/3 pump*)
#18
((animas or vibe) near/3 (pump* or infus* or system*))
#19
dexcom
#20
#13 or #14 or #15 or #16 or #17 or #18 or #19
#21
MeSH descriptor: [Insulin Infusion Systems] this term only
#22
MeSH descriptor: [Pancreas, Artificial] this term only
#23
(insulin* near/3 (pump* or infus* or deliver* or catheter*)):ti,ab,kw
#24
(pump* near/2 (therap* or treatment*)):ti,ab,kw
#25
((subcutaneous near/2 insulin*) or CSII):ti,ab,kw
#26
(artificial near/3 (pancreas or beta next cell*)):ti,ab,kw
#27
(closed next loop near/3 (pump* or deliver* or infus* or therap* or treatment* or
system*)):ti,ab,kw
#28
accu-chek or cellnovo or dana next diabecare or omnipod
#29
((integrat* or dual or combined or unified) near/3 (system* or device*)):ti,ab,kw
#30
#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29
#31
MeSH descriptor: [Insulin] this term only
#32
MeSH descriptor: [Injections, Subcutaneous] this term only
#33
#31 and #32
#34
"multiple daily" near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#35
"multiple dose" near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#36
multiple near/3 (inject* or insulin* or regime* or routine*):ti,ab,kw
#37
MDI:ti,ab,kw
#38
injection near/3 therapy:ti,ab,kw
#39
(basal* and bolus) near/3 (inject* or regime* or routine* or system*):ti,ab,kw
#40
("short acting" near/3 insulin) or ("rapid acting" near/3 insulin):ti,ab,kw
#41
#34 or #35 or #36 or #37 or #38 or #39 or #40
#42
#12 and (#20 or #30 or #41)
NHS EED retrieved 16 records
HEED (Wiley): up to 2014/9/5
Searched 5.9.14
AX='sensor augmented' or sensor-augmented or SAPT (1)
AX=minimed or paradigmveo or 'paradigm veo' or 'paradigm pump' or 'veo pump' or 'animas
pump' or 'animas infusion' or 'vibe pump' or 'vibe infusion' or 'g4 platinum' or dexcom (0)
CS=1 or 2 (1)
AX=diabetes or dm1 or 'dm 1' or dmt1 or 'dm t1' or t1dm or 't1 dm' or t1d or iddm (2289)
AX=ketoacidosis or acidoketosis or 'keto acidosis' or ketoacidemia or ketosis (28)
AX=hyperglycemia or hypoglycemia or hyperglycaemia or hypoglycaemia (146)
CS=4 or 5 or 6 (2321)
AX='insulin pump' or 'insulin pumps' or 'insulin infusion' or 'insulin infusions' or 'insulin
delivery' (46)
AX='pump therapy' or 'subcutaneous insulin' or CSII or 'artificial pancreas' or 'artificial betacell' (41)
AX='closed loop' or accu-chek or cellnovo or 'dana diabecare' or omnipod (1)
AX='integrated system' or 'integrated systems' or 'integrated device' or 'integrated devices' or
'dual system' or 'dual systems' or 'dual device' or 'dual devices' (7)
AX='multiple daily injection' or 'multiple daily injections' or 'multiple daily insulin' or
'multiple dose injection' or 'multiple dose injections' or 'multiple dose insulin' or AX='multiple
injection' or 'multiple injections' or 'multiple insulin' OR MDI (45)
158
CONFIDENTIAL UNTIL PUBLISHED
CS=8 or 9 or 10 or 11 or 12 (86)
CS=7 and 12 (52)
CS=3 or 14 (52)
Embase (OvidSP): 1974-2014/week 34
Searched 5.9.14
1 insulin dependent diabetes mellitus/ (78607)
2 exp diabetic ketoacidosis/ (7787)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (49088)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (29355)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (217259)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (20038)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(14231)
8 hypoglycemia/ or hyperglycemia/ (108615)
9 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (104051)
10
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (126603)
11 or/1-10 (436900)
12 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (598)
13 SAPT.ti,ab,ot,hw. (114)
14 (minimed or paradigmveo).ti,ab,ot,hw,dm,dv. (727)
15 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot,dm,dv. (127)
16 (veo adj3 pump$).ti,ab,ot,hw,dm,dv. (38)
17 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw,dm,dv. (25)
18 (g4 adj3 platinum).ti,ab,ot,hw,dm,dv. (27)
19 dexcom.ti,ab,ot,hw,dm,dv. (298)
20 or/12-19 (1674)
21 insulin pump/ (3425)
22 insulin infusion/ (5096)
23 artificial pancreas/ (1433)
24 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (17265)
25 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (3171)
26 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (4218)
27 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (2050)
28
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (1941)
29 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw,dm,dv. (529)
30
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(39256)
31 or/21-30 (62055)
32 insulin/ and exp injection/ (3392)
33 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (1188)
34 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (561)
35 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (9358)
36 MDI.ti,ab,hw,ot. (3791)
37 (injection adj3 therapy).ti,ab,ot,hw. (4157)
38
((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot.
(1491)
39 (short acting adj3 insulin).ti,ab,hw,ot. (1038)
40 (rapid acting adj3 insulin).ti,ab,hw,ot. (864)
159
CONFIDENTIAL UNTIL PUBLISHED
41 or/32-40 (22079)
42 20 or 31 or 41 (82594)
43 11 and 42 (18536)
44 health-economics/ (33789)
45 exp economic-evaluation/ (214699)
46 exp health-care-cost/ (207493)
47 exp pharmacoeconomics/ (168062)
48 or/44-47 (484055)
49
(econom$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (620526)
50 (expenditure$ not energy).ti,ab. (24446)
51 (value adj2 money).ti,ab. (1422)
52 budget$.ti,ab. (24740)
53 or/49-52 (645088)
54 48 or 53 (918375)
55 letter.pt. (853934)
56 editorial.pt. (454769)
57 note.pt. (566292)
58 or/55-57 (1874995)
59 54 not 58 (830092)
60 (metabolic adj cost).ti,ab. (913)
61 ((energy or oxygen) adj cost).ti,ab. (3189)
62 ((energy or oxygen) adj expenditure).ti,ab. (20605)
63 or/60-62 (23877)
64 59 not 63 (824949)
65 exp animal/ (19314568)
66 exp animal-experiment/ (1798176)
67 nonhuman/ (4359920)
68 (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dog or dogs
or cat or cats or bovine or sheep).ti,ab,sh. (4850843)
69 or/65-68 (20707342)
70 exp human/ (15050997)
71 exp human-experiment/ (328369)
72 70 or 71 (15052426)
73 69 not (69 and 72) (5655873)
74 64 not 73 (761307)
75 43 and 74 (1027)
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED EMBASE using OvidSP
(economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014 [accessed
2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedembase
MEDLINE (OvidSP): 1946-2014/Aug week 4
Searched 5.9.14
1 Diabetes Mellitus, Type 1/ (62323)
2 Diabetic Ketoacidosis/ (5178)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (69580)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (20273)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (30469)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (13085)
160
CONFIDENTIAL UNTIL PUBLISHED
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(9331)
8 Hyperglycemia/ (20833)
9 Hypoglycemia/ (21743)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (72656)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (94623)
12 or/1-11 (245714)
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (312)
14 SAPT.ti,ab,ot,hw. (93)
15 (minimed or paradigmveo).ti,ab,ot,hw. (197)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (34)
17 (veo adj3 pump$).ti,ab,ot,hw. (5)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (7)
19 (g4 adj3 platinum).ti,ab,ot,hw. (3)
20 dexcom.ti,ab,ot,hw. (44)
21 or/13-20 (645)
22 Insulin Infusion Systems/ (3988)
23 Pancreas, Artificial/ (402)
24 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (11972)
25 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (1810)
26 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (2474)
27 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (1203)
28
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (1310)
29 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw. (150)
30
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(32573)
31 or/22-30 (47787)
32 Insulin/ and Injections, Subcutaneous/ (2134)
33 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (624)
34 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (452)
35 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (6795)
36 MDI.ti,ab,hw,ot. (2372)
37 (injection adj3 therapy).ti,ab,ot,hw. (2858)
38
((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot.
(1015)
39 (short acting adj3 insulin).ti,ab,hw,ot. (466)
40 (rapid acting adj3 insulin).ti,ab,hw,ot. (468)
41 or/32-40 (15196)
42 21 or 31 or 41 (61753)
43 12 and 42 (10730)
44 economics/ (27125)
45 exp "costs and cost analysis"/ (184746)
46 economics, dental/ (1867)
47 exp "economics, hospital"/ (19806)
48 economics, medical/ (8680)
49 economics, nursing/ (3985)
50 economics, pharmaceutical/ (2574)
51
(economic$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (431861)
52 (expenditure$ not energy).ti,ab. (17649)
53 (value adj1 money).ti,ab. (23)
161
CONFIDENTIAL UNTIL PUBLISHED
54
55
56
57
58
59
60
61
62
63
64
65
66
budget$.ti,ab. (17373)
or/44-54 (557969)
((energy or oxygen) adj cost).ti,ab. (2704)
(metabolic adj cost).ti,ab. (788)
((energy or oxygen) adj expenditure).ti,ab. (16809)
or/56-58 (19580)
55 not 59 (553698)
letter.pt. (826900)
editorial.pt. (346911)
historical article.pt. (306574)
or/61-63 (1465388)
60 not 64 (525046)
43 and 65 (327)
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily Update
(OvidSP): September 4, 2014
Searched 5.9.14
1 Diabetes Mellitus, Type 1/ (36)
2 Diabetic Ketoacidosis/ (3)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (2614)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (1105)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (701)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (884)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(430)
8 Hyperglycemia/ (20)
9 Hypoglycemia/ (10)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (5462)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (7457)
12 or/1-11 (14909)
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (59)
14 SAPT.ti,ab,ot,hw. (83)
15 (minimed or paradigmveo).ti,ab,ot,hw. (13)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (4)
17 (veo adj3 pump$).ti,ab,ot,hw. (1)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (0)
19 (g4 adj3 platinum).ti,ab,ot,hw. (3)
20 dexcom.ti,ab,ot,hw. (7)
21 or/13-20 (164)
22 Insulin Infusion Systems/ (2)
23 Pancreas, Artificial/ (2)
24 (insulin$ adj3 (pump$ or infus$ or deliver$ or catheter$)).ti,ab,ot,hw. (504)
25 (pump$ adj2 (therap$ or treatment$)).ti,ab,ot,hw. (189)
26 ((subcutaneous adj2 insulin$) or CSII).ti,ab,ot,hw. (172)
162
CONFIDENTIAL UNTIL PUBLISHED
27 (artificial adj3 (pancreas or beta cell$)).ti,ab,ot,hw. (61)
28
(closed loop adj3 (pump$ or deliver$ or infus$ or therap$ or treatment$ or
system$)).ti,ab,ot,hw. (343)
29 (accu-chek or cellnovo or dana diabecare or omnipod).ti,ab,ot,hw. (16)
30
((integrat$ or dual or combined or unified) adj3 (system$ or device$)).ti,ab,ot,hw.
(4137)
31 or/22-30 (5154)
32 Insulin/ and Injections, Subcutaneous/ (3)
33 (multiple daily adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (66)
34 (multiple dose adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (9)
35 (multiple adj3 (inject$ or insulin$ or regime$ or routine$)).ti,ab,ot,hw. (492)
36 MDI.ti,ab,hw,ot. (161)
37 (injection adj3 therapy).ti,ab,ot,hw. (206)
38 ((basal$ and bolus) adj3 (injection$ or regime$ or routine$ or system$)).ti,ab,hw,ot. (51)
39 (short acting adj3 insulin).ti,ab,hw,ot. (29)
40 (rapid acting adj3 insulin).ti,ab,hw,ot. (59)
41 or/32-40 (937)
42 21 or 31 or 41 (6140)
43 12 and 42 (543)
44 economics/ (0)
45 exp "costs and cost analysis"/ (103)
46 economics, dental/ (0)
47 exp "economics, hospital"/ (10)
48 economics, medical/ (0)
49 economics, nursing/ (0)
50 economics, pharmaceutical/ (0)
51
(economic$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (51540)
52 (expenditure$ not energy).ti,ab. (1501)
53 (value adj1 money).ti,ab. (5)
54 budget$.ti,ab. (2211)
55 or/44-54 (53783)
56 ((energy or oxygen) adj cost).ti,ab. (294)
57 (metabolic adj cost).ti,ab. (80)
58 ((energy or oxygen) adj expenditure).ti,ab. (1183)
59 or/56-58 (1507)
60 55 not 59 (53348)
61 letter.pt. (30310)
62 editorial.pt. (18730)
63 historical article.pt. (112)
64 or/61-63 (49132)
65 60 not 64 (52805)
66 43 and 65 (35)
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
PubMed (NLM): up to 2014/9/5
http://www.ncbi.nlm.nih.gov/pubmed/
Searched 5.9.14
163
CONFIDENTIAL UNTIL PUBLISHED
#59
#58
#57
#56
#55
#54
#53
#52
#51
#50
#49
#48
#47
#46
#45
#44
#43
#42
#41
#40
#39
#38
#37
#36
#35
#34
#33
#32
#31
#30
#29
Search (#57 and #58)
Search (pubstatusaheadofprint OR publisher[sb] OR pubmednotmedline[sb])
Search (#46 and #56)
Search (#51 not #55)
Search (#52 or #53 or #54)
Search "energy expenditure"[tiab] or "oxygen expenditure"[tiab]
Search "metabolic cost"[tiab]
Search "energy cost"[tiab] or "oxygen cost"[tiab]
Search (#47 or #48 or #49 or #50)
Search budget*[tiab]
Search "value for money"
Search (expenditure*[tiab] not energy[tiab])
Search (economic*[tiab] or cost[tiab] or costs[tiab] or costly[tiab] or
costing[tiab] or price[tiab] or prices[tiab] or pricing[tiab] or
pharmacoeconomic*[tiab])
Search (#20 and #45)
Search (#28 or #36 or #44)
Search (#37 or #38 or #39 or #40 or #41 or #42 or #43)
Search ("short acting insulin"[tiab] OR "rapid acting insulin"[tiab])
Search (basal*[tiab] AND bolus[tiab] AND (injection*[tiab] OR regime*[tiab]
OR routine*[tiab] OR system*[tiab]))
Search "injection therapy"[tiab]
Search MDI[tiab]
Search "multiple injection"[tiab] or "multiple injections"[tiab] or "multiple
insulin"[tiab] or "multiple regime"[tiab] or "multiple regimes"[tiab] or "multiple
routine"[tiab] or "multiple routines"[tiab]
Search "multiple dose injection"[tiab] or "multiple dose injections"[tiab] or
"multiple dose insulin"[tiab] or "multiple dose regime"[tiab] or "multiple dose
regimes"[tiab] or "multiple dose routine"[tiab] or "multiple dose routines"[tiab]
Search "multiple daily injection"[tiab] or "multiple daily injections"[tiab] or
"multiple daily insulin"[tiab] or "multiple daily regime"[tiab] or "multiple daily
regimes"[tiab] or "multiple daily routine"[tiab] or "multiple daily routines"[tiab]
Search (#29 or #30 or #31 or #32 or #33 or #34 or #35)
Search "integrated system"[tiab] or "integrated systems"[tiab] "integrated
device"[tiab] or "integrated devices"[tiab] or "dual system"[tiab] or "dual
systems"[tiab] or "dual device"[tiab] or "dual devices"[tiab] or "combined
system"[tiab] or "combined systems"[tiab] or "combined device"[tiab] or
"combined devices"[tiab] or "unified system"[tiab] or "unified systems"[tiab] or
"unified device"[tiab] or "unified devices"[tiab]
Search (accu-chek[tiab] or cellnovo[tiab] or "dana diabecare"[tiab] or
omnipod[tiab])
Search "closed loop pump"[tiab] or "closed loop pumps"[tiab] or "closed loop
delivery"[tiab] or "closed loop infusion"[tiab] or "closed loop infusions"[tiab] or
"closed loop therapy"[tiab] or "closed loop treatment"[tiab] or "closed loop
treatments"[tiab] or "closed loop system"[tiab] or "closed loop systems"[tiab]
Search "artificial pancreas"[tiab] or "artificial beta cell"[tiab]
Search "subcutaneous insulin"[tiab] or CSII[tiab]
Search "pump therapy"[tiab] or "pump therapies"[tiab] or "pump
treatment"[tiab] or "pump treatments"[tiab]
Search "insulin pump"[tiab] or "insulin pumps"[tiab] or "insulin infusion"[tiab]
or "insulin infuse"[tiab] or "insulin infused"[tiab] or "insulin deliver"[tiab] or
164
20
1815003
188
498516
20445
17356
879
2972
503197
19728
928
19130
482242
5237
20242
9426
810
1549
2098
2524
2414
48
603
10964
1317
159
812
822
2385
920
7485
CONFIDENTIAL UNTIL PUBLISHED
"insulin delivery"[tiab]
#28
#27
#26
#25
#24
#23
#22
#21
#20
#19
#18
#17
#16
#15
Search (#21 or #22 or #23 or #24 or #25 or #26 or #27)
Search dexcom
Search (animas or vibe) AND (pump* or infus* or system*)
Search "veo pump" or "veo pumps"
Search ((paradigm* AND (veo or pump*)))
Search minimed or paradigmveo
Search SAPT[tiab]
Search "sensor augmented"[tiab] or "sensor augment"[tiab] or "sensor
pump"[tiab] or "pump sensor"[tiab] or "sensor pumps"[tiab]
Search (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12
or #13 or #14 or #15 or #16 or #17 or #18 or #19)
Search "high glycohemoglobin"[tiab] or "higher glycohemoglobin"[tiab] or "low
glycohemoglobin"[tiab] or "lower glycohemoglobin"[tiab] or "increase
glycohemoglobin"[tiab] or "increased glycohemoglobin"[tiab] or "increases
glycohemoglobin"[tiab] or "decrease glycohemoglobin"[tiab] or "decreased
glycohemoglobin"[tiab] or "decreases glycohemoglobin"[tiab] or "deficient
glycohemoglobin"[tiab] or "sufficient glycohemoglobin"[tiab] or "insufficient
glycohemoglobin"[tiab] or "reduce glycohemoglobin"[tiab] or "reduced
glycohemoglobin"[tiab] or "glycohemoglobin reduction"[tiab] or "fallen
glycohemoglobin"[tiab] or "falling glycohemoglobin"[tiab] or "glycohemoglobin
threshold"[tiab] or "safe glycohemoglobin"[tiab]
Search ("high haemoglobin"[tiab] or "higher haemoglobin"[tiab] or "low
haemoglobin"[tiab]
or
"lower
haemoglobin"[tiab]
or
"increase
haemoglobin"[tiab] or "increased haemoglobin"[tiab] or "increases
haemoglobin"[tiab] or "decrease haemoglobin"[tiab] or "decreased
haemoglobin"[tiab] or "decreases haemoglobin"[tiab] or "deficient
haemoglobin"[tiab] or "sufficient haemoglobin"[tiab] or "insufficient
haemoglobin"[tiab]
or
"reduce
haemoglobin"[tiab]
or
"reduced
haemoglobin"[tiab]
or
"haemoglobin
reduction"[tiab]
or
"fallen
haemoglobin"[tiab] or "falling haemoglobin"[tiab] or "haemoglobin
threshold"[tiab] or "safe haemoglobin"[tiab])
Search "high hemoglobin"[tiab] or "higher hemoglobin"[tiab] or "low
hemoglobin"[tiab] or "lower hemoglobin"[tiab] or "increase hemoglobin"[tiab]
or "increased hemoglobin"[tiab] or "increases hemoglobin"[tiab] or "decrease
hemoglobin"[tiab]
or
"decreasedchemoglobin"[tiab]
or
"decreases
hemoglobin"[tiab]
or
"deficient
hemoglobin"[tiab]
or
"sufficient
hemoglobin"[tiab]
or
"insufficient
hemoglobin"[tiab]
or
"reduce
hemoglobin"[tiab] or "reduced hemoglobin"[tiab] or "hemoglobin
reduction"[tiab] or "fallen hemoglobin"[tiab] or "falling hemoglobin"[tiab] or
"hemoglobin threshold"[tiab] or "safe hemoglobin"[tiab]
Search "high a1c"[tiab] or "higher a1c"[tiab] or "low a1c"[tiab] or "lower
a1c"[tiab] or "increase a1c"[tiab] or "increased a1c"[tiab] or "increases
a1c"[tiab] or "decrease a1c"[tiab] or "decreasedca1c"[tiab] or "decreases
a1c"[tiab] or "deficient a1c"[tiab] or "sufficient a1c"[tiab] or "insufficient
a1c"[tiab] or "reduce a1c"[tiab] or "reduced a1c"[tiab] or "a1c reduction"[tiab] or
"fallen a1c"[tiab] or "falling a1c"[tiab] or "a1c threshold"[tiab] or "safe
a1c"[tiab]
Search ((("high hba1"[tiab] or "higher hba1"[tiab] or "low hba1"[tiab] or "lower
hba1"[tiab] or "increase hba1"[tiab] or "increased hba1"[tiab] or "increases
hba1"[tiab] or "decrease hba1"[tiab] or "decreasedchba1"[tiab] or "decreases
hba1"[tiab] or "deficient hba1"[tiab] or "sufficient hba1"[tiab] or "insufficient
hba1"[tiab] or "reduce hba1"[tiab] or "reduced hba1"[tiab] or "hba1
165
928
54
81
15
350
216
184
91
126838
17
1161
3476
291
76
CONFIDENTIAL UNTIL PUBLISHED
#14
#13
#12
#11
#10
#9
#8
#7
#6
#5
#4
#3
#2
reduction"[tiab] or "fallen hba1"[tiab] or "falling hba1"[tiab] or "hba1
threshold"[tiab] or "safe hba1"[tiab])))
Search "high hb a1"[tiab] or "higher hb a1"[tiab] or "low hb a1"[tiab] or "lower
hb a1"[tiab] or "increase hb a1"[tiab] or "increased hb a1"[tiab] or "increases hb
a1"[tiab] or "decrease hb a1"[tiab] or "decreasedchb a1"[tiab] or "decreases hb
a1"[tiab] or "deficient hb a1"[tiab] or "sufficient hb a1"[tiab] or "insufficient hb
a1"[tiab] or "reduce hb a1"[tiab] or "reduced hb a1"[tiab] or "hb a1
reduction"[tiab] or "fallen hb a1"[tiab] or "falling hb a1"[tiab] or "hb a1
threshold"[tiab] or "safe hb a1"[tiab]
Search "high hba1c"[tiab] or "higher hba1c"[tiab] or "low hba1c"[tiab] or "lower
hba1c"[tiab] or "increase hba1c"[tiab] or "increased hba1c"[tiab] or "increases
hba1c"[tiab] or "decrease hba1c"[tiab] or "decreasedchba1c"[tiab] or "decreases
hba1c"[tiab] or "deficient hba1c"[tiab] or "sufficient hba1c"[tiab] or "insufficient
hba1c"[tiab] or "reduce hba1c"[tiab] or "reduced hba1c"[tiab] or "hba1c
reduction"[tiab] or "fallen hba1c"[tiab] or "falling hba1c"[tiab] or "hba1c
threshold"[tiab] or "safe hba1c"[tiab]
Search "high sugar"[tiab] or "higher sugar"[tiab] or "low sugar"[tiab] or "lower
sugar"[tiab] or "increase sugar"[tiab] or "increased sugar"[tiab] or "increases
sugar"[tiab] or "decrease sugar"[tiab] or "decreasedcsugar"[tiab] or "decreases
sugar"[tiab] or "deficient sugar"[tiab] or "sufficient sugar"[tiab] or "insufficient
sugar"[tiab] or "reduce sugar"[tiab] or "reduced sugar"[tiab] or "sugar
reduction"[tiab] or "fallen sugar"[tiab] or "falling sugar"[tiab] or "sugar
threshold"[tiab] or "safe sugar"[tiab]
Search ("high glucose"[tiab] or "higher glucose"[tiab] or "low glucose"[tiab] or
"lower glucose"[tiab] or "increase glucose"[tiab] or "increased glucose"[tiab] or
"increases
glucose"[tiab]
or
"decrease
glucose"[tiab]
or
"decreasedcglucose"[tiab] or "decreases glucose"[tiab] or "deficient
glucose"[tiab] or "sufficient glucose"[tiab] or "insufficient glucose"[tiab] or
"reduce glucose"[tiab] or "reduced glucose"[tiab] or "glucose reduction"[tiab] or
"fallen glucose"[tiab] or "falling glucose"[tiab] or "glucose threshold"[tiab] or
"safe glucose"[tiab])
Search (hyperglycemia[tiab] or hypoglycaemia[tiab] or hyperglycemic[tiab] or
hypoglycaemic[tiab])
Search ketoacidosis[tiab] or acidoketosis[tiab] or "keto acidosis"[tiab] or
ketoacidemia[tiab] or ketosis[tiab]
Search dm1[tiab] or "dm 1"[tiab] or t1dm[tiab] or "t1 dm"[tiab] or t1d[tiab] or
iddm[tiab]
Search "insulin dependent"[tiab] or insulindepend*[tiab]
Search "brittle diabetic"[tiab] or "diabetic juvenile"[tiab] or "diabetic
pediatric"[tiab] or "diabetic paediatric"[tiab] or "diabetic early"[tiab] or "diabetic
labile"[tiab] or "diabetic acidosis"[tiab] or "diabetic sudden onset"[tiab]
Search "diabetic brittle"[tiab] or "juvenile diabetic"[tiab] or "pediatric
diabetic"[tiab] or "paediatric diabetic"[tiab] or "early diabetic"[tiab] or "labile
diabetic"[tiab] or "acidosis diabetic"[tiab] or "sudden onset diabetic"[tiab]
Search "brittle diabetes"[tiab] or "diabetes juvenile"[tiab] or "diabetes
pediatric"[tiab] or "diabetes paediatric"[tiab] or "diabetes early"[tiab] or
"diabetes ketosis"[tiab] or "diabetes labile"[tiab] or "diabetes acidosis"[tiab] or
"diabetes sudden onset"[tiab]
Search "diabetes brittle"[tiab] or "juvenile diabetes"[tiab] or "pediatric
diabetes"[tiab] or "paediatric diabetes"[tiab] or "early diabetes"[tiab] or "ketosis
diabetes"[tiab] or "labile diabetes"[tiab] or "acidosis diabetes"[tiab] or "sudden
onset diabetes"[tiab]
Search "diabetic type 1"[tiab] OR "type 1 diabetic"[tiab] OR "diabetic type
i"[tiab] OR "type i diabetic"[tiab] OR "diabetic type1"[tiab] OR "type1
166
0
1271
1539
16645
44267
7293
13131
27550
348
1122
264
2238
6044
CONFIDENTIAL UNTIL PUBLISHED
#1
diabetic"[tiab] OR "diabetic typei"[tiab] OR "typei diabetic"[tiab]
Search ((("diabetes type 1"[tiab] OR "type 1 diabetes"[tiab] OR "diabetes type
i"[tiab] OR "type i diabetes"[tiab] OR "diabetes type1"[tiab] OR "type1
diabetes"[tiab] OR "diabetes typei"[tiab] OR "typei diabetes"[tiab])))
28884
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
EconLit (EBSCO): 1969-20140801
Searched 5.9.14
S28
S7 AND S27
(1)
S27
(S11 OR S19 OR S26) (2,379)
S26
S20 OR S21 OR S22 OR S23 OR S24 OR S25 (174)
S25
TI ("short acting" N3 insulin or "rapid acting" N3 insulin) or AB ("short acting" N3
insulin or "rapid acting" N3 insulin)
(0)
S24
TI (((basal* and bolus) N3 injection*) or ((basal* and bolus) N3 regime*) or ((basal*
and bolus) N3 routine*) or ((basal* and bolus) N3 system*)) or AB (((basal* and bolus) N3
injection*) or ((basal* and bolus) N3 regime*) or ((basal* and bolus) N3 routine*) or ((basal*
and bolus) N3 system*))
(0)
S23
TI (MDI or injection N3 therapy) or AB (MDI or injection N3 therapy) (11)
S22
TI (multiple N3 inject* or multiple N3 insulin* or multiple N3 regime* or multiple
N3 routine*) or AB (multiple N3 inject* or multiple N3 insulin* or multiple N3 regime* or
multiple N3 routine*) (163)
S21
TI ("multiple dose" N3 inject* or "multiple dose" N3 insulin* or "multiple dose" N3
regime* or "multiple dose" N3 routine*) or AB ("multiple dose" N3 inject* or "multiple
dose" N3 insulin* or "multiple dose" N3 regime* or "multiple dose" N3 routine*)
(0)
S20
TI ("multiple daily" N3 inject* or "multiple daily" N3 insulin* or "multiple daily" N3
regime* or "multiple daily" N3 routine*) or AB ("multiple daily" N3 inject* or "multiple
daily" N3 insulin* or "multiple daily" N3 regime* or "multiple daily" N3 routine*)
(0)
S19
S12 or S13 or S14 or S15 or S16 or S17 or S18 (2,206)
S18
TI (integrat* N3 system* or integrat* N3 device* or dual N3 system* or dual N3
device* or combined N3 system* or combined N3 device* or unified N3 system* or unified
N3 device) or AB (integrat* N3 system* or integrat* N3 device* or dual N3 system* or dual
N3 device* or combined N3 system* or combined N3 device* or unified N3 system* or
unified N3 device)
(2,187)
S17
TI (accu-chek or cellnovo or "dana diabecare" or omnipod) or AB (accu-chek or
cellnovo or "dana diabecare" or omnipod)
(0)
S16
TI ("closed loop" N3 pump* or "closed loop" N3 deliver* or "closed loop" N3 infus*
or "closed loop" N3 therap* or "closed loop" N3 treatment* or "closed loop" N3 system*) or
AB ("closed loop" N3 pump* or "closed loop" N3 deliver* or "closed loop" N3 infus* or
"closed loop" N3 therap* or "closed loop" N3 treatment* or "closed loop" N3 system*)
(18)
S15
TI (artificial N3 pancreas or artificial N3 "beta cell*" or artificial N2 beta-cell*) or
AB (artificial N3 pancreas or artificial N3 "beta cell*" or artificial N3 beta-cell*)
(0)
S14
TI (subcutaneous N2 insulin* or CSII) or AB (subcutaneous N2 insulin* or CSII
(2)
S13
TI (pump* N3 therap* or pump* N3 treatment*) or AB (pump* N3 therap* or pump*
N3 treatment*)
(1)
167
CONFIDENTIAL UNTIL PUBLISHED
S12
TI (insulin* N3 pump* or insulin* N3 infus* or insulin* N3 deliver* or insulin N3
catheter*) or AB (insulin* N3 pump* or insulin* N3 infus* or insulin* N3 deliver* or insulin
N3 catheter*) (1)
S11
S8 or S9 or S10
(0)
S10
TI (animas N3 pump* or animas N3 infus* or animas N3 system* or vibe N3 pump*
or vibe N3 infus* or vibe N3 system* or g4 N3 platinum or dexcom) or AB (animas N3
pump* or animas N3 infus* or animas N3 system* or vibe N3 pump* or vibe N3 infus* or
vibe N3 system* or g4 N3 platinum or dexcom)
(0)
S9
TI (minimed or paradigmveo or paradigm* N3 veo or paradigm* N3 pump* or veo
N3 pump*) or AB (minimed or paradigmveo or paradigm* N3 veo or paradigm* N3 pump*
or veo N3 pump*)
(0)
S8
TI (sensor* N3 augment* or sensor* N3 pump* or sensor-augment* or SAPT) or AB
(sensor* N3 augment* or sensor* N3 pump* or sensor-augment* or SAPT)
(0)
S7
S1 or S2 or S3 or S4 or S5 or S6
(26)
S6
TI (hyperglycem* or hypoglycem* or hyperglycaem* or hypoglycaem*) or AB
(hyperglycem* or hypoglycem* or hyperglycaem* or hypoglycaem*)
(5)
S5
TI (ketoacidosis or acidoketosis or "keto acidosis" or ketoacidemia or ketosis) or AB
(ketoacidosis or acidoketosis or "keto acidosis" or ketoacidemia or ketosis)
(0)
S4
TI (dm1 or "dm 1" or dmt1 or "dm t1" or t1dm or "t1 dm" or t1d or iddm) or AB
(dm1 or "dm 1" or dmt1 or "dm t1" or t1dm or "t1 dm" or t1d or iddm) (2)
S3
TI (insulin* N2 depend* or insulindepend*) or AB (insulin* N2 depend* or
insulindepend*)
(5)
S2
TI (diabet* N3 britt* or diabet* N3 juvenil* or diabet* N3 pediatric or diabet* N3
paediatric or diabet* N3 early or diabet* N3 keto* or diabet* N3 labil* or diabet* N3 acidos*
or diabet* N3 autoimmun* or diabet* N3 "auto immune*" or diabet* N3 "sudden onset") or
AB (diabet* N3 britt* or diabet* N3 juvenil* or diabet* N3 pediatric or diabet* N3 paediatric
or diabet* N3 early or diabet* N3 keto* or diabet* N3 labil* or diabet* N3 acidos* or diabet*
N3 autoimmun* or diabet* N3 "auto immune*" or di ... (2)
S1
TI (diabet* N3 "typ* 1" or diabet* N3 "typ* i" or diabet* N3 type1 or diabet* N3
typei or diabet* N3 "typ* one") or AB (diabet* N3 "typ* 1" or diabet* N3 "typ* i" or diabet*
N3 type1 or diabet* N3 typei or diabet* N3 "typ* one") (14)
CEA Registry (Internet): up to 2014/9/5
www.cearegistry.org
Searched 5.9.14
7 records retrieved
sensor augmented
sensor-augmented
SAPT
minimed
paradigmveo
paradigm veo
paradigm-veo
veo pump
animas
vibe pump
vibe infusion
vibe system
vibe systems
g4 platinum
dexcom
insulin pump
insulin pumps
168
CONFIDENTIAL UNTIL PUBLISHED
insulin infusion
insulin delivery
pump therapy
pump treatment
pump treatments
subcutaneous insulin
CSII
artificial pancreas
artificial beta cell
artificial beta-cell
closed loop
integrated system
integrated systems
integrated device
integrated devices
multiple daily injection
multiple daily injections
multiple dose injection
multiple dose injections
multiple daily insulin
multiple dose insulin
multiple injection
multiple injections
MDI
injection therapy
basal bolus
short acting insulin
rapid acting insulin
RePEc (Internet):up to 2014/9/5
http://repec.org/
Searched 5.9.14
IDEAS search interface
("diabetes mellitus type 1" | "diabetes type 1" | "diabetes mellitus type1" | "diabetes type1" |
"diabetes mellitus type I" | "diabetes type I" | "diabetes mellitus typeI" | "diabetes typeI" |
"diabetes mellitus type one" | "diabetes type one" | dm1 | "dm 1" | dmt1 | "dm t1" | t1dm | "t1
dm" | t1d | iddm | ketoacidosis) + ("sensor augmented" | sensor-augmented | SAPT | minimed |
paradigmveo | "paradigm veo" | "paradigm pump" | "veo pump" | animas | vibe | "g4
platinum" | dexcom)
Records retrieved: 0
("brittle diabetes" | "juvenile diabetes" | "pediatric diabetes" | "paediatric diabetes" | "early
diabetes" | "autoimmune diabetes" | "auto immune diabetes" | "sudden onset diabetes") +
("sensor augmented" | sensor-augmented | SAPT | minimed | paradigmveo | "paradigm veo" |
"paradigm pump" | "veo pump" | animas | vibe | "g4 platinum" | dexcom)
Records retrieved: 0
(hyperglycemia | hypoglycemia | hyperglycaemia | hypoglycaemia) + ("sensor augmented" |
sensor-augmented | SAPT | minimed | paradigmveo | "paradigm veo" | "paradigm pump" |
"veo pump" | animas | vibe | "g4 platinum" | dexcom)
Records retrieved: 0
169
CONFIDENTIAL UNTIL PUBLISHED
("diabetes mellitus type 1" | "diabetes type 1" | "diabetes mellitus type1" | "diabetes type1" |
"diabetes mellitus type I" | "diabetes type I" | "diabetes mellitus typeI" | "diabetes typeI" |
"diabetes mellitus type one" | "diabetes type one" | dm1 | "dm 1" | dmt1 | "dm t1" | t1dm | "t1
dm" | t1d | iddm | ketoacidosis) + ("insulin pump" | "insulin pumps" | "insulin infusion" |
"insulin delivery" | "pump therapy" | "pump treatment" | "pump treatments")
Records retrieved: 1
("diabetes mellitus type 1" | "diabetes type 1" | "diabetes mellitus type1" | "diabetes type1" |
"diabetes mellitus type I" | "diabetes type I" | "diabetes mellitus typeI" | "diabetes typeI" |
"diabetes mellitus type one" | "diabetes type one" | dm1 | "dm 1" | dmt1 | "dm t1" | t1dm | "t1
dm" | t1d | iddm | ketoacidosis) + ("subcutaneous insulin" | CSII | "artificial pancreas" |
"artificial beta cell" | "artificial beta-cell" | "artificial beta cells" | "artificial beta-cells" |
"closed loop" | closed-loop | "integrated system" | "integrated systems | "dual system" | "dual
systems" | "integrated device" | "integrated devices | "dual device" | "dual devices")
Records retrieved: 11
("brittle diabetes" | "juvenile diabetes" | "pediatric diabetes" | "paediatric diabetes" | "early
diabetes" | "autoimmune diabetes" | "auto immune diabetes" | "sudden onset diabetes") +
("insulin pump" | "insulin pumps" | "insulin infusion" | "insulin delivery" | "pump therapy" |
"pump treatment" | "pump treatments")
Records retrieved: 0
("brittle diabetes" | "juvenile diabetes" | "pediatric diabetes" | "paediatric diabetes" | "early
diabetes" | "autoimmune diabetes" | "auto immune diabetes" | "sudden onset diabetes") +
("subcutaneous insulin" | CSII | "artificial pancreas" | "artificial beta cell" | "artificial betacell" | "artificial beta cells" | "artificial beta-cells" | "closed loop" | closed-loop | "integrated
system" | "integrated systems | "dual system" | "dual systems" | "integrated device" |
"integrated devices | "dual device" | "dual devices")
Records retrieved: 0
(hyperglycemia | hypoglycemia | hyperglycaemia | hypoglycaemia) + ("insulin pump" |
"insulin pumps" | "insulin infusion" | "insulin delivery" | "pump therapy" | "pump treatment" |
"pump treatments")
Records retrieved: 0
(hyperglycemia | hypoglycemia | hyperglycaemia | hypoglycaemia) + ("subcutaneous insulin"
| CSII | "artificial pancreas" | "artificial beta cell" | "artificial beta-cell" | "artificial beta cells" |
"artificial beta-cells" | "closed loop" | closed-loop | "integrated system" | "integrated systems |
"dual system" | "dual systems" | "integrated device" | "integrated devices | "dual device" |
"dual devices")
Records retrieved: 0
("diabetes mellitus type 1" | "diabetes type 1" | "diabetes mellitus type1" | "diabetes type1" |
"diabetes mellitus type I" | "diabetes type I" | "diabetes mellitus typeI" | "diabetes typeI" |
"diabetes mellitus type one" | "diabetes type one" | dm1 | "dm 1" | dmt1 | "dm t1" | t1dm | "t1
dm" | t1d | iddm | ketoacidosis) + ("multiple daily injection" | "multiple daily injections" |
"multiple dose injection" | "multiple dose injections" | "multiple daily insulin" | "multiple dose
insulin" | "multiple injection" | "multiple injections" | MDI | "injection therapy" | "basal bolus"
| basal-bolus | basalbolus | "short acting insulin" | "rapid acting insulin")
Records retrieved: 11
("brittle diabetes" | "juvenile diabetes" | "pediatric diabetes" | "paediatric diabetes" | "early
diabetes" | "autoimmune diabetes" | "auto immune diabetes" | "sudden onset diabetes") +
("multiple daily injection" | "multiple daily injections" | "multiple dose injection" | "multiple
dose injections" | "multiple daily insulin" | "multiple dose insulin" | "multiple injection" |
170
CONFIDENTIAL UNTIL PUBLISHED
"multiple injections" | MDI | "injection therapy" | "basal bolus" | basal-bolus | basalbolus |
"short acting insulin" | "rapid acting insulin")
Records retrieved: 0
(hyperglycemia | hypoglycemia | hyperglycaemia | hypoglycaemia) + ("multiple daily
injection" | "multiple daily injections" | "multiple dose injection" | "multiple dose injections" |
"multiple daily insulin" | "multiple dose insulin" | "multiple injection" | "multiple injections" |
MDI | "injection therapy" | "basal bolus" | basal-bolus | basalbolus | "short acting insulin" |
"rapid acting insulin")
Records retrieved: 1
Records retrieved in Total: 24
Records retrieved after dedup: 11
Key:
|
+
" "
OR
AND
phrase search
Specific economic searches (MiniMed and Animas Vibe only)
NHS Economic Evaluation Database (NHS EED) (Wiley). Issue 3 of 4: July 2014
Searched 2.10.14
#1
#2
#3
#4
#5
#6
#7
#8
(sensor* near/3 (augment* or pump*))
SAPT:ti,ab,kw
minimed or paradigmveo
(paradigm* near/3 (veo or pump*))
(veo near/3 pump*)
((animas or vibe) near/3 (pump* or infus* or system*))
dexcom
#1 or #2 or #3 or #4 or #5 or #6 or #7
NHS EED
4
HEED (Wiley): up to 2014/10/2
Searched 2.10.14
AX='sensor augmented' or sensor-augmented or SAPT (1)
AX=minimed or paradigmveo or 'paradigm veo' or 'paradigm pump' or 'veo pump' or 'animas
pump' or 'animas infusion' or 'vibe pump' or 'vibe infusion' or 'g4 platinum' or dexcom (0)
CS=1 or 2 (1)
Embase (OvidSP): 1974-2014/week 39
Searched 2.10.14
1 insulin dependent diabetes mellitus/ (79725)
2 exp diabetic ketoacidosis/ (7880)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (50200)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (29720)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (221115)
171
CONFIDENTIAL UNTIL PUBLISHED
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (20641)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(14385)
8 hypoglycemia/ or hyperglycemia/ (110120)
9 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (105704)
10
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (128520)
11 or/1-10 (442805)
12 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (611)
13 SAPT.ti,ab,ot,hw. (114)
14 (minimed or paradigmveo).ti,ab,ot,hw,dm,dv. (746)
15 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot,dm,dv. (134)
16 (veo adj3 pump$).ti,ab,ot,hw,dm,dv. (41)
17 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw,dm,dv. (29)
18 (g4 adj3 platinum).ti,ab,ot,hw,dm,dv. (29)
19 dexcom.ti,ab,ot,hw,dm,dv. (314)
20 or/12-19 (1730)
21 11 and 20 (1156)
22 health-economics/ (33844)
23 exp economic-evaluation/ (215823)
24 exp health-care-cost/ (208556)
25 exp pharmacoeconomics/ (168747)
26 or/22-25 (486347)
27
(econom$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (625347)
28 (expenditure$ not energy).ti,ab. (24608)
29 (value adj2 money).ti,ab. (1430)
30 budget$.ti,ab. (24869)
31 or/27-30 (650042)
32 26 or 31 (924348)
33 letter.pt. (856710)
34 editorial.pt. (456641)
35 note.pt. (570035)
36 or/33-35 (1883386)
37 32 not 36 (835648)
38 (metabolic adj cost).ti,ab. (924)
39 ((energy or oxygen) adj cost).ti,ab. (3207)
40 ((energy or oxygen) adj expenditure).ti,ab. (20769)
41 or/38-40 (24065)
42 37 not 41 (830473)
43 exp animal/ (19415638)
44 exp animal-experiment/ (1804426)
45 nonhuman/ (4376931)
46 (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dog or dogs
or cat or cats or bovine or sheep).ti,ab,sh. (4869940)
47 or/43-46 (20812704)
48 exp human/ (15138243)
49 exp human-experiment/ (329281)
50 48 or 49 (15139672)
51 47 not (47 and 50) (5673989)
52 42 not 51 (766321)
53 21 and 52 (73)
172
CONFIDENTIAL UNTIL PUBLISHED
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED EMBASE using OvidSP
(economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014 [accessed
2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedembase
MEDLINE (OvidSP): 1946-2014/Sep week 4
Searched 2.10.14
1 Diabetes Mellitus, Type 1/ (62498)
2 Diabetic Ketoacidosis/ (5186)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (69786)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (20339)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (30496)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (13154)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(9345)
8 Hyperglycemia/ (20917)
9 Hypoglycemia/ (21796)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (72929)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (95034)
12 or/1-11 (246558)
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (313)
14 SAPT.ti,ab,ot,hw. (93)
15 (minimed or paradigmveo).ti,ab,ot,hw. (198)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (34)
17 (veo adj3 pump$).ti,ab,ot,hw. (5)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (7)
19 (g4 adj3 platinum).ti,ab,ot,hw. (4)
20 dexcom.ti,ab,ot,hw. (45)
21 or/13-20 (648)
22 12 and 21 (300)
23 economics/ (27132)
24 exp "costs and cost analysis"/ (185352)
25 economics, dental/ (1867)
26 exp "economics, hospital"/ (19852)
27 economics, medical/ (8682)
28 economics, nursing/ (3987)
29 economics, pharmaceutical/ (2577)
30
(economic$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (434246)
31 (expenditure$ not energy).ti,ab. (17736)
32 (value adj1 money).ti,ab. (23)
33 budget$.ti,ab. (17453)
34 or/23-33 (560640)
35 ((energy or oxygen) adj cost).ti,ab. (2713)
36 (metabolic adj cost).ti,ab. (793)
37 ((energy or oxygen) adj expenditure).ti,ab. (16876)
38 or/35-37 (19659)
39 34 not 38 (556354)
40 letter.pt. (829485)
173
CONFIDENTIAL UNTIL PUBLISHED
41
42
43
44
45
editorial.pt. (348438)
historical article.pt. (307377)
or/40-42 (1470234)
39 not 43 (527602)
22 and 44 (8)
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily Update
(OvidSP): October 1, 2014
Searched 2.10.14
1 Diabetes Mellitus, Type 1/ (64)
2 Diabetic Ketoacidosis/ (5)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (2660)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (1112)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (712)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (879)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(440)
8 Hyperglycemia/ (32)
9 Hypoglycemia/ (27)
10 (hyperglyc?em$ or hypoglyc?em$).ti,ab,ot. (5503)
11
((high or higher or low or lower or increas$ or decreas$ or deficien$ or sufficien$ or
insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or falling or threshold or safe) adj3
(glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$ or
glycoh?emoglob$)).ti,ab,ot,hw. (7549)
12 or/1-11 (15088)
13 (sensor$ adj3 (augment$ or pump$)).ti,ab,hw,ot. (61)
14 SAPT.ti,ab,ot,hw. (86)
15 (minimed or paradigmveo).ti,ab,ot,hw. (12)
16 (paradigm$ adj3 (veo or pump$)).ti,ab,hw,ot. (4)
17 (veo adj3 pump$).ti,ab,ot,hw. (1)
18 ((animas or vibe) adj3 (pump$ or infus$ or system$)).ti,ab,ot,hw. (0)
19 (g4 adj3 platinum).ti,ab,ot,hw. (3)
20 dexcom.ti,ab,ot,hw. (7)
21 or/13-20 (167)
22 12 and 21 (39)
23 economics/ (3)
24 exp "costs and cost analysis"/ (243)
25 economics, dental/ (0)
26 exp "economics, hospital"/ (22)
27 economics, medical/ (3)
28 economics, nursing/ (3)
29 economics, pharmaceutical/ (1)
30
(economic$ or cost or costs or costly or costing or price or prices or pricing or
pharmacoeconomic$).ti,ab. (52040)
31 (expenditure$ not energy).ti,ab. (1513)
32 (value adj1 money).ti,ab. (5)
33 budget$.ti,ab. (2216)
174
CONFIDENTIAL UNTIL PUBLISHED
34
35
36
37
38
39
40
41
42
43
44
45
or/23-33 (54328)
((energy or oxygen) adj cost).ti,ab. (303)
(metabolic adj cost).ti,ab. (83)
((energy or oxygen) adj expenditure).ti,ab. (1206)
or/35-37 (1538)
34 not 38 (53879)
letter.pt. (30601)
editorial.pt. (18927)
historical article.pt. (188)
or/40-42 (49699)
39 not 43 (53316)
22 and 44 (3)
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
PubMed (NLM): up to 2014/9/5
http://www.ncbi.nlm.nih.gov/pubmed/
Searched 5.9.14
#42
#41
#40
#39
#38
#37
#36
#35
#34
#33
#32
#31
#30
#29
#28
#27
#26
#25
#24
#23
#22
#21
#20
#19
Search (#41 and #42)
Search (pubstatusaheadofprint OR publisher[sb] OR pubmednotmedline[sb])
Search (#35 not #39)
Search ((#36 or #37 or #38))
Search "energy expenditure"[tiab] or "oxygen expenditure"[tiab]
Search "metabolic cost"[tiab]
Search "energy cost"[tiab] or "oxygen cost"[tiab]
Search ((#31 or #32 or #33 or #34))
Search budget*[tiab]
Search "value for money"
Search (expenditure*[tiab] not energy[tiab])
Search (economic*[tiab] or cost[tiab] or costs[tiab] or costly[tiab] or costing[tiab] or
price[tiab] or prices[tiab] or pricing[tiab] or pharmacoeconomic*[tiab])
Search (#20 and #29)
Search (#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28)
Search "g4 platinum"
Search dexcom
Search (animas or vibe) AND (pump* or infus* or system*)
Search "veo pump" or "veo pumps"
Search ((paradigm* AND (veo or pump*)))
Search minimed or paradigmveo
Search SAPT[tiab]
Search "sensor augmented"[tiab] or "sensor augment"[tiab] or "sensor pump"[tiab] or
"pump sensor"[tiab] or "sensor pumps"[tiab]
Search ((#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13
or #14 or #15 or #16 or #17 or #18 or #19))
Search "high glycohemoglobin"[tiab] or "higher glycohemoglobin"[tiab] or "low
glycohemoglobin"[tiab]
or
"lower
glycohemoglobin"[tiab]
or
"increase
175
0
1826775
501673
20549
17441
888
2986
506382
19827
934
19227
485328
276
937
10
56
81
15
354
217
187
92
127385
17
CONFIDENTIAL UNTIL PUBLISHED
#18
#17
#16
#15
#14
#13
#12
glycohemoglobin"[tiab] or "increased glycohemoglobin"[tiab] or "increases
glycohemoglobin"[tiab] or "decrease glycohemoglobin"[tiab] or "decreased
glycohemoglobin"[tiab] or "decreases glycohemoglobin"[tiab] or "deficient
glycohemoglobin"[tiab] or "sufficient glycohemoglobin"[tiab] or "insufficient
glycohemoglobin"[tiab]
or
"reduce
glycohemoglobin"[tiab]
or
"reduced
glycohemoglobin"[tiab]
or
"glycohemoglobin
reduction"[tiab]
or
"fallen
glycohemoglobin"[tiab] or "falling glycohemoglobin"[tiab] or "glycohemoglobin
threshold"[tiab] or "safe glycohemoglobin"[tiab]
Search ("high haemoglobin"[tiab] or "higher haemoglobin"[tiab] or "low
haemoglobin"[tiab] or "lower haemoglobin"[tiab] or "increase haemoglobin"[tiab] or
"increased haemoglobin"[tiab] or "increases haemoglobin"[tiab] or "decrease
haemoglobin"[tiab] or "decreased haemoglobin"[tiab] or "decreases haemoglobin"[tiab]
or "deficient haemoglobin"[tiab] or "sufficient haemoglobin"[tiab] or "insufficient
haemoglobin"[tiab] or "reduce haemoglobin"[tiab] or "reduced haemoglobin"[tiab] or
"haemoglobin reduction"[tiab] or "fallen haemoglobin"[tiab] or "falling
haemoglobin"[tiab] or "haemoglobin threshold"[tiab] or "safe haemoglobin"[tiab])
Search "high hemoglobin"[tiab] or "higher hemoglobin"[tiab] or "low
hemoglobin"[tiab] or "lower hemoglobin"[tiab] or "increase hemoglobin"[tiab] or
"increased hemoglobin"[tiab] or "increases hemoglobin"[tiab] or "decrease
hemoglobin"[tiab] or "decreasedchemoglobin"[tiab] or "decreases hemoglobin"[tiab] or
"deficient hemoglobin"[tiab] or "sufficient hemoglobin"[tiab] or "insufficient
hemoglobin"[tiab] or "reduce hemoglobin"[tiab] or "reduced hemoglobin"[tiab] or
"hemoglobin reduction"[tiab] or "fallen hemoglobin"[tiab] or "falling hemoglobin"[tiab]
or "hemoglobin threshold"[tiab] or "safe hemoglobin"[tiab]
Search "high a1c"[tiab] or "higher a1c"[tiab] or "low a1c"[tiab] or "lower a1c"[tiab] or
"increase a1c"[tiab] or "increased a1c"[tiab] or "increases a1c"[tiab] or "decrease
a1c"[tiab] or "decreasedca1c"[tiab] or "decreases a1c"[tiab] or "deficient a1c"[tiab] or
"sufficient a1c"[tiab] or "insufficient a1c"[tiab] or "reduce a1c"[tiab] or "reduced
a1c"[tiab] or "a1c reduction"[tiab] or "fallen a1c"[tiab] or "falling a1c"[tiab] or "a1c
threshold"[tiab] or "safe a1c"[tiab]
Search (((("high hba1"[tiab] or "higher hba1"[tiab] or "low hba1"[tiab] or "lower
hba1"[tiab] or "increase hba1"[tiab] or "increased hba1"[tiab] or "increases hba1"[tiab]
or "decrease hba1"[tiab] or "decreasedchba1"[tiab] or "decreases hba1"[tiab] or
"deficient hba1"[tiab] or "sufficient hba1"[tiab] or "insufficient hba1"[tiab] or "reduce
hba1"[tiab] or "reduced hba1"[tiab] or "hba1 reduction"[tiab] or "fallen hba1"[tiab] or
"falling hba1"[tiab] or "hba1 threshold"[tiab] or "safe hba1"[tiab]))))
Search "high hb a1"[tiab] or "higher hb a1"[tiab] or "low hb a1"[tiab] or "lower hb
a1"[tiab] or "increase hb a1"[tiab] or "increased hb a1"[tiab] or "increases hb a1"[tiab]
or "decrease hb a1"[tiab] or "decreasedchb a1"[tiab] or "decreases hb a1"[tiab] or
"deficient hb a1"[tiab] or "sufficient hb a1"[tiab] or "insufficient hb a1"[tiab] or "reduce
hb a1"[tiab] or "reduced hb a1"[tiab] or "hb a1 reduction"[tiab] or "fallen hb a1"[tiab] or
"falling hb a1"[tiab] or "hb a1 threshold"[tiab] or "safe hb a1"[tiab]
Search "high hba1c"[tiab] or "higher hba1c"[tiab] or "low hba1c"[tiab] or "lower
hba1c"[tiab] or "increase hba1c"[tiab] or "increased hba1c"[tiab] or "increases
hba1c"[tiab] or "decrease hba1c"[tiab] or "decreasedchba1c"[tiab] or "decreases
hba1c"[tiab] or "deficient hba1c"[tiab] or "sufficient hba1c"[tiab] or "insufficient
hba1c"[tiab] or "reduce hba1c"[tiab] or "reduced hba1c"[tiab] or "hba1c reduction"[tiab]
or "fallen hba1c"[tiab] or "falling hba1c"[tiab] or "hba1c threshold"[tiab] or "safe
hba1c"[tiab]
Search "high sugar"[tiab] or "higher sugar"[tiab] or "low sugar"[tiab] or "lower
sugar"[tiab] or "increase sugar"[tiab] or "increased sugar"[tiab] or "increases
sugar"[tiab] or "decrease sugar"[tiab] or "decreasedcsugar"[tiab] or "decreases
sugar"[tiab] or "deficient sugar"[tiab] or "sufficient sugar"[tiab] or "insufficient
sugar"[tiab] or "reduce sugar"[tiab] or "reduced sugar"[tiab] or "sugar reduction"[tiab]
or "fallen sugar"[tiab] or "falling sugar"[tiab] or "sugar threshold"[tiab] or "safe
176
1167
3497
294
76
0
1287
1551
CONFIDENTIAL UNTIL PUBLISHED
#11
#10
#9
#8
#7
#6
#5
#4
#3
#2
#1
sugar"[tiab]
Search ("high glucose"[tiab] or "higher glucose"[tiab] or "low glucose"[tiab] or "lower
glucose"[tiab] or "increase glucose"[tiab] or "increased glucose"[tiab] or "increases
glucose"[tiab] or "decrease glucose"[tiab] or "decreasedcglucose"[tiab] or "decreases
glucose"[tiab] or "deficient glucose"[tiab] or "sufficient glucose"[tiab] or "insufficient
glucose"[tiab] or "reduce glucose"[tiab] or "reduced glucose"[tiab] or "glucose
reduction"[tiab] or "fallen glucose"[tiab] or "falling glucose"[tiab] or "glucose
threshold"[tiab] or "safe glucose"[tiab])
Search (hyperglycemia[tiab] or hypoglycaemia[tiab] or hyperglycemic[tiab] or
hypoglycaemic[tiab])
Search ketoacidosis[tiab] or acidoketosis[tiab] or "keto acidosis"[tiab] or
ketoacidemia[tiab] or ketosis[tiab]
Search dm1[tiab] or "dm 1"[tiab] or t1dm[tiab] or "t1 dm"[tiab] or t1d[tiab] or
iddm[tiab]
Search "insulin dependent"[tiab] or insulindepend*[tiab]
Search "brittle diabetic"[tiab] or "diabetic juvenile"[tiab] or "diabetic pediatric"[tiab] or
"diabetic paediatric"[tiab] or "diabetic early"[tiab] or "diabetic labile"[tiab] or "diabetic
acidosis"[tiab] or "diabetic sudden onset"[tiab]
Search "diabetic brittle"[tiab] or "juvenile diabetic"[tiab] or "pediatric diabetic"[tiab] or
"paediatric diabetic"[tiab] or "early diabetic"[tiab] or "labile diabetic"[tiab] or "acidosis
diabetic"[tiab] or "sudden onset diabetic"[tiab]
Search "brittle diabetes"[tiab] or "diabetes juvenile"[tiab] or "diabetes pediatric"[tiab] or
"diabetes paediatric"[tiab] or "diabetes early"[tiab] or "diabetes ketosis"[tiab] or
"diabetes labile"[tiab] or "diabetes acidosis"[tiab] or "diabetes sudden onset"[tiab]
Search "diabetes brittle"[tiab] or "juvenile diabetes"[tiab] or "pediatric diabetes"[tiab] or
"paediatric diabetes"[tiab] or "early diabetes"[tiab] or "ketosis diabetes"[tiab] or "labile
diabetes"[tiab] or "acidosis diabetes"[tiab] or "sudden onset diabetes"[tiab]
Search "diabetic type 1"[tiab] OR "type 1 diabetic"[tiab] OR "diabetic type i"[tiab] OR
"type i diabetic"[tiab] OR "diabetic type1"[tiab] OR "type1 diabetic"[tiab] OR "diabetic
typei"[tiab] OR "typei diabetic"[tiab]
Search (((("diabetes type 1"[tiab] OR "type 1 diabetes"[tiab] OR "diabetes type i"[tiab]
OR "type i diabetes"[tiab] OR "diabetes type1"[tiab] OR "type1 diabetes"[tiab] OR
"diabetes typei"[tiab] OR "typei diabetes"[tiab]))))
Economics terms based on Costs filter:
Centre for Reviews and Dissemination. Search strategies: NHS EED MEDLINE using
OvidSP (economics filter) [Internet]. York: Centre for Reviews and Dissemination; 2014
[accessed 2.6.14]. Available from:
http://www.crd.york.ac.uk/crdweb/searchstrategies.asp#nhseedmedline
EconLit (EBSCO): 1969-20140801
Searched 2.10.14
S4
S1 or S2 or S3 (0)
S3
TI (animas N3 pump* or animas N3 infus* or animas N3 system* or vibe N3 pump*
or vibe N3 infus* or vibe N3 system* or g4 N3 platinum or dexcom) or AB (animas N3
pump* or animas N3 infus* or animas N3 system* or vibe N3 pump* or vibe N3 infus* or
vibe N3 system* or g4 N3 platinum or dexcom)
(0)
S2
TI (minimed or paradigmveo or paradigm* N3 veo or paradigm* N3 pump* or veo
N3 pump*) or AB (minimed or paradigmveo or paradigm* N3 veo or paradigm* N3 pump*
or veo N3 pump*)
(0)
S1
TI (sensor* N3 augment* or sensor* N3 pump* or sensor-augment* or SAPT) or AB
(sensor* N3 augment* or sensor* N3 pump* or sensor-augment* or SAPT)
(0)
177
16743
44476
7314
13200
27576
348
1125
264
2243
6061
29036
CONFIDENTIAL UNTIL PUBLISHED
CEA Registry (Internet): up to 2014/10/2
www.cearegistry.org
Searched 2.10.14
1 record retrieved
sensor augmented
sensor-augmented
SAPT
minimed
paradigmveo
paradigm veo
paradigm-veo
veo pump
animas
vibe pump
vibe infusion
vibe system
vibe systems
g4 platinum
dexcom
RePEc (Internet): up to 2014/10/2
http://repec.org/
Searched 2.10.14
IDEAS search interface
("diabetes mellitus type 1" | "diabetes type 1" | "diabetes mellitus type1" | "diabetes type1" |
"diabetes mellitus type I" | "diabetes type I" | "diabetes mellitus typeI" | "diabetes typeI" |
"diabetes mellitus type one" | "diabetes type one" | dm1 | "dm 1" | dmt1 | "dm t1" | t1dm | "t1
dm" | t1d | iddm | ketoacidosis) + ("sensor augmented" | sensor-augmented | SAPT | minimed |
paradigmveo | "paradigm veo" | "paradigm pump" | "veo pump" | animas | vibe | "g4
platinum" | dexcom)
Records retrieved: 0
("brittle diabetes" | "juvenile diabetes" | "pediatric diabetes" | "paediatric diabetes" | "early
diabetes" | "autoimmune diabetes" | "auto immune diabetes" | "sudden onset diabetes") +
("sensor augmented" | sensor-augmented | SAPT | minimed | paradigmveo | "paradigm veo" |
"paradigm pump" | "veo pump" | animas | vibe | "g4 platinum" | dexcom)
Records retrieved: 0
(hyperglycemia | hypoglycemia | hyperglycaemia | hypoglycaemia) + ("sensor augmented" |
sensor-augmented | SAPT | minimed | paradigmveo | "paradigm veo" | "paradigm pump" |
"veo pump" | animas | vibe | "g4 platinum" | dexcom)
Records retrieved: 0
Records retrieved in Total: 0
Key:
|
+
" "
OR
AND
phrase search
178
CONFIDENTIAL UNTIL PUBLISHED
Appendix 2: Risk of Bias assessment – results
Table 63: Risk of Bias assessment for all included studies
Study ID
Random
Allocation
Participant
sequence
Concealment
blinding
generation
ASPIRE-in-home
Unclear
Unclear
High
Bolli 2009
Low
Low
High
DeVries 2002
Low
Low
High
Doyle 2004
Low
Low
High
Eurythmics
Low
Low
High
Hirsch 2008
Unclear
Unclear
High
Lee 2007
Unclear
Unclear
Unclear
Ly 2013
Low
Unclear
High
Nosadini 1988
Unclear
Low
High
Nosari 1993
Unclear
Unclear
High
O'Connell 2009
Low
Unclear
High
OSLO
Low
Unclear
High
Peyrot 2009
Unclear
Unclear
Unclear
RealTrend
Unclear
Unclear
High
STAR-3
Unclear
Low
High
Thomas 2007
Unclear
Unclear
High
Thrailkill 2011
Low
Unclear
High
Tsui 2001
Low
Low
Unclear
Weintrob 2003
Unclear
Unclear
Unclear
Care staff
blinding
High
High
High
High
High
High
Unclear
High
High
High
High
High
Unclear
High
High
High
High
Unclear
Unclear
Outcome
assessor
blinding
High
High
High
High
High
High
Unclear
High
High
High
High
High
Unclear
High
High
High
High
Unclear
Unclear
Selective
outcome
reporting
Low
Low
Low
High
Low
Low
Low
Low
High
Low
Low
Low
Low
High
Low
Low
Low
Low
Low
Incomplete
data
Overall
High
High
High
Low
Unclear
High
Unclear
High
High
High
High
Low
Unclear
High
High
Unclear
High
High
Low
High
High
High
Low
Low
High
Unclear
High
High
High
High
Low
Unclear
High
High
Unclear
High
Unclear
Low
179
CONFIDENTIAL UNTIL PUBLISHED
Appendix 3: Data extraction tables
Table 64: Study characteristics for included studies in adults
Follow-up
Study name
Countries
Inclusion
(mths)
3
3.45
3.69
3.69
ASPIRE inhome
Lee 2007
Peyrot 2009
DeVries 2002
USA
USA
USA
The
Netherlands
Age: 16-70
HbA1c: 5.8-10%
CSII Experience: 6 months prior CSII
treatment
No. of Hypoglycaemic events: >1
episode of severe hypoglycaemia in the
previous 6 months excluded. ≥2
nocturnal hypoglycaemic events in the
run in period required
Age: Adults
HbA1c: ≥7.5%
CSII Experience: CSII naïve
No. of Hypoglycaemic events: NR
Age: Adults
HbA1c: NR
CSII Experience: CSII naïve
No. of Hypoglycaemic events: NR
Age: 18-70
HbA1c: ≥8.5%
CSII Experience: NR
Intervention
 CSII + CGM + Suspend: Paradigm Veo
pump + Enlite sensor
 CSII + CGM Integrated: Paradigm Revel
2.0 pump + Enlite sensor
 CSII + CGM Integrated: MiniMed
Paradigm REAL-Time 722 System as
adjunct to SMBG (Paradigm Link glucose
meter)
 MDI + SMBG: SMBG (Paradigm Link
glucose meter)
 CSII + CGM Integrated: Paradigm® 722
System (smart CSII pump with RT-CGM
and CareLink™ data management
software) as adjunct to SMBG (Becton
Dickinson meters and strips).
 MDI + SMBG: SMBG (Becton Dickinson
meters and strips) with CareLink™ data
management software
 CSII + SMBG: Disetronic H-TRONplus
insulin pump; Glucotouch or One Touch
Profile memory glucose meter (Lifescan)
No. analysed
for efficacy per
arm
121
126
8
8
14
13
32
180
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
6
Study name
Bolli 2009
Europe
Eurythmics
Denmark;
Switzerland;
Sweden; The
Netherlands;
France; UK;
Belgium;
Italy
USA
Hirsch 2008
9
Countries
Thomas 2007
UK
Tsui 2001
Canada
Inclusion
Intervention
No. of Hypoglycaemic events: NR
 MDI + SMBG: Glucotouch or One Touch
Profile memory glucose meter (Lifescan)
 CSII + SMBG: Minimed 508 + SMBG
 MDI + SMBG: NR
Age: 18-70
HbA1c: 6.5-9%
CSII Experience: CSII naïve
No. of Hypoglycaemic events: ≥2
episodes of severe hypoglycaemia in the
previous 6 months excluded
Age: 18-65
HbA1c: ≥8.2%
CSII Experience: CSII in the previous 6
months excluded
No. of Hypoglycaemic events: NR
Age: 18-80
HbA1c: ≥7.5%
CSII Experience: ≥6 months prior CSII
treatment
No. of Hypoglycaemic events: NR
Age: Adults
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: ≥1
episode of severe hypoglyaemia in the
previous 6 months
Age: 18-60
HbA1c: NR
CSII Experience: CSII naïve
No. analysed
for efficacy per
arm
40
24
26
 CSII + CGM Integrated: Paradigm REALTime System (Medtronic MiniMed Inc.)
with SMBG (meter not described)
 MDI + SMBG: SMBG (meter not
described)
41
 CSII + CGM Integrated: Paradigm 722
System (Medtronic)
 CSII + SMBG: SMBG and a Paradigm 715
Insulin Pump (Medtronic)
17
 CSII + SMBG: Medtronic 508 + SMBG
 MDI + SMBG: NR
7
7
 CSII + SMBG: MiniMed (Sylmar) 507
insulin infusion pump; Advantage meter
(Roche Diagnostics)
12
36
23
181
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
12
Study name
Nosadini 1988
STAR-3
84
OSLO
Countries
Inclusion
Intervention
 MDI + SMBG: Advantage meter (Roche
Diagnostics)
Italy
No. of Hypoglycaemic events: ≥2
episodes of severe hypoglycaemia in the
previous year excluded
Age: NR
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: NR
USA;
Canada
Norway
Age: 7-70
HbA1c: 7.4-9.5%
CSII Experience: CSII naïve or no CSII
in the last 3 years
No. of Hypoglycaemic events: ≥2
episodes of severe hypoglycaemia in the
previous year excluded
Age: 18-45
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: NR
 CSII + SMBG: Betatron II + SMBG (CSIIHOR)
 CSII + SMBG: Microjet Mc 20 + SMBG
(CSII-FBR)
 MDI + SMBG: NR (ICIT)
 CSII + CGM Integrated: MiniMed
Paradigm REAL-Time System, Medtronic
 MDI + SMBG: Guardian REAL-Time
Clinical, Medtronic
 CSII + SMBG: Nordisk Infuser (n=3) or
AutoSyringe AS6C (n=12)
 MDI + SMBG: NR
No. analysed
for efficacy per
arm
14
10
19
15
166
163
15
15
182
CONFIDENTIAL UNTIL PUBLISHED
Table 65: Study characteristics for included studies in children
Follow-up
Study name
Countries
Inclusion
(mths)
3.5
Age: 8-14
Weintrob 2003 Israel
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: NR
3.69
USA
Age: 8-21
Doyle 2004
HbA1c: 6.5-11%
CSII Experience: CSII naïve
No. of Hypoglycaemic events: NR
6
12
Hirsch 2008
STAR-3
Thrailkill 2011
USA
USA;
Canada
USA
Age: 12-<18
HbA1c: ≥7.5%
CSII Experience: ≥6 months prior
CSII treatment
No. of Hypoglycaemic events: NR
Age: 7-70
HbA1c: 7.4-9.5%
CSII Experience: CSII naïve or no
CSII in the last 3 years
No. of Hypoglycaemic events: ≥2
episodes of severe hypoglycaemia in
the previous year excluded
Age: 8-18
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: NR
Intervention
 CSII + SMBG: Programmable external
pump (MiniMed 508; MiniMed, Sylmar,
CA) using lispro (Humalog; Eli Lilli)
 MDI + SMBG: NR
 CSII + SMBG: Medtronic MiniMed 508
or Paradigm 511; Lifescan InDuo glucose
meter
 MDI + SMBG: MDI; Lifescan InDuo
glucose meter
 CSII + CGM Integrated: Paradigm 722
System (Medtronic)
 CSII + SMBG: SMBG and a Paradigm
715 Insulin Pump (Medtronic)
No. analysed for
efficacy per arm
11
12
16
16
49
49
 CSII + CGM Integrated: MiniMed
Paradigm REAL-Time System,
Medtronic
 MDI + SMBG: Guardian REAL-Time
Clinical, Medtronic
78
 CSII + SMBG: Animas pump model IR
1250; OneTouch Ultra blood glucose
meter (LifeScan, Inc., Milpitas, CA)
 MDI + SMBG: MDI; OneTouch Ultra
blood glucose meter (LifeScan, Inc.,
Milpitas, CA)
NR
78
NR
183
CONFIDENTIAL UNTIL PUBLISHED
Table 66: Study characteristics for included studies in mixed populations
FollowStudy name
Countries
Inclusion
up (mths)
3
6
12
O'Connell
2009
Hirsch 2008
Australia
USA
Ly 2013
Australia
RealTrend
France
STAR-3
USA;
Canada
Age: 13-40
HbA1c: ≤8.5%
CSII Experience: >3 months experience
with CSII
No. of Hypoglycaemic events: History of
severe hypoglycaemia while using CSII
excluded.
Age: 12-72
HbA1c: ≥7.5%
CSII Experience: ≥6 months prior CSII
treatment
No. of Hypoglycaemic events: NR
Age: 4-50
HbA1c: ≤8.5%
CSII Experience: ≥6 months prior CSII
treatment
No. of Hypoglycaemic events: NR
Age: 2-65
HbA1c: >8%
CSII Experience: NR
No. of Hypoglycaemic events: NR
Age: 7-70
HbA1c: 7.4-9.5%
CSII Experience: CSII naïve or no CSII in
the last 3 years
No. of Hypoglycaemic events: ≥2 episodes
of severe hypoglycaemia in the previous
year excluded
Intervention
 CSII + CGM Integrated: MiniMed Paradigm REALTime system (Medtronic MiniMed, Northridge, CA,
USA)
 CSII + SMBG: NR-Continue their usual insulin
pump therapy and SMBG regimen.
No. analysed
for efficacy per
arm
26
29
 CSII + CGM Integrated: Paradigm 722 System
(Medtronic)
 CSII + SMBG: SMBG and a Paradigm 715 Insulin
Pump (Medtronic)
66
 CSII + CGM + Suspend: Sensor-augmented pump
(Medtronic Paradigm Veo System, Medtronic
Minimed) with automated insulin suspension
 CSII + SMBG: Continue using their insulin pump
46
 CSII + CGM Non-integrated: Insulin pump + Holtertype CGM device
 CSII + SMBG: Paradigm 512/712 + SMBG
 CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
 MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
72
49
55
60
244
241
184
CONFIDENTIAL UNTIL PUBLISHED
Table 67: Study characteristics for included studies in pregnant women
Follow-up
Study name
Countries
Inclusion
(mths)
NR (9 months)
Nosari 1993
Italy
Age: Adults
HbA1c: NR
CSII Experience: NR
No. of Hypoglycaemic events: NR
Intervention
 CSII + SMBG: Microjet MC 20 and
Dahedi B.V. portable battery-powered
syringe infusion pumps
 MDI + SMBG: NR
No. analysed
for efficacy per
arm
16
16
185
CONFIDENTIAL UNTIL PUBLISHED
Table 68: Baseline characteristics for included studies in adults
Follow-up Study name Intervention
Total N
(mths)
3
3.45
3.69
ASPIRE inhome
Lee 2007
Peyrot 2009
CSII + CGM + Suspend:
Paradigm Veo pump +
Enlite sensor
CSII + CGM Integrated:
Paradigm Revel 2.0
pump + Enlite sensor
CSII + CGM Integrated:
MiniMed Paradigm
REAL-Time 722
System as adjunct to
SMBG (Paradigm Link
glucose meter)
MDI + SMBG: SMBG
(Paradigm Link glucose
meter)
CSII + CGM Integrated:
Paradigm® 722 System
(smart CSII pump with
RT-CGM and
CareLink™ data
management software)
as adjunct to SMBG
(Becton Dickinson
meters and strips).
MDI + SMBG: SMBG
(Becton Dickinson
meters and strips) with
CareLink™ data
Age in yrs
Gender N (%)
Duration
Diabetes
(yrs)
27.1 (12.5)
BMI
Weight (kg)
HbA1c
(%)
121
41.6 (12.8)
Male: 46 (38.0)
Female: 75 (62.0)
27.6
(4.6)
79.6 (15.9)
7.26 (0.7)
126
44.8 (13.8)
Male: 50 (39.7)
Female: 76 (60.3)
26.7 (12.7)
27.1
(4.3)
79.1 (15.1)
7.21 (0.8)
8
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR
(NR)
NR (NR)
9.45 (0.6)
8
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR
(NR)
NR (NR)
8.58 (1.3)
14
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR
(NR)
77.69 (18.7)
8.87 (0.9)
13
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR
(NR)
82.61 (16.0)
8.32 (1.1)
186
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
3.69
6
Study name
DeVries
2002
Bolli 2009
Eurythmics
Hirsch 2008
Intervention
management software
CSII + SMBG:
Disetronic H-TRONplus
insulin pump;
Glucotouch or One
Touch Profile memory
glucose meter (Lifescan)
MDI + SMBG:
Glucotouch or One
Touch Profile memory
glucose meter (Lifescan)
CSII + SMBG:
Minimed 508 + SMBG
MDI + SMBG: NR
CSII + CGM Integrated:
Paradigm REAL-Time
System (Medtronic
MiniMed Inc.) with
SMBG (meter not
described)
MDI + SMBG: SMBG
(meter not described)
CSII + CGM Integrated:
Paradigm 722 System
(Medtronic)
CSII + SMBG: SMBG
and a Paradigm 715
Insulin Pump
Total N
Age in yrs
Gender N (%)
Duration
Diabetes
(yrs)
BMI
Weight (kg)
HbA1c
(%)
32
36.2 (10.3)
Male: 21 (54.0)
Female: 18 (46.0)
17.6 (9.8)
NR
(NR)
77.3 (13.6)
9.27 (1.4)
40
37.3 (10.6)
Male: 21 (53.0)
Female: 19 (47.0)
18 (9.4)
NR
(NR)
79.8 (13.5)
9.25 (1.4)
24
37.6 (12.3)
18.5 (8.4)
7.7 (0.7)
42.4 (9.9)
70.8 (10.5)
7.8 (0.6)
41
39.3 (11.9)
23.8
(2.7)
24.3
(1.9)
NR
(NR)
70.1 (11.6)
26
Male: 13 (54.2)
Female: 11 (45.8)
Male: 14 (53.8)
Female: 12 (46.2)
Male: 22 (50.0)
Female: 22 (50.0)
NR (NR)
8.47 (0.9)
36
37.3 (10.7)
21 (9.4)
8.64 (0.9)
NR (NR)
NR
(NR)
NR
(NR)
NR (NR)
17
Male: 21 (53.8)
Female: 18 (46.2)
Male: NR (NR)
Female: NR (NR)
NR (NR)
8.37 (0.6)
23
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR
(NR)
NR (NR)
8.3 (0.5)
20.9 (10.6)
16.9 (10.7)
NR (NR)
187
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
9
12
Study name
Intervention
Thomas
2007
(Medtronic)
CSII + SMBG:
Medtronic 508 + SMBG
MDI + SMBG: NR
Tsui 2001
Nosadini
1988
STAR-3
84
OSLO
CSII + SMBG:
MiniMed (Sylmar) 507
insulin infusion pump;
Advantage meter
(Roche Diagnostics)
MDI + SMBG:
Advantage meter
(Roche Diagnostics)
CSII + SMBG: Betatron
II + SMBG (CSII-HOR)
CSII + SMBG: Microjet
Mc 20 + SMBG (CSIIFBR)
MDI + SMBG: NR
(ICIT)
CSII + CGM Integrated:
MiniMed Paradigm
REAL-Time System,
Medtronic
MDI + SMBG:
Guardian REAL-Time
Clinical, Medtronic
CSII + SMBG: Nordisk
Infuser (n=3) or
Total N
Age in yrs
Gender N (%)
Duration
Diabetes
(yrs)
BMI
Weight (kg)
HbA1c
(%)
7
NR (NR)
NR (NR)
8.5 (1.9)
NR (NR)
78 (15.2)
8.6 (1.1)
12
36 (12.0)
17 (10.0)
NR
(NR)
NR
(NR)
27 (4.0)
72.5 (8.6)
7
Male: NR (NR)
Female: NR (NR)
Male: NR (NR)
Female: NR (NR)
Male: 8 (62.0)
Female: 5 (38.0)
NR (NR)
7.7 (0.6)
14
36 (10.0)
Male: 10 (71.0)
Female: 4 (29.0)
15 (9.0)
26 (3.0)
NR (NR)
8.2 (0.7)
10
34 (3.0)
7 (3.0)
NR (NR)
36 (6.0)
NR
(NR)
NR
(NR)
70 (7.0)
19
Male: 6 (60.0)
Female: 4 (40.0)
Male: 11 (57.9)
Female: 8 (42.1)
77 (7.0)
NR (NR)
15
32 (9.0)
7 (4.0)
NR (NR)
41.9 (12.3)
NR
(NR)
27.4
(4.4)
71 (6.0)
166
Male: 11 (73.3)
Female: 4 (26.7)
Male: 94 (57.0)
Female: 72 (43.0)
80.8 (15.9)
8.3 (0.5)
163
40.6 (12.0)
Male: 93 (57.0)
Female: 70 (43.0)
20.2 (11.7)
28.4
(5.7)
85.1 (18.5)
8.3 (0.5)
15
26 (19.8)
Male: 7 (46.7)
Female: 8 (53.3)
12.75 (NR)
NR
(NR)
68.6 (NR)
8.7 (NR)
NR (NR)
8 (3.0)
20.2 (12.2)
188
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study name
Intervention
Total N
Age in yrs
Gender N (%)
Duration
Diabetes
(yrs)
BMI
Weight (kg)
HbA1c
(%)
AutoSyringe AS6C
(n=12)
MDI + SMBG: NR
15
26 (22.7)
Male: 7 (46.7)
Female: 8 (53.3)
12.83 (NR)
NR
(NR)
71.7 (NR)
8.3 (NR)
189
CONFIDENTIAL UNTIL PUBLISHED
Table 69: Baseline characteristics for included studies in children
Follow-up Study name Intervention
Total
(mths)
N
3.5
3.69
6
12
Weintrob
2003
Doyle 2004
Hirsch 2008
STAR-3
Thrailkill
2011
Age in
yrs
Gender N (%)
Duration
Diabetes
(yrs)
5.3 (1.9)
BMI
Weight (kg)
HbA1c
(%)
NR (NR)
NR (NR)
7.9 (1.3)
CSII + SMBG:
Programmable external pump
(MiniMed 508; MiniMed,
Sylmar, CA) using lispro
(Humalog; Eli Lilli)
MDI + SMBG: NR
11
11.9 (1.4)
Male: 4 (36.4)
Female: 7 (63.6)
12
11.6 (1.5)
6.3 (2.6)
NR (NR)
NR (NR)
8.6 (0.8)
CSII + SMBG: Medtronic
MiniMed 508 or Paradigm
511; Lifescan InDuo glucose
meter
MDI + SMBG: MDI;
Lifescan InDuo glucose
meter
CSII + CGM Integrated:
Paradigm 722 System
(Medtronic)
CSII + SMBG: SMBG and a
Paradigm 715 Insulin Pump
(Medtronic)
CSII + CGM Integrated:
MiniMed Paradigm REALTime System, Medtronic
MDI + SMBG: Guardian
REAL-Time Clinical,
Medtronic
CSII + SMBG: Animas
pump model IR 1250;
16
12.5 (3.2)
Male: 6 (50.0)
Female: 6 (50.0)
Male: 6 (37.5)
Female: 10 (62.5)
6.8 (3.8)
NR (NR)
NR (NR)
8.1 (1.2)
16
13 (2.8)
Male: 8 (50.0)
Female: 8 (50.0)
5.6 (4.0)
NR (NR)
NR (NR)
8.2 (1.1)
49
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR (NR)
NR (NR)
8.82 (1.1)
49
NR (NR)
Male: NR (NR)
Female: NR (NR)
NR (NR)
NR (NR)
NR (NR)
8.59 (0.8)
78
11.7 (3.0)
Male: 46 (59.0)
Female: 32 (41.0)
4.7 (3.1)
20.2 (3.8)
49 (17.9)
8.3 (0.6)
78
12.7 (3.1)
Male: 41 (53.0)
Female: 37 (47.0)
5.4 (3.7)
20.6 (4.5)
51.6 (19.3)
8.3 (0.5)
NR
12.1 (3.6)
Male: 5 (41.7)
Female: 7 (58.3)
0 (NA)
19.56
(4.1)
40.56 (13.6)
11.2 (2.1)
190
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study name
Intervention
OneTouch Ultra blood
glucose meter (LifeScan,
Inc., Milpitas, CA)
MDI + SMBG: MDI;
OneTouch Ultra blood
glucose meter (LifeScan,
Inc., Milpitas, CA)
Total
N
Age in
yrs
Gender N (%)
Duration
Diabetes
(yrs)
BMI
Weight (kg)
HbA1c
(%)
NR
12.1 (2.5)
Male: 6 (50.0)
Female: 6 (50.0)
0 (NA)
18.82
(3.4)
46.53 (12.6)
11.7 (2.6)
191
CONFIDENTIAL UNTIL PUBLISHED
Table 70: Baseline characteristics for included studies in mixed populations
Follow-up Study name Intervention
Total
Age in
(mths)
N
yrs
3
6
O'Connell
2009
Hirsch 2008
Ly 2013
RealTrend
12
STAR-3
CSII + CGM Integrated:
MiniMed Paradigm REALTime system (Medtronic
MiniMed, Northridge, CA,
USA)
CSII + SMBG: NR-Continue
their usual insulin pump
therapy and SMBG regimen.
CSII + CGM Integrated:
Paradigm 722 System
(Medtronic)
CSII + SMBG: SMBG and a
Paradigm 715 Insulin Pump
(Medtronic)
CSII + CGM + Suspend:
Sensor-augmented pump
(Medtronic Paradigm Veo
System, Medtronic Minimed)
with automated insulin
suspension
CSII + SMBG: Continue using
their insulin pump
CSII + CGM Non-integrated:
Insulin pump + Holter-type
CGM device
CSII + SMBG: Paradigm
512/712 + SMBG
CSII + CGM Integrated:
Gender N (%)
Duration
Diabetes
(yrs)
11.1 (7.6)
BMI
Weight (kg)
HbA1c
(%)
NR
(NR)
NR (NR)
7.3 (0.6)
26
23.4
(8.6)
Male: 9 (29.0)
Female: 22 (71.0)
29
23 (8.1)
Male: 9 (29.0)
Female: 22 (71.0)
9.2 (7.2)
NR
(NR)
NR (NR)
7.5 (0.7)
66
33
(14.6)
Male: 32 (48.5)
Female: 34 (51.5)
20.8 (12.4)
26.9
(5.5)
76.8 (19.3)
8.49 (0.8)
72
33.2
(16.4)
Male: 28 (39.9)
Female: 44 (61.1)
16.7 (10.5)
26.3
(5.1)
75.4 (18.0)
8.39 (0.6)
46
17.4
(10.6)
Male: 26 (56.5)
Female: 20 (43.5)
9.8 (7.4)
NR
(NR)
NR (NR)
7.6 (0.9)
49
19.7
(12.9)
28.1
(15.1)
Male: 21 (42.9)
Female: 28 (57.1)
Male: 30 (54.5)
Female: 25 (45.5)
12.1 (10.0)
NR
(NR)
23.5
(4.1)
NR (NR)
7.4 (0.7)
65.7 (17.4)
9.11 (1.3)
28.8
(16.7)
32.2
Male: 34 (56.7)
Female: 26 (43.3)
Male: 140 (57.0)
12.3 (8.8)
22.5
(4.4)
25.3
62.6 (18.6)
9.28 (1.2)
71.9 (25.3)
8.3 (0.5)
55
60
244
11.2 (9.0)
15.2 (12.5)
192
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study name
Intervention
MiniMed Paradigm REALTime System, Medtronic
MDI + SMBG: Guardian
REAL-Time Clinical,
Medtronic
Total
N
241
Age in
yrs
Gender N (%)
(17.5)
Female: 104
(43.0)
Male: 134 (56.0)
Female: 107
(44.0)
31.5
(16.5)
Duration
Diabetes
(yrs)
BMI
Weight (kg)
HbA1c
(%)
73 (21.8)
8.3 (0.5)
(6.0)
15.4 (12.0)
25.6
(5.6)
193
CONFIDENTIAL UNTIL PUBLISHED
Table 71: Baseline characteristics for included studies in pregnant women
Study name
Intervention
Total N Age in yrs
Nosari 1993
CSII + SMBG: Microjet MC 20 and
Dahedi B.V. portable batterypowered syringe infusion pumps
MDI + SMBG: NR
16
25.5 (1.8)
16
27 (3.0)
Gender N (%)
Male: 0 (.0)
Female: 16
(100.0)
Male: 0 (.0)
Female: 16
(100.0)
Duration
Diabetes
(yrs)
NR (NR)
BMI
Weight (kg)
HbA1c
(%)
21.8 (.4)
NR (NR)
NR (NR)
NR (NR)
21.6 (.6)
NR (NR)
NR (NR)
194
CONFIDENTIAL UNTIL PUBLISHED
Table 72: Results – change from baseline in HbA1c – adults
Follow-up
Study ID
Intervention
(mths)
2
CSII + SMBG: Medtronic 508 + SMBG
Thomas 2007
MDI + SMBG: NR
3
ASPIRE in-home
OSLO
3.45
3.68
Lee 2007
Peyrot 2009
Number
analysed
7
7
CSII + CGM + Suspend: Paradigm Veo pump + Enlite
sensor
121
CSII + CGM Integrated: Paradigm Revel 2.0 pump +
Enlite sensor
126
CSII + SMBG: NR
15
MDI + SMBG: NR
15
CSII + CGM Integrated: MiniMed Paradigm REALTime 722 System as adjunct to SMBG (Paradigm Link
glucose meter)
MDI + SMBG: SMBG (Paradigm Link glucose meter)
8
CSII + CGM Integrated: Paradigm® 722 System
(smart CSII pump with RT-CGM and CareLink™ data
management software) as adjunct to SMBG (Becton
Dickinson meters and strips).
MDI + SMBG: SMBG (Becton Dickinson meters and
14
8
13
Change from baseline in HbA1c
(%)
Baseline: 8.5 (1.9)
Follow-up: 7.3 (0.67)
Change from baseline: NR (NR)
Baseline: 8.6 (1.1)
Follow-up: 8.3 (1)
Change from baseline: NR (NR)
Baseline: 7.26 (0.71)
Follow-up: 7.24 (0.67)
Change from baseline: 0 (0.44)
Baseline: 7.21 (0.77)
Follow-up: 7.14 (0.77)
Change from baseline: -0.04 (0.42)
Baseline: 10.1 (NR)
Follow-up: 8.9 (NR)
Change from baseline: NR (NR)
Baseline: 9.4 (NR)
Follow-up: 8.7 (NR)
Change from baseline: NR (NR)
Baseline: 9.45 (0.55)
Follow-up: 7.4 (0.66)
Change from baseline: -2.05 (NR)
Baseline: 8.58 (1.3)
Follow-up: 7.5 (1.01)
Change from baseline: -1.08 (NR)
Baseline: 8.87 (0.89)
Follow-up: 7.16 (0.75)
Change from baseline: -1.71 (NR)
Baseline: 8.32 (1.05)
195
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study ID
Intervention
Number
analysed
strips) with CareLink™ data management software
3.69
4
6
DeVries 2002
Thomas 2007
Bolli 2009
Eurythmics
Hirsch 2008
CSII + SMBG: Disetronic H-TRONplus insulin pump;
Glucotouch or One Touch Profile memory glucose
meter (Lifescan)
MDI + SMBG: Glucotouch or One Touch Profile
memory glucose meter (Lifescan)
32
CSII + SMBG: Medtronic 508 + SMBG
7
MDI + SMBG: NR
7
CSII + SMBG: Minimed 508 + Glucose Monitor not
reported
24
MDI + SMBG: Insulin glargine plus mealtime insulin
lispro. Glucose monitor not reported.
26
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
41
CSII + CGM Integrated: Paradigm 722 System
(Medtronic)
49
CSII + SMBG: SMBG and a Paradigm 715 Insulin
49
40
36
Change from baseline in HbA1c
(%)
Follow-up: 7.3 (0.92)
Change from baseline: -1.02 (NR)
Baseline: 9.27 (1.4)
Follow-up: NR (NR)
Change from baseline: -0.91 (1.28)
Baseline: 9.25 (1.4)
Follow-up: NR (NR)
Change from baseline: -0.07 (0.7)
Baseline: 8.5 (1.9)
Follow-up: 7.4 (1.16)
Change from baseline: NR (NR)
Baseline: 8.6 (1.1)
Follow-up: 8 (0.9)
Change from baseline: NR (NR)
Baseline: 7.7 (0.7)
Follow-up: 7 (0.8)
Change from baseline: -0.7 (0.7)
Baseline: 7.8 (0.6)
Follow-up: 7.2 (0.7)
Change from baseline: -0.6 (0.8)
Baseline: 8.46 (0.95)
Follow-up: 7.23 (0.65)
Change from baseline: -1.23 (1.01)
Baseline: 8.59 (0.82)
Follow-up: 8.46 (1.04)
Change from baseline: -0.13 (0.56)
Baseline: 8.37 (0.6)
Follow-up: 7.68 (0.84)
Change from baseline: -0.69 (0.73)
Baseline: 8.3 (0.54)
196
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study ID
Intervention
Number
analysed
Pump (Medtronic)
OSLO
Thomas 2007
9
12
Tsui 2001
Nosadini 1988
OSLO
CSII + SMBG: NR
15
MDI + SMBG: NR
15
CSII + SMBG: Medtronic 508 + SMBG
7
MDI + SMBG: NR
7
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
CSII + SMBG: Betatron II + SMBG (CSII-HOR)
10
CSII + SMBG: Microjet Mc 20 + SMBG (CSII-FBR)
19
MDI + SMBG: NR (ICIT)
15
CSII + SMBG: NR
15
Change from baseline in HbA1c
(%)
Follow-up: 7.66 (0.67)
Change from baseline: -0.64 (0.57)
Baseline: 10.1 (NR)
Follow-up: 9.1 (NR)
Change from baseline: NR (NR)
Baseline: 9.4 (NR)
Follow-up: 8.8 (NR)
Change from baseline: NR (NR)
Baseline: 8.5 (1.9)
Follow-up: 7.4 (1)
Change from baseline: NR (NR)
Baseline: 8.6 (1.1)
Follow-up: 7.6 (0.7)
Change from baseline: NR (NR)
Baseline: 7.73 (0.6)
Follow-up: 7.38 (NR)
Change from baseline: NR (NR)
Baseline: 8.16 (0.7)
Follow-up: 7.56 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.1 (0.9)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.3 (0.7)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 7.1 (0.9)
Change from baseline: NR (NR)
Baseline: 10.1 (NR)
197
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study ID
STAR-3
24
OSLO
Intervention
Number
analysed
MDI + SMBG: NR
15
CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
166
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
163
CSII + SMBG: NR
15
MDI + SMBG: NR
15
Change from baseline in HbA1c
(%)
Follow-up: 8.5 (NR)
Change from baseline: NR (NR)
Baseline: 9.4 (NR)
Follow-up: 8.5 (NR)
Change from baseline: NR (NR)
Baseline: 8.3 (0.5)
Follow-up: NR (NR)
Change from baseline: -1 (0.7)
Baseline: 8.3 (0.5)
Follow-up: NR (NR)
Change from baseline: -0.4 (0.8)
Baseline: 10.1 (NR)
Follow-up: 8.7 (NR)
Change from baseline: NR (NR)
Baseline: 9.4 (NR)
Follow-up: 9.1 (NR)
Change from baseline: NR (NR)
198
CONFIDENTIAL UNTIL PUBLISHED
Table 73: Results – change from baseline in HbA1c – children
Follow-up
Study ID
Intervention
(mths)
3.5
CSII + SMBG: Programmable external pump
Weintrob 2003
(MiniMed 508; MiniMed, Sylmar, CA) using lispro
(Humalog; Eli Lilli)
MDI + SMBG: NR
3.69
6
Doyle 2004
Hirsch 2008
Thrailkill 2011
12
STAR-3
Number
analysed
11
12
CSII + SMBG: Medtronic MiniMed 508 or Paradigm
511; Lifescan InDuo glucose meter
16
MDI + SMBG: MDI; Lifescan InDuo glucose meter
16
CSII + CGM Integrated: Paradigm 722 System
(Medtronic)
17
CSII + SMBG: SMBG and a Paradigm 715 Insulin
Pump (Medtronic)
23
CSII + SMBG: Animas pump model IR 1250;
OneTouch Ultra blood glucose meter (LifeScan, Inc.,
Milpitas, CA)
MDI + SMBG: MDI; OneTouch Ultra blood glucose
meter (LifeScan, Inc., Milpitas, CA)
NR
CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
78
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
78
NR
Change from baseline in HbA1c
(%)
Baseline: 7.9 (1.3)
Follow-up: 7.9 (0.7)
Change from baseline: NR (NR)
Baseline: 8.6 (0.8)
Follow-up: 8.2 (0.8)
Change from baseline: NR (NR)
Baseline: 8.1 (1.2)
Follow-up: 7.2 (1)
Change from baseline: NR (NR)
Baseline: 8.2 (1.1)
Follow-up: 8.1 (1.2)
Change from baseline: NR (NR)
Baseline: 8.82 (1.05)
Follow-up: 8.02 (1.11)
Change from baseline: -0.79 (0.65)
Baseline: 8.59 (0.8)
Follow-up: 8.21 (0.97)
Change from baseline: -0.37 (0.95)
Baseline: 11.2 (2.1)
Follow-up: 6.34 (0.7)
Change from baseline: NR (NR)
Baseline: 11.7 (2.6)
Follow-up: 7 (1.1)
Change from baseline: NR (NR)
Baseline: 8.3 (0.6)
Follow-up: NR (NR)
Change from baseline: -0.4 (0.9)
Baseline: 8.3 (0.5)
Follow-up: NR (NR)
199
CONFIDENTIAL UNTIL PUBLISHED
Follow-up
(mths)
Study ID
Intervention
Thrailkill 2011
CSII + SMBG: Animas pump model IR 1250;
OneTouch Ultra blood glucose meter (LifeScan, Inc.,
Milpitas, CA)
MDI + SMBG: MDI; OneTouch Ultra blood glucose
meter (LifeScan, Inc., Milpitas, CA)
Number
analysed
NR
NR
Change from baseline in HbA1c
(%)
Change from baseline: 0.2 (1)
Baseline: 11.2 (2.1)
Follow-up: 6.9 (0.7)
Change from baseline: NR (NR)
Baseline: 11.7 (2.6)
Follow-up: 6.9 (0.9)
Change from baseline: NR (NR)
200
CONFIDENTIAL UNTIL PUBLISHED
Table 74: Results – change from baseline in HbA1c – mixed populations
Follow-up (mths) Study ID
Intervention
3
O'Connell 2009 CSII + CGM Integrated: MiniMed Paradigm
REAL-Time system (Medtronic MiniMed,
Northridge, CA, USA)
CSII + SMBG: Continue their usual insulin pump
therapy and SMBG regimen.
6
Hirsch 2008
Ly 2013
RealTrend
12
STAR-3
Number analysed
26
29
CSII + CGM Integrated: Paradigm 722 System
(Medtronic)
66
CSII + SMBG: SMBG and a Paradigm 715
Insulin Pump (Medtronic)
72
CSII + CGM + Suspend: Sensor-augmented pump
(Medtronic Paradigm Veo System, Medtronic
Minimed) with automated insulin suspension
CSII + SMBG: Continue using their insulin pump
46
CSII + CGM Non-integrated: Insulin pump +
Holter-type CGM device
55
CSII + SMBG: Paradigm 512/712 + SMBG
60
CSII + CGM Integrated: MiniMed Paradigm
REAL-Time System, Medtronic
244
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
241
49
Change from baseline in HbA1c (%)
Baseline: 7.3 (0.6)
Follow-up: 7.1 (0.8)
Change from baseline: NR (NR)
Baseline: 7.5 (0.7)
Follow-up: 7.8 (0.9)
Change from baseline: NR (NR)
Baseline: 8.39 (0.64)
Follow-up: 7.77 (0.92)
Change from baseline: -0.71 (0.71)
Baseline: 8.49 (0.76)
Follow-up: 7.84 (0.81)
Change from baseline: -0.56 (0.72)
Baseline: 7.6 (NR)
Follow-up: 7.5 (NR)
Change from baseline: −0.1 (NR)
Baseline: 7.4 (NR)
Follow-up: 7.4 (NR)
Change from baseline: −0.06 (NR)
Baseline: 9.11 (1.28)
Follow-up: NR (NR)
Change from baseline: -0.81 (1.09)
Baseline: 9.28 (1.19)
Follow-up: NR (NR)
Change from baseline: -0.57 (0.94)
Baseline: 8.3 (0.5)
Follow-up: 7.5 (NR)
Change from baseline: -0.8 (0.84)
Baseline: 8.3 (0.5)
Follow-up: 8.1 (NR)
Change from baseline: -0.2 (0.89)
201
CONFIDENTIAL UNTIL PUBLISHED
Table 75: Results – change from baseline in HbA1c – pregnant women
Study ID
Follow-up (mths) Intervention
Nosari 1993
1st trimester
2nd trimester
3rd trimester
CSII + SMBG: Microjet MC 20 and Dahedi B.V.
portable battery-powered syringe infusion pumps
Number
analysed
16
MDI + SMBG: NR
16
CSII + SMBG: Microjet MC 20 and Dahedi B.V.
portable battery-powered syringe infusion pumps
16
MDI + SMBG: NR
16
CSII + SMBG: Microjet MC 20 and Dahedi B.V.
portable battery-powered syringe infusion pumps
16
MDI + SMBG: NR
16
Change from baseline in HbA1c
(%)
Baseline: NR (NR)
Follow-up: 6 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.2 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.8 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.1 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.3 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 6.2 (NR)
Change from baseline: NR (NR)
202
CONFIDENTIAL UNTIL PUBLISHED
Table 76: Results – proportion achieving HbA1c ≤7% – adults
Follow-up (mths)
Study ID
Intervention
6
12
Eurythmics
STAR-3
CSII + CGM Integrated: Paradigm REAL-Time System
(Medtronic MiniMed Inc.) with SMBG (meter not described)
MDI + SMBG: SMBG (meter not described)
CSII + CGM Integrated: MiniMed Paradigm REAL-Time
System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical, Medtronic
Proportion achieving
HbA1c ≤7% (N, (%))
14 (34)
Total
Number
analysed
41
0 (0)
57 (34)
36
166
19 (12)
163
203
CONFIDENTIAL UNTIL PUBLISHED
Table 77: Results – proportion achieving HbA1c ≤7% – children
Follow-up (mths)
Study ID
Intervention
3.69
12
Doyle 2004
STAR-3
CSII + SMBG: Medtronic MiniMed 508 or Paradigm 511;
Lifescan InDuo glucose meter
MDI + SMBG: MDI; Lifescan InDuo glucose meter
CSII + CGM Integrated: MiniMed Paradigm REAL-Time
System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical, Medtronic
Proportion achieving
HbA1c ≤7% (N, (%))
8 (50)
Total
Number
analysed
16
2 (12.5)
10 (13)
16
78
4 (5)
78
204
CONFIDENTIAL UNTIL PUBLISHED
Table 78: Results – proportion achieving HbA1c ≤7% – mixed populations
Follow-up (mths) Study ID
Intervention
3
O'Connell 2009
6
Hirsch 2008
12
STAR-3
CSII + CGM Integrated: MiniMed Paradigm REAL-Time system
(Medtronic MiniMed, Northridge, CA, USA)
CSII + SMBG: Continue their usual insulin pump therapy and
SMBG regimen.
CSII + CGM Integrated: Paradigm 722 System (Medtronic)
CSII + SMBG: SMBG and a Paradigm 715 Insulin Pump
(Medtronic)
CSII + CGM Integrated: MiniMed Paradigm REAL-Time System,
Medtronic
MDI + SMBG: Guardian REAL-Time Clinical, Medtronic
Proportion achieving
HbA1c ≤7% (N, (%))
14 (56)
Total Number
analysed
26
5 (17)
29
16 (24.2)
12 (19.4)
66
72
67 (27)
244
23 (10)
241
205
CONFIDENTIAL UNTIL PUBLISHED
Table 79: Results – hypoglycaemia
Population Severity Followup (mths)
Adults
Any
6
Mild
6
NR
3.45
Severe
3.68
Study ID
Intervention
No. of people with Hypoglycaemia (No. with
event/ No. Analysed (%))
Bolli 2009
CSII + SMBG: Minimed 508 + Glucose
Monitor not reported
MDI + SMBG: Insulin glargine plus mealtime
insulin lispro. Glucose monitor not reported.
CSII + SMBG: Medtronic 508 + SMBG
MDI + SMBG: NR
CSII + CGM Integrated: MiniMed Paradigm
REAL-Time 722 System as adjunct to SMBG
(Paradigm Link glucose meter)
MDI + SMBG: SMBG (Paradigm Link glucose
meter)
CSII + SMBG: Disetronic H-TRONplus
insulin pump; Glucotouch or One Touch
Profile memory glucose meter (Lifescan)
MDI + SMBG: Glucotouch or One Touch
Profile memory glucose meter (Lifescan)
CSII + CGM Integrated: Paradigm® 722
System (smart CSII pump with RT-CGM and
CareLink™ data management software) as
adjunct to SMBG (Becton Dickinson meters
and strips).
MDI + SMBG: SMBG (Becton Dickinson
meters and strips) with CareLink™ data
management software
CSII + SMBG: Minimed 508 + Glucose
Monitor not reported
2/28 (7.14)
No. of
Hypoglycaemic
events (No. of events/
No. of people
Analysed)
NR
2/29 (6.90)
NR
NR
NR
0/8 (0.00)
141/7
75/7
NR
1/8 (12.50)
NR
3/32 (9.40)
NR
6/40 (15.00)
NR
NR
0/14
NR
3/13
23/28 (82.14)
NR
Thomas
2007
Lee 2007
DeVries
2002
Peyrot 2009
6
Bolli 2009
206
CONFIDENTIAL UNTIL PUBLISHED
Population Severity
Followup (mths)
12
Children
Severe
3.68
12
Study ID
Thomas
2007
STAR-3
Doyle 2004
STAR-3
Thrailkill
2011
Mixed
Moderate 6
Ly 2013
Intervention
No. of people with Hypoglycaemia (No. with
event/ No. Analysed (%))
MDI + SMBG: Insulin glargine plus mealtime
insulin lispro. Glucose monitor not reported.
CSII + SMBG: Medtronic 508 + SMBG
MDI + SMBG: NR
CSII + CGM Integrated: MiniMed Paradigm
REAL-Time System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
CSII + SMBG: Medtronic MiniMed 508 or
Paradigm 511; Lifescan InDuo glucose meter
MDI + SMBG: MDI; Lifescan InDuo glucose
meter
CSII + CGM Integrated: MiniMed Paradigm
REAL-Time System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
CSII + SMBG: Animas pump model IR 1250;
OneTouch Ultra blood glucose meter
(LifeScan, Inc., Milpitas, CA)
MDI + SMBG: MDI; OneTouch Ultra blood
glucose meter (LifeScan, Inc., Milpitas, CA)
CSII + CGM + Suspend: Sensor-augmented
pump (Medtronic Paradigm Veo System,
Medtronic Minimed) with automated insulin
suspension
CSII + SMBG: Continue using their insulin
pump
27/29 (93.10)
No. of
Hypoglycaemic
events (No. of events/
No. of people
Analysed)
NR
NR
NR
17/169 (10.10)
3/7
2/7
NR
13/167 (7.80)
NR
2/16 (12.50)
2/16
4/16 (25.00)
5/16
4/78 (5.10)
NR
4/81 (4.90)
NR
0/0 (0.00)
NR
0/0 (0.00)
NR
35/41 (85.37)
NR
13/45 (28.89)
NR
207
CONFIDENTIAL UNTIL PUBLISHED
Population Severity
Followup (mths)
Moderate 6
+ Severe
Severe
6
Study ID
Intervention
No. of people with Hypoglycaemia (No. with
event/ No. Analysed (%))
Ly 2013
CSII + CGM + Suspend: Sensor-augmented
pump (Medtronic Paradigm Veo System,
Medtronic Minimed) with automated insulin
suspension
CSII + SMBG: Continue using their insulin
pump
CSII + CGM Integrated: Paradigm 722 System
(Medtronic)
CSII + SMBG: SMBG and a Paradigm 715
Insulin Pump (Medtronic)
CSII + CGM + Suspend: Sensor-augmented
pump (Medtronic Paradigm Veo System,
Medtronic Minimed) with automated insulin
suspension
CSII + SMBG: Continue using their insulin
pump
CSII + CGM Integrated: MiniMed Paradigm
REAL-Time System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
CSII + SMBG: Microjet MC 20 and Dahedi
B.V. portable battery-powered syringe infusion
pumps
MDI + SMBG: NR
35/41 (85.37)
No. of
Hypoglycaemic
events (No. of events/
No. of people
Analysed)
NR
13/45 (28.89)
NR
Hirsch 2008
Ly 2013
12
Pregnant
Severe
NR
STAR-3
Nosari 1993
8/66 (NR)
11/66
3/72 (NR)
3/72
0/41 (0.00)
NR
6/45 (13.33)
NR
21/247 (8.50)
NR
17/248 (6.90)
NR
NR
3/NR
NR
1/NR
208
CONFIDENTIAL UNTIL PUBLISHED
Table 80: Results – hypoglycaemia event rate
Populatio Severity FollowEvent rate
n
up (mths) definition
Adults
Mild
3.69
6
12
NR
3
6
Number of mild
hypoglycaemic
episodes per patient
week
Study ID
Intervention
Hypoglycaemia
event rate
Hyperglycaemia
event rate
DeVries
2002
CSII + SMBG: Disetronic H-TRONplus
insulin pump; Glucotouch or One Touch
Profile memory glucose meter
(Lifescan)
MDI + SMBG: Glucotouch or One
Touch Profile memory glucose meter
(Lifescan)
CSII + SMBG: Medtronic 508 + SMBG
MDI + SMBG: NR
0.98 (2.0)
NR
Total
Number
analyse
d
32
-0.02 (1.2)
NR
40
40 (NR)
21 (NR)
NR
NR
7
7
CSII + SMBG: Betatron II + SMBG
(CSII-HOR)
CSII + SMBG: Microjet Mc 20 +
SMBG (CSII-FBR)
MDI + SMBG: NR (ICIT)
CSII + CGM + Suspend: Paradigm Veo
pump + Enlite sensor
CSII + CGM Integrated: Paradigm
Revel 2.0 pump + Enlite sensor
CSII + CGM + Suspend: Paradigm Veo
pump + Enlite sensor
CSII + CGM Integrated: Paradigm
Revel 2.0 pump + Enlite sensor
CSII + CGM Integrated: Paradigm
REAL-Time System (Medtronic
MiniMed Inc.) with SMBG (meter not
30 (11.0)
NR
10
36 (10.0)
NR
19
59 (12.0)
3.3 (2.0)
NR
NR
15
121
4.7 (2.7)
NR
126
1.5 (1.0)
NR
121
2.2 (1.3)
NR
126
NR
2.1 (0.8)
40
Mild Symptomatic
hypoglycaemia events per patient
year
Hypoglycaemic
events - events per
patient per year
Thomas
2007
Day and night
hypoglycaemia Events per patientweek
Nocturnal
hypoglycaemia Events per patientweek
Number of
hyperglycaemic
events standardized
ASPIRE inhome
Nosadini
1988
ASPIRE inhome
Eurythmics
209
CONFIDENTIAL UNTIL PUBLISHED
Populatio
n
Severity
Followup (mths)
Event rate
definition
Study ID
per day
Number of
hypoglycaemic
events standardized
per day
12
24
Severe
6
12
Hyperglycaemic
events - events per
patient per year
Symptomatic
hypoglycaemic
episodes Episodes/patient/w
eek
Severe
Hypoglycaemia events per patient
year
Hypoglycaemic
events - events per
patient per year
Eurythmics
Nosadini
1988
OSLO
Intervention
described)
MDI + SMBG: SMBG (meter not
described)
CSII + CGM Integrated: Paradigm
REAL-Time System (Medtronic
MiniMed Inc.) with SMBG (meter not
described)
MDI + SMBG: SMBG (meter not
described)
CSII + SMBG: Betatron II + SMBG
(CSII-HOR)
CSII + SMBG: Microjet Mc 20 +
SMBG (CSII-FBR)
MDI + SMBG: NR (ICIT)
CSII + SMBG: NR
MDI + SMBG: NR
Hypoglycaemia
event rate
Hyperglycaemia
event rate
Total
Number
analyse
d
NR
2.2 (0.7)
31
0.7 (0.7)
NR
40
0.6 (0.7)
NR
31
NR
17 (4.0)
10
NR
18 (5.0)
19
NR
1.7 (NR)
1.2 (NR)
20 (3.0)
NR
NR
15
15
15
Thomas
2007
CSII + SMBG: Medtronic 508 + SMBG
MDI + SMBG: NR
0.9 (NR)
0.6 (NR)
NR
NR
7
7
Nosadini
1988
CSII + SMBG: Betatron II + SMBG
(CSII-HOR)
CSII + SMBG: Microjet Mc 20 +
SMBG (CSII-FBR)
MDI + SMBG: NR (ICIT)
0.16 (0.1)
NR
10
0.14 (0.1)
NR
19
0.42 (0.2)
NR
15
210
CONFIDENTIAL UNTIL PUBLISHED
Populatio
n
Children
Mixed
Severity
Severe
Moderat
e
Moderat
e+
Severe
Followup (mths)
12
6
6
Event rate
definition
Study ID
Intervention
Hypoglycaemia
event rate
Hyperglycaemia
event rate
Severe
hypoglycaemia
event rate per 100
person-year
STAR-3
15.31 (NR)
NR
17.62 (NR)
NR
167
Severe
hypoglycaemia
event rate per 100
person-year
STAR-3
8.98 (NR)
NR
78
4.95 (NR)
NR
81
Rate of
Hypoglycaemic
events - 6-Month
rate per 100
patient-months
Ly 2013
28.5 (NR)
NR
46
9.6 (NR)
NR
49
Rate of
Hypoglycaemic
events - Incidence
rate per 100
patient-months
Ly 2013
9.6 (NR)
NR
41
26.3 (NR)
NR
45
Rate of
Hypoglycaemic
events - 6-Month
rate per 100
patient-months
Ly 2013
CSII + CGM Integrated: MiniMed
Paradigm REAL-Time System,
Medtronic
MDI + SMBG: Guardian REAL-Time
Clinical, Medtronic
CSII + CGM Integrated: MiniMed
Paradigm REAL-Time System,
Medtronic
MDI + SMBG: Guardian REAL-Time
Clinical, Medtronic
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
Total
Number
analyse
d
169
28.4 (NR)
NR
46
11.9 (NR)
NR
49
211
CONFIDENTIAL UNTIL PUBLISHED
Populatio
n
Severity
Severe
Followup (mths)
6
12
Event rate
definition
Study ID
Intervention
Hypoglycaemia
event rate
Hyperglycaemia
event rate
Rate of
Hypoglycaemic
events - Incidence
rate per 100
patient-months
Ly 2013
9.5 (NR)
NR
34.2 (NR)
NR
45
Rate of
Hypoglycaemic
events - 6-Month
rate per 100
patient-months
Ly 2013
0 (NR)
NR
46
2.2 (NR)
NR
49
Rate of
Hypoglycaemic
events - Incidence
rate per 100
patient-months
Ly 2013
NR (NR)
NR
41
NR (NR)
NR
45
Severe
hypoglycaemia
event rate per 100
person-year
STAR-3
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
CSII + CGM + Suspend: Sensoraugmented pump (Medtronic Paradigm
Veo System, Medtronic Minimed) with
automated insulin suspension
CSII + SMBG: Continue using their
insulin pump
CSII + CGM Integrated: MiniMed
Paradigm REAL-Time System,
Medtronic
MDI + SMBG: Guardian REAL-Time
Clinical, Medtronic
Total
Number
analyse
d
41
13.31 (NR)
NR
247
13.48 (NR)
NR
248
212
CONFIDENTIAL UNTIL PUBLISHED
Table 81: Results – HRQoL – adults (no data for children, mixed populations and pregnant women)
HRQoL Scale
FollowStudy ID
Intervention
up (mths)
Diabetes QOL
6
CSII + SMBG: Medtronic 508 + SMBG
Thomas
2007
Diabetes QOL
Diabetic worry
Diabetes QOL Global
health
Diabetes QOL Impact
Diabetes QOL
Satisfaction
9
9
9
9
Tsui 2001
Tsui 2001
Tsui 2001
Tsui 2001
Number
analysed
7
MDI + SMBG: NR
7
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
HRQoL Score
Baseline: 69 (19)
Follow-up: 74 (20)
Change from baseline: NR (NR)
Baseline: 47 (20)
Follow-up: 70 (11)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 85.2 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 79.8 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 68.2 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 67.3 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 69.9 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 68.4 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 75.6 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 68.3 (NR)
213
CONFIDENTIAL UNTIL PUBLISHED
HRQoL Scale
Followup (mths)
Study ID
Intervention
Diabetes QOL Social
worry
9
Tsui 2001
CSII + SMBG: MiniMed (Sylmar) 507 insulin infusion
pump; Advantage meter (Roche Diagnostics)
12
MDI + SMBG: Advantage meter (Roche Diagnostics)
14
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
153
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
151
CSII + SMBG: Disetronic H-TRONplus insulin pump;
Glucotouch or One Touch Profile memory glucose
meter (Lifescan)
NR
SF-36 Bodily Pain
SF-36 General Health
6
6
12
SF-36 General health
subscale
3.68
Eurythmics
Eurythmics
STAR-3
DeVries
2002
Number
analysed
33
33
HRQoL Score
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 89.6 (NR)
Change from baseline: NR (NR)
Baseline: NR (NR)
Follow-up: 94 (NR)
Change from baseline: NR (NR)
Baseline: 78.9 (25.4)
Follow-up: 79.9 (24.4)
Change from baseline: 1 (NR)
Baseline: 78.7 (23)
Follow-up: 78.7 (22.6)
Change from baseline: 0 (NR)
Baseline: 55.5 (20.3)
Follow-up: 67.7 (21.6)
Change from baseline: 12.2 (NR)
Baseline: 59.8 (22.3)
Follow-up: 63.1 (19.1)
Change from baseline: 3.3 (NR)
Baseline: NR (NR)
Follow-up: NR (NR)
Change from baseline: 2.7 (8.07)
Baseline: NR (NR)
Follow-up: NR (NR)
Change from baseline: -0.3 (7.13)
Baseline: 59.8 (37)
Follow-up: NR (NR)
Change from baseline: -1.2 (NR)
Baseline: 61.4 (20.5)
Follow-up: NR (NR)
214
CONFIDENTIAL UNTIL PUBLISHED
HRQoL Scale
Followup (mths)
Study ID
Intervention
SF-36 Mental
Composite Score
12
STAR-3
CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
166
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
168
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
SF-36 Mental Health
6
Eurythmics
Number
analysed
33
SF-36 Mental health
subscale
3.68
DeVries
2002
CSII + SMBG: Disetronic H-TRONplus insulin pump;
Glucotouch or One Touch Profile memory glucose
meter (Lifescan)
NR
SF-36 Physical
Composite Score
12
STAR-3
CSII + CGM Integrated: MiniMed Paradigm REALTime System, Medtronic
166
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
168
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
SF-36 Physical
Functioning
6
Eurythmics
33
HRQoL Score
Change from baseline: 5.9 (NR)
Baseline: 49.86 (9.64)
Follow-up: NR (NR)
Change from baseline: 0.05 (NR)
Baseline: 49.5 (9.09)
Follow-up: NR (NR)
Change from baseline: -1.26 (NR)
Baseline: 72.6 (14.8)
Follow-up: 79.2 (12.5)
Change from baseline: 6.6 (NR)
Baseline: 77.9 (20.2)
Follow-up: 76.8 (16.5)
Change from baseline: -1.1 (NR)
Baseline: 78 (NR)
Follow-up: NR (NR)
Change from baseline: -0.6 (NR)
Baseline: 80 (NR)
Follow-up: NR (NR)
Change from baseline: 5.2 (NR)
Baseline: 50.61 (7.12)
Follow-up: NR (NR)
Change from baseline: 1.22 (NR)
Baseline: 50.97 (7.86)
Follow-up: NR (NR)
Change from baseline: 0.26 (NR)
Baseline: 89.4 (14.5)
Follow-up: 92.7 (11.2)
Change from baseline: 3.3 (NR)
Baseline: 90.5 (14.3)
Follow-up: 91.4 (12.7)
215
CONFIDENTIAL UNTIL PUBLISHED
HRQoL Scale
Followup (mths)
Study ID
Intervention
SF-36 Role Emotional
6
Eurythmics
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
CSII + CGM Integrated: Paradigm REAL-Time
System (Medtronic MiniMed Inc.) with SMBG (meter
not described)
MDI + SMBG: SMBG (meter not described)
42
SF-36 Role - Physical
SF-36 Social
Functioning
SF-36 Vitality
6
6
6
Eurythmics
Eurythmics
Eurythmics
Number
analysed
33
33
33
33
HRQoL Score
Change from baseline: 0.9 (NR)
Baseline: 84.9 (20.4)
Follow-up: 87.1 (19.6)
Change from baseline: 2.2 (NR)
Baseline: 89.6 (16.7)
Follow-up: 88 (16)
Change from baseline: -1.6 (NR)
Baseline: 76.8 (23.8)
Follow-up: 85.7 (20.7)
Change from baseline: 8.9 (NR)
Baseline: 84.4 (19.3)
Follow-up: 87.3 (20.4)
Change from baseline: 2.9 (NR)
Baseline: 81.5 (20.3)
Follow-up: 89.3 (16)
Change from baseline: 7.8 (NR)
Baseline: 86.4 (21)
Follow-up: 82.2 (25.2)
Change from baseline: -4.2 (NR)
Baseline: 53.9 (20)
Follow-up: 66.7 (20.2)
Change from baseline: 12.8 (NR)
Baseline: 61 (23.7)
Follow-up: 65.2 (19.3)
Change from baseline: 4.2 (NR)
216
CONFIDENTIAL UNTIL PUBLISHED
Table 82: Results – adverse events
Outcome
Population Follow-up
Definition
(mths)
All Serious AE
Adults
Mixed
3.45
6
12
Death
Device-related
serious AEs
Hypoglycaemic
coma
Subcutaneous
abcess
Total AEs, not
including
serious AEs
Adults
Adults
3
3
Study ID
Intervention
Lee 2007
CSII + CGM Integrated: MiniMed Paradigm REAL-Time
722 System as adjunct to SMBG (Paradigm Link glucose
meter)
MDI + SMBG: SMBG (Paradigm Link glucose meter)
CSII + CGM Non-integrated: Insulin pump + Holter-type
CGM device
CSII + SMBG: Paradigm 512/712 + SMBG
CSII + CGM Integrated: MiniMed Paradigm REAL-Time
System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
CSII + CGM Integrated: Paradigm Revel 2.0 pump +
Enlite sensor
CSII + CGM + Suspend: Paradigm Veo pump + Enlite
sensor
CSII + CGM Integrated: Paradigm Revel 2.0 pump +
Enlite sensor
CSII + CGM + Suspend: Paradigm Veo pump + Enlite
sensor
MDI + SMBG: NR
CSII + SMBG: NR
MDI + SMBG: NR
CSII + SMBG: NR
CSII + CGM Integrated: MiniMed Paradigm REAL-Time
System, Medtronic
MDI + SMBG: Guardian REAL-Time Clinical,
Medtronic
RealTrend
STAR-3
ASPIRE
in-home
ASPIRE
in-home
Adults
24
OSLO
Adults
24
OSLO
Mixed
12
STAR-3
No. with
adverse event
N(%)
0 (0.0)
Total
Number
analysed
8
1 (12.5)
3 (NR)
8
NR
7 (NR)
32 (13.0)
NR
247
30 (12.1)
248
0 (0.0)
126
0 (0.0)
121
0 (0.0)
126
0 (0.0)
121
6 (40.0)
2 (13.3)
0 (0.0)
6 (40.0)
96 (38.9)
15
15
15
15
247
49 (19.8)
248
217
CONFIDENTIAL UNTIL PUBLISHED
Outcome
Definition
Population
Follow-up
(mths)
Study ID
Intervention
Treatment
emergent AE
Adults
6
Bolli 2009
CSII + SMBG: Minimed 508 + Glucose Monitor not
reported
MDI + SMBG: Insulin glargine plus mealtime insulin
lispro. Glucose monitor not reported.
No. with
adverse event
N(%)
18 (64.3)
Total
Number
analysed
28
22 (75.9)
29
218
CONFIDENTIAL UNTIL PUBLISHED
Table 83: Results – adverse events – pregnant women
Outcome Definition
Follow-up Study ID
(mths)
Fetal respiratory distress
syndrome
NR
Nosari 1993
Intrauterine death
NR
Nosari 1993
Large for gestational age
NR
Nosari 1993
Neonatal hypoglycaemia
(plasma glucose <30
mg/dL)
Premature birth of a
viable fetus
NR
Nosari 1993
NR
Nosari 1993
Small for gestational age
NR
Nosari 1993
Intervention
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
CSII + SMBG: Microjet MC 20 and Dahedi B.V. portable
battery-powered syringe infusion pumps
MDI + SMBG: NR
No. with
adverse event
N (%)
1 (6.3)
Total
Number
analysed
16
0 (0.0)
2 (12.5)
16
16
1 (6.3)
1 (6.3)
16
16
0 (0.0)
1 (6.3)
16
16
1 (6.3)
0 (0.0)
16
16
1 (6.3)
0 (0.0)
16
16
2 (12.5)
16
219
CONFIDENTIAL UNTIL PUBLISHED
Appendix 4: Table of excluded studies with rationale
The following is a list of studies excluded at the full paper screening stage of the review,
along with the reasons for their exclusion.
Table 84: Summary of reasons for exclusion for excluded studies at full paper screening stage
Reason for Exclusion
Count
Population
8
Intervention
86
Outcomes
109
Study design
206
Systematic Review/Meta-analysis
36
Background
3
Duplicate
5
Not Found
29
Grand Total
482
220
CONFIDENTIAL UNTIL PUBLISHED
Table 85: Excluded studies at full paper screening stage with reason for exclusion
Citation
11th Annual Diabetes Technology Meeting. In: Journal of Diabetes Science and Technology. Conference: 11th Annual Diabetes Technology
Meeting San Francisco, CA United States. Conference Start: 20111027 Conference End: 20111029. Conference Publication: (var.pagings). 6 (2)
, 2012. Date of Publication: March 2012., 2012.
4th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2011. Diabetes Technology and Therapeutics.
Conference: 4th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2011 London United Kingdom.
Conference Start: 20110216 Conference End: 20110219. Conference Publication: (var.pagings). 13 (2) , 2011. Date of Publication: February
2011. 2011.
Abraham M, Davey R, Paramalingam N, Keenan B, Ambler G, Fairchild J, Cameron F, King B, Jones T, Davis E. Prevention of hypoglycaemia
with predictive low glucose management system: Comparison of hypoglyclaemia induction with exercise and subcutaneous bolus. Diabetes
Technology and Therapeutics. Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014
Vienna Austria. Conference Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp A43), 2014. Date of
Publication: February 2014. 2014.
Abstracts from ATTD 2014 - 7th International Conference on Advanced Technologies and Treatments for Diabetes. Diabetes Technology and
Therapeutics. Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria.
Conference Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 , 2014. Date of Publication: February 2014.
2014.
ACTRN12607000198426. The Australian Sensor-Augmented Pump Algorithm Study. 2007.
ACTRN12614000035628. The Performance of an Artificial Pancreas at Home in People with Type 1 Diabetes. 2014.
ACTRN12614000482662. Closed loop insulin delivery and glucose control for type 1 diabetes, seven days and nights, hospital to home. 2014.
Agrawal P, Kannard B, Shin J, Huang S, Welsh JB, Kaufman FR. Improvement in glycemic parameters with use of the low glucose suspend
feature of the veo insulin pump. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA United
States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A229-A230), 2012. Date of
Publication: June 2012. 2012.
Agrawal P, Welsh JB, Kannard B, Askari S, Yang Q, Kaufman FR. Usage and effectiveness of the low glucose suspend feature of the Medtronic
Paradigm Veo insulin pump. J Diabetes Sci Technol 2011;5(5):1137-41.
Agrawal P, Welsh JB, Kaufman FR. Use of the low glucose suspend (LGS) feature results in significant reduction in hypoglycemia in pediatric
Reason for
Exclusion
Study
design
Study
design
Study
design
Study
design
Study
design
Study
design
Study
design
Study
design
Outcomes
Study
221
CONFIDENTIAL UNTIL PUBLISHED
Citation
and adult patients with type 1 diabetes. Pediatric Diabetes. Conference: 38th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD 2012 Istanbul Turkey. Conference Start: 20121010 Conference End: 20121013. Conference Publication:
(var.pagings). 13 (pp 116), 2012. Date of Publication: October 2012. 2012.
Alemzadeh R, Palma-Sisto P, Parton E, Holzum M, Kichler J. Insulin pump therapy attenuated glycemic instability without improving glycemic
control in a one-year study of preschool children with type 1 diabetes. Paper presented at 66th Annual Meeting of the American Diabetes
Association; 9-13 Jun 2006; Washington DC: USA. Diabetes 2006;55:A97.
Alemzadeh R, Palma-Sisto P, Parton EA, Holzum MK. Continuous subcutaneous insulin infusion and multiple dose of insulin regimen display
similar patterns of blood glucose excursions in pediatric type 1 diabetes. Diabetes Technol Ther 2005;7(4):587-96.
Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME. High-dose intravenous insulin infusion versus intensive insulin treatment in newly
diagnosed IDDM. Diabetes 1997;46(10):1612-8.
Ambrosino JM, Weinzimer SA, Steffen AT, Ruedy K. Short-term psychosocial impact of sensor-augmented pump therapy within three months
of diagnosis of type 1 diabetes. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA United
States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A586), 2012. Date of Publication:
June 2012. 2012.
American Diabetes Association 72nd Scientific Sessions. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association
Philadelphia, PA United States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 , 2012. Date
of Publication: June 2012. 2012.
Arias P, Kerner W, Zier H, Navascues I, Pfeiffer EF. Incidence of hypoglycemic episodes in diabetic patients under continuous subcutaneous
insulin infusion and intensified conventional insulin treatment: assessment by means of semiambulatory 24-hour continuous blood glucose
monitoring. Diabetes Care 1985;8(2):134-40.
Bailey TS, Weiss R, Bode BW, Garg S, Ahmann AJ, Welsh JB, Lee SW. Hypoglycemia reduction and changes in A1C in the aspire in-home
study. Diabetes. Conference: 74th Scientific Sessions of the American Diabetes Association San Francisco, CA United States. Conference Start:
20140613 Conference End: 20140617. Conference Publication: (var.pagings). 63 (pp A60), 2014. Date of Publication: June 2014. 2014.
Bak JF, Nielsen OH, Pedersen O, Beck-Nielsen H. Multiple insulin injections using a pen injector versus insulin pump treatment in young
diabetic patients. Diabetes Res 1987;6(3):155-8.
Bangstad HJ, Kofoed-Enevoldsen A, Dahl-Jorgensen K, Hanssen KF. Glomerular charge selectivity and the influence of improved blood glucose
control in type 1 (insulin-dependent) diabetic patients with microalbuminuria. Diabetologia 1992;35(12):1165-9.
Bangstad HJ, Osterby R, Dahl-Jorgensen K, Berg KJ, Hartmann A, Hanssen KF. Improvement of blood glucose control in IDDM patients retards
the progression of morphological changes in early diabetic nephropathy. Diabetologia 1994;37(5):483-90.
Barcelo-Rico F, Luis Diez J, Vehi J, Ampudia-Blasco FJ, Rossetti P, Bondia J. Evaluation of a local-model-based calibration algorithm for
Reason for
Exclusion
design
Not Found
Study
design
Population
Outcomes
Study
design
Study
design
Outcomes
Outcomes
Population
Study
design
Study
222
CONFIDENTIAL UNTIL PUBLISHED
Citation
continuous glucose monitoring in subjects with type 1 diabetes. In: Journal of Diabetes Science and Technology. Conference: 12th Annual
Diabetes Technology Meeting Bethesda, MD United States. Conference Start: 20121108 Conference End: 20121110. Conference Publication:
(var.pagings). 7 (1) (pp A5), 2013. Date of Publication: January 2013., 2013.
Battelino T, Conget I, Olsen B, Schutz-Fuhrmann I, Hommel E, Hoogma R, Schierloh U, Sulli N, Bolinder J, Group SS. The use and efficacy of
continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomised controlled trial. Diabetologia
2012;55(12):3155-62.
Battelino T, Conget I, Olsen B, Schutz-Fuhrmann I, Hommel E, Hoogma R, Schierloh U, Sulli N, Bolinder J. The SWITCH study: Continuous
glucose monitoring in type 1 diabetes. Pediatric Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022. Conference Publication:
(var.pagings). 12 (pp 30), 2011. Date of Publication: October 2011. 2011.
Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J. Effect of continuous glucose monitoring on hypoglycemia in type 1
diabetes. Diabetes Care 2011;34(4):795-800.
Beck RW, Raghinaru D, Wadwa RP, Chase HP, Maahs DM, Buckingham BA, In Home Closed Loop Study G. Frequency of morning ketosis
after overnight insulin suspension using an automated nocturnal predictive low glucose suspend system. Diabetes Care 2014;37(5):1224-9.
Beck RW. The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care 2009;32(8):1378-83.
Bell PM, Hayes JR, Hadden DR. A comparison of continuous subcutaneous insulin infusion (CSII) and conventional therapy in insulin
dependent diabetes mellitus (IDDM). Ir J Med Sci 1984;153(3):116.
Berg TJ, Nourooz-Zadeh J, Wolff SP, Tritschler HJ, Bangstad HJ, Hanssen KF. Hydroperoxides in plasma are reduced by intensified insulin
treatment. A randomized controlled study of IDDM patients with microalbuminuria. Diabetes Care 1998;21(8):1295-300.
Bergenstal RM, Dupre J, Lawson PM, Rizza RA, Rubenstein AH. Observations on C-peptide and free insulin in the blood during continuous
subcutaneous insulin infusion and conventional insulin therapy. Diabetes 1985;34 Suppl 3:31-6.
Bergenstal RM, Lee SW, Welsh JB, Shin J, Kaufman FR. Prevention of hypoglycemia in the aspire in-home study. Diabetes Technology and
Therapeutics. Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria.
Conference Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp A107), 2014. Date of Publication:
February 2014. 2014.
Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Perkins BA, Welsh JB, Willi SM, Wood MA, Group SS.
Sensor-augmented pump therapy for A1C reduction (STAR 3) study: results from the 6-month continuation phase. Diabetes Care
2011;34(11):2403-5.
Bergenstal RM. Sensor-augmented insulin-pump therapy in type 1 diabetes. REPLY. N Engl J Med 2010;363(21):2071.
Reason for
Exclusion
design
Outcomes
Outcomes
Study
design
Study
design
Intervention
Intervention
Intervention
Intervention
Outcomes
Study
design
Study
design
223
CONFIDENTIAL UNTIL PUBLISHED
Citation
Berhe T, Innocenti M. Insulin pump therapy as a routine care for children with type 1 diabetes: improvement in glycemic control using insulin
pump therapy with intermittent higher basal rate in adolescents with type 1 diabetes who have a previous history of poor glycemic control
(HbA1c > 10%). Paper presented at 68th Annual Meeting of the American Diabetes Association; 6-10 Jun 2008; San Francisco: USA. Diabetes
2008;57:A748.
Blair J, Gregory JW, Peak M. Insulin delivery by multiple daily injections or continuous subcutaneous insulin infusion in childhood: addressing
the evidence gap. Practical Diabetes 2012;29(2):47-8.
Blue Cross Blue Shield Association. Artificial pancreas device systems. Technology Evaluation Center Assessment Program 2014;28(14):1-22.
Bode B, Gross K, Rikalo N, Schwartz S, Wahl T, Page C, Gross T, Mastrototaro J. Alarms based on real-time sensor glucose values alert patients
to hypo- and hyperglycemia: the guardian continuous monitoring system. Diabetes Technol Ther 2004;6(2):105-13.
Bode B, Lee SW, Kaufman FR. Predictors of hypoglycemia during the run-in period of the aspire-2 study. Diabetes Technology and
Therapeutics. Conference: 6th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France.
Conference Start: 20130227 Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A35), 2013. Date of Publication:
February 2013. 2013.
Bode B, Shelmet J, Gooch B, Hassman DR, Liang J, Smedegaard JK, Skovlund S, Berg B, Lyness W, Schneider SH, InDuo Study G. Patient
perception and use of an insulin injector/glucose monitor combined device. Diabetes Educ 2004;30(2):301-9.
Bode BW, Lee SW, Kaufman FR. Predictors of nocturnal hypoglycemia during the run-in period of the ASPIRE-2 study. Diabetes. Conference:
73rd Scientific Sessions of the American Diabetes Association Chicago, IL United States. Conference Start: 20130621 Conference End:
20130625. Conference Publication: (var.pagings). 62 (pp A252), 2013. Date of Publication: July 2013. 2013.
Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type I
diabetes. Diabetes Care 1996;19(4):324-7.
Bode BW, Steed RD, Schleusener DS, Strange P. Switch to multiple daily injections with insulin glargine and insulin lispro from continuous
subcutaneous insulin infusion with insulin lispro: a randomized, open-label study using a continuous glucose monitoring system. Endocr Pract
2005;11(3):157-64.
Bolli GB, Capani F, Home PD, Kerr D, Thomas R, Torlone E, Selam JL, Sola-Gazagnes A, Vitacolonna E. Comparison of a multiple daily
injection regimen with once-daily insulin glargine basal insulin and mealtime lispro, to continuous subcutaneous insulin infusion: a randomised,
open, parallel study. Paper presented at 64th Annual Meeting of the American Diabetes Association; 4-8 Jun 2004; Orlando: USA. Diabetes
2004;53(Suppl 2):A107–8.
Bonfanti R, Meschi F, Viscardi M, Rigamonti A, Biffi V, Frontino G, Battaglino R, Favalli V, Bonura C, Chiumello G. Insulin pump therapy
Reason for
Exclusion
Not Found
Study
design
Systematic
Review/Met
a-analysis
Study
design
Outcomes
Outcomes
Outcomes
Study
design
Study
design
Intervention
Study
224
CONFIDENTIAL UNTIL PUBLISHED
Citation
versus multiple injections in young children with diabetes: Comparison of long-term efficacy. Pediatric Diabetes. Conference: 36th Annual
Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027
Conference End: 20101030. Conference Publication: (var.pagings). 11 (pp 100), 2010. Date of Publication: October 2010. 2010.
Bonfanti R, Meschi F, Viscardi M, Rigamonti A, Biffi V, Frontino G, Battaglino R, Favalli V, Bonura C, Chiumello G. Long-term efficacy of
insulin pump therapy in young children with diabetes. Diabetologia. Conference: 46th Annual Meeting of the European Association for the Study
of Diabetes, EASD 2010 Stockholm Sweden. Conference Start: 20100920 Conference End: 20100924. Conference Publication: (var.pagings). 53
(pp S372), 2010. Date of Publication: September 2010. 2010.
Bonnemaison E, Hasselmann C, Dieckmann K, Perdereau S, Marques C, Faure N, Mercat I, Monceaux F, Mouna H, Roze C. Observational
study: Continuous glucose monitoring in children under 7 years old. Pediatric Diabetes. Conference: 37th Annual Meeting of the International
Society for Pediatric and Adolescent Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022.
Conference Publication: (var.pagings). 12 (pp 132), 2011. Date of Publication: October 2011. 2011.
Boston U, Massachusetts General H, Juvenile Diabetes Research F. Closed-loop Glucose Control for Automated Management of Type 1
Diabetes. NCT00811317 2010.
Botta RM, Sinagra D, Angelico MC, Bompiani GD. [Comparison of intensified traditional insulin therapy and micropump therapy in pregnant
women with type 1 diabetes mellitus]. Minerva Med 1986;77(17):657-61.
Bragd J, Adamson U, Lins PE, Von Dobeln A, Oskarsson P. Basal insulin substitution with glargine or CSII in adult type I diabetes patients: a
randomized controlled trial. Paper presented at 69th Annual Meeting of the American Diabetes Association; 5-9 Jun 2009; New Orleans: USA.
Diabetes 2009;58:A60-A61.
Bratina N. The switch study: The impact of continuous glucose monitoring on health care resource utilization. Diabetes Technology and
Therapeutics. Conference: 6th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France.
Conference Start: 20130227 Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A3), 2013. Date of Publication: February
2013. 2013.
Brazg R, Garg S, Bailey T, Buckingham B, Slover R, Klonoff D, Kaufman FR, Uhrinak AN, Shin J, Myers SJ. Interim analysis of an in-clinic,
randomized, crossover study to assess efficacy of the low glucose suspend feature of the paradigm veo system with hypoglycemic induction from
exercise. In: Journal of Diabetes Science and Technology. Conference: 11th Annual Diabetes Technology Meeting San Francisco, CA United
States. Conference Start: 20111027 Conference End: 20111029. Conference Publication: (var.pagings). 6 (2) (pp A19), 2012. Date of
Publication: March 2012., 2012.
Brazg RL, Bailey TS, Garg S, Buckingham BA, Slover RH, Klonoff DC, Nguyen X, Shin J, Welsh JB, Lee SW. The ASPIRE study: design and
methods of an in-clinic crossover trial on the efficacy of automatic insulin pump suspension in exercise-induced hypoglycemia. J Diabetes Sci
Technol 2011;5(6):1466-71.
Reason for
Exclusion
design
Study
design
Study
design
Intervention
Not Found
Not Found
Outcomes
Study
design
Study
design
225
CONFIDENTIAL UNTIL PUBLISHED
Citation
Brinchmann-Hansen O, Dahl-Jorgensen K, Hanssen KF, Sandvik L. The response of diabetic retinopathy to 41 months of multiple insulin
injections, insulin pumps, and conventional insulin therapy. Arch Ophthalmol 1988;106(9):1242-6.
Bruttomesso D, Bonomo M, Costa S, Dal Pos M, Di Cianni G, Pellicano F, Vitacolonna E, Dodesini AR, Tonutti L, Lapolla A, Di Benedetto A,
Torlone E, Italian Group for Continuous Subcutaneous Insulin Infusion in P. Type 1 diabetes control and pregnancy outcomes in women treated
with continuous subcutaneous insulin infusion (CSII) or with insulin glargine and multiple daily injections of rapid-acting insulin analogues
(glargine-MDI). Diabetes Metab 2011;37(5):426-31.
Bruttomesso D, Crazzolara D, Maran A, Costa S, Dal Pos M, Girelli A, Lepore G, Aragona M, Iori E, Valentini U, Del Prato S, Tiengo A, Buhr
A, Trevisan R, Baritussio A. In Type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous
subcutaneous insulin infusion than during multiple daily injections with insulin glargine. Diabet Med 2008;25(3):326-32.
Buckingham B, Beck RW, Ruedy KJ, Cheng P, Kollman C, Weinzimer SA, DiMeglio LA, Bremer AA, Slover R, Tamborlane WV, Diabetes
Research in Children Network Study G, Type 1 Diabetes TrialNet Study G. Effectiveness of early intensive therapy on beta-cell preservation in
type 1 diabetes. Diabetes Care 2013;36(12):4030-5.
Buckingham B, Nakamura K, Benassi K, Realsen J, Liljenquist D, Chase P. Effectiveness and safety study of the prototype 4th generation seven
day continuous glucose monitoring system in youth with type 1 diabetes mellitus. Paper presented at 47th EASD Annual Meeting of the
European Association for the Study of Diabetes, EASD 2011; 12-16 Sep 2011; Lisbon: Portugal. 2011.
Buckingham B, Ruedy K, Chase HP, Weinzimer S, DiMeglio L, Russell W, Wilson D, Tamborlane W, Bremer A, Sherr J, Slover R, Kollman C,
Cheng P, Beck R. Does intensive metabolic control at the onset of diabetes followed by one year of sensor augmented pump therapy improve Cpeptide levels one year post diagnosis? Diabetes Technology and Therapeutics. Conference: 6th International Conference on Advanced
Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227 Conference End: 20130302. Conference
Publication: (var.pagings). 15 (pp A137), 2013. Date of Publication: February 2013. 2013.
Buckingham BA, Cameron F, Calhoun P, Maahs DM, Wilson DM, Chase HP, Bequette BW, Lum J, Sibayan J, Beck RW, Kollman C.
Outpatient safety assessment of an in-home predictive low-glucose suspend system with type 1 diabetes subjects at elevated risk of nocturnal
hypoglycemia. Diabetes Technol Ther 2013;15(8):622-7.
Buckingham BA, Cheng P, Beck RW, Kollman C, Ruedy K, Weinzimer SA, Slover R, Bremer AA, Tamborlane WV, Fuqua J. Relationship of
glycemic control and c-peptide levels 2 years following diagnosis of T1D. Diabetes. Conference: 74th Scientific Sessions of the American
Diabetes Association San Francisco, CA United States. Conference Start: 20140613 Conference End: 20140617. Conference Publication:
(var.pagings). 63 (pp A392), 2014. Date of Publication: June 2014. 2014.
Buckingham BA, Tanner JP. Factors predictive of continuous glucose monitoring (CGM) use and benefit in the JDRF CGM RCT. Diabetes.
Conference: 69th Annual Meeting of the American Diabetes Association New Orleans, LA United States. Conference Start: 20090605
Conference End: 20090609. Conference Publication: (var.pagings). 58 , 2009. Date of Publication: 2009. 2009.
Reason for
Exclusion
Outcomes
Study
design
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Intervention
Study
design
Study
design
Study
design
Outcomes
Study
design
226
CONFIDENTIAL UNTIL PUBLISHED
Citation
Bukara-Radujkovic G, Zdravkovic D, Lakic S. Short-term use of continuous glucose monitoring system adds to glycemic control in young type 1
diabetes mellitus patients in the long run: a clinical trial. Vojnosanit Pregl 2011;68(8):650-4.
Burkart W, Hanker JP, Schneider HP. Complications and fetal outcome in diabetic pregnancy. Intensified conventional versus insulin pump
therapy. Gynecol Obstet Invest 1988;26(2):104–12.
Buse JB, Kudva YC, Guthrie RA, Laffel L, Battelino T, Shin J, Welsh JB, Yang Q. Assessment of glycemic variability and CD40 ligand in the
STAR 3 study. Diabetes. Conference: 71st Scientific Sessions of the American Diabetes Association San Diego, CA United States. Conference
Start: 20110624 Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A252), 2011. Date of Publication: July 2011. 2011.
Butcher B, Jones T. Safety, efficacy and quality of life associated with continuous glucose monitoring in people with diabetes. PROSPERO:
CRD42014013270 [Internet]. 2014 [accessed 5.9.14].
Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane
Database of Systematic Reviews 2012, Issue 6. Art. No.: CD007543. DOI: 10.1002/14651858.CD007543.pub2.
Cander S, Oz Gul O, Deligonul A, O.K Un, Kiyici S, Tuncel E, Imamotlu S. Weight gain in type 1 diabetic patients with insulin pump therapy.
Obesity Reviews. Conference: 18th European Congress on Obesity, ECO 2011 Istanbul Turkey. Conference Start: 20110525 Conference End:
20110528. Conference Publication: (var.pagings). 12 (pp 214), 2011. Date of Publication: May 2011. 2011.
Capel I, Rigla M, Garcia-Saez G, Rodriguez-Herrero A, Pons B, Subias D, Garcia-Garcia F, Gallach M, Aguilar M, Perez-Gandia C, Gomez EJ,
Caixas A, Hernando ME. Artificial pancreas using a personalized rule-based controller achieves overnight normoglycemia in patients with type 1
diabetes. Diabetes Technol Ther 2014;16(3):172-9.
Carta Q, Meriggi E, Trossarelli GF, Catella G, Dal Molin V, Menato G, Gagliardi L, Massobrio M, Vitelli A. Continuous subcutaneous insulin
infusion versus intensive conventional insulin therapy in type I and type II diabetic pregnancy. Diabete Metab 1986;12(3):121-9.
Centre d’Etudes et de Recherche pour l’Intensification du Traitement du D, Abbott. Are the Continuous Glucose Monitoring Systems Able to
Improve Long Term Glycaemic Control in Type 1 Diabetic Patients? NCT00726440 2012.
Chase HP, Beck R, Tamborlane W, Buckingham B, Mauras N, Tsalikian E, Wysocki T, Weinzimer S, Kollman C, Ruedy K, Xing D. A
randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes
Care 2005;28(5):1101-6.
Chase HP, Beck RW, Xing D, Tamborlane WV, Coffey J, Fox LA, Ives B, Keady J, Kollman C, Laffel L, Ruedy KJ. Continuous glucose
monitoring in youth with type 1 diabetes: 12-month follow-up of the juvenile diabetes research foundation continuous glucose monitoring
randomized trial. Diabetes Technol Ther 2010;12(7):507-15.
Chase HP, Kim LM, Owen SL, MacKenzie TA, Klingensmith GJ, Murtfeldt R, Garg SK. Continuous subcutaneous glucose monitoring in
children with type 1 diabetes. Pediatrics 2001;107(2):222-6.
Reason for
Exclusion
Study
design
Population
Outcomes
Systematic
Review/Met
a-analysis
Study
design
Outcomes
Study
design
Not Found
Outcomes
Study
design
Intervention
Intervention
227
CONFIDENTIAL UNTIL PUBLISHED
Citation
Chase HP. A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1 diabetes. Diabetes Technology and Therapeutics.
Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria. Conference
Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp A2), 2014. Date of Publication: February 2014. 2014.
Chatelais L, Voinot C, Robine A, Gatelais F, Dufresne S, Bouhours-Nouet N, Coutant R. Continuous subcutaneous insulin infusion in type 1
diabetic adolescents with poor glycemic control under multiple daily injections: 1-year evaluation of HbA1C and acceptability. Paper presented
at LWPES/ESPE 8th Joint Meeting Global Care in Pediatric Endocrinology in collaboration with APEG, APPES, JSPE and SLEP; 9–12 Sep
2009; New York: USA. Horm Res 2009;72(Suppl 3):182.
Chen R, Yogev Y, Weissman-Brenner A, Ben-Haroush A, Hod M. Level of glycemic control and pregnancy outcome in type-1 diabetes: a
comparison between multiple daily injections (MDI) and continuous subcutaneous insulin infusions (CSII). Paper presented at 67th Annual
Meeting of the American Diabetes Association; 22-26 Jun 2007; Chicago: USA. Diabetes 2007;56:A703.
Chen R, Yogev Y, Weissman-Brenner A, Haroush AB, Hod M. Level of glycemic control and pregnancy outcome in type-1 diabetes: a
comparison between multiple daily injections (MDI) and continuous subcutaneous insulin infusions (CSII). Paper presented at 27th Annual
Meeting of the Society of Maternal Fetal Medicine; 5-10 Feb 2007; San Francisco: USA. Am J Obstet Gynecol 2006;195(6):S132.
Chen Y, Ben-Haroush A, Weismann-Brenner A, Melamed N, Hod M, Yogev Y. Level of glycemic control and pregnancy outcome in type 1
diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions [erratum in Am J Obstet
Gynecol. 2008 May;198(5):610]. Am J Obstet Gynecol 2007;197(4):e1-5.
Chevremont A, Collet-Gaudillat C, Duvezin-Caubet P, Franc S, Gouet D, Jan P, Leguerrier AM, Lopez S, Ozenne G, Plat F, Raccah D, Reznik
Y, Thivolet C, Fay R, Guerci B. [Insulin pump Paradigm Veo with automated insulin suspension function: results of a pilot study in type 1
diabetic patients at high hypoglycemic risk]. Medecine des Maladies Metaboliques 2012;6(6):531-8.
Chiasson JL, Ducros F, Poliquin-Hamet M, Lopez D, Lecavalier L, Hamet P. Continuous subcutaneous insulin infusion (Mill-Hill Infuser)
versus multiple injections (Medi-Jector) in the treatment of insulin-dependent diabetes mellitus and the effect of metabolic control on
microangiopathy. Diabetes Care 1984;7(4):331-7.
Chico A, Saigi I, Garcia-Patterson A, Santos MD, Adelantado JM, Ginovart G, de Leiva A, Corcoy R. Glycemic control and perinatal outcomes
of pregnancies complicated by type 1 diabetes: influence of continuous subcutaneous insulin infusion and lispro insulin. Diabetes Technol Ther
2010;12(12):937-45.
Chico A, Vidal-Rios P, Subira M, Novials A. The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in
patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes
Care 2003;26(4):1153-7.
Choudhary P, Shin J, Wang Y, Evans ML, Hammond PJ, Kerr D, Shaw JA, Pickup JC, Amiel SA. Insulin pump therapy with automated insulin
suspension in response to hypoglycemia: reduction in nocturnal hypoglycemia in those at greatest risk. Diabetes Care 2011;34(9):2023-5.
Reason for
Exclusion
Study
design
Study
design
Not Found
Study
design
Study
design
Study
design
Study
design
Study
design
Population
Study
design
228
CONFIDENTIAL UNTIL PUBLISHED
Citation
Christensen CK, Christiansen JS, Christensen T, Hermansen K, Mogensen CE. The effect of six months continuous subcutaneous insulin
infusion on kidney function and size in insulin-dependent diabetics. Diabet Med 1986;3(1):29-32.
Christensen CK, Christiansen JS, Schmitz A, Christensen T, Hermansen K, Mogensen CE. Effect of continuous subcutaneous insulin infusion on
kidney function and size in IDDM patients: a 2 year controlled study. J Diabet Complications 1987;1(3):91-5.
Christiansen JS, Ingerslev J, Bernvil SS, Christensen CK, Hermansen K, Schmitz A. Near normoglycemia for 1 year has no effect on platelet
reactivity, factor VIII, and von Willebrand factor in insulin-dependent diabetes mellitus: a controlled trial. J Diabet Complications
1987;1(3):100-6.
Churchill JN, Ruppe RL, Smaldone A. Use of continuous insulin infusion pumps in young children with type 1 diabetes: a systematic review. J
Pediatr Health Care 2009;23(3):173-9.
Ciavarella A, Vannini P, Flammini M, Bacci L, Forlani G, Borgnino LC. Effect of long-term near-normoglycemia on the progression of diabetic
nephropathy. Diabete Metab 1985;11(1):3-8.
Cinar A, Turksoy K, Quinn L, Littlejohn E. An integrated hypoglycemia early alarm and adaptive control system for artificial pancreas. Paper
presented at 7th International Conference on Advanced Technologies & Treatments for Diabetes; 5-8 Feb 2014; Vienna: Austria. Diabetes
Technol Ther 2014;16(Suppl 1):A103.
Clarke WL, Anderson S, Breton M, Patek S, Kashmer L, Kovatchev B. Closed-loop artificial pancreas using subcutaneous glucose sensing and
insulin delivery and a model predictive control algorithm: the Virginia experience. J Diabetes Sci Technol 2009;3(5):1031-8.
Cobry E, Chase HP, Burdick P, McFann K, Yetzer H, Scrimgeour L. Use of CoZmonitor in youth with type 1 diabetes. Pediatr Diabetes
2008;9(2):148-51.
Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, Phillip M. Continuous subcutaneous insulin infusion versus multiple daily
injections in adolescents with type I diabetes mellitus: a randomized open crossover trial. J Pediatr Endocrinol 2003;16(7):1047-50.
Cohen N, Minshall ME, Sharon-Nash L, Zakrzewska K, Valentine WJ, Palmer AJ. Continuous subcutaneous insulin infusion versus multiple
daily injections of insulin: economic comparison in adult and adolescent Type 1 diabetes mellitus in Australia. Pharmacoeconomics
2007;25(10):881-97.
Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.
Health Technol Assess 2004;8(43):iii, 1-171.
Conget I, Battelino T, Gimenez M, Gough H, Castaneda J, Bolinder J, Group SS. The SWITCH study (sensing with insulin pump therapy to
control HbA(1c)): design and methods of a randomized controlled crossover trial on sensor-augmented insulin pump efficacy in type 1 diabetes
suboptimally controlled with pump therapy. Diabetes Technol Ther 2011;13(1):49-54.
Reason for
Exclusion
Not Found
Intervention
Intervention
Systematic
Review/Met
a-analysis
Not Found
Study
design
Study
design
Study
design
Intervention
Outcomes
Systematic
Review/Met
a-analysis
Study
design
229
CONFIDENTIAL UNTIL PUBLISHED
Citation
Conget I, Battelino T, Gimenez M, Gough H, Castaneda J, Bolinder J. The SWITCH study (Sensing with insulin pump therapy to control
HbA1c). Design and methods of a randomized controlled cross-over trial on sensor-augmented insulin pump efficacy in type 1 diabetes suboptimally controlled with pump therapy. Pediatric Diabetes. Conference: 36th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027 Conference End: 20101030. Conference Publication:
(var.pagings). 11 (pp 105), 2010. Date of Publication: October 2010. 2010.
Cooke D, Hurel SJ, Casbard A, Steed L, Walker S, Meredith S, Nunn AJ, Manca A, Sculpher M, Barnard M, Kerr D, Weaver JU, Ahlquist J,
Newman SP. Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA(1c) in insulin-treated diabetes (MITRE
Study). Diabet Med 2009;26(5):540-7.
Corabian P, Guo B, Harstall C, Chuck A, Yan C. Insulin pump therapy for type 1 diabetes. Edmonton, Alberta: Institute of Health Economics,
2012
Cordua S, Secher AL, Ringholm L, Damm P, Mathiesen ER. Real-time continuous glucose monitoring during labour and delivery in women
with Type 1 diabetes - observations from a randomized controlled trial. Diabet Med 2013;30(11):1374-81.
Cosson E, Hamo Tchatchouang E, Dufaitre Patouraux L, Attali JR, Pariès J, Schaepelynck-Bélicar P. Multicentre, randomised, controlled study
of the impact of continuous sub cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients. Diabetes
Metab 2009;35(4):312-8.
Coustan DR, Reece EA, Sherwin RS, Rudolf MC, Bates SE, Sockin SM, Holford T, Tamborlane WV. A randomized clinical trial of the insulin
pump vs intensive conventional therapy in diabetic pregnancies. JAMA 1986;255(5):631-6.
Crepaldi C, Nosadini R, Bruttomesso D, Fioretto P, Fedele D, Segato T, Piermarocchi S, Midena E, Pozza G, Micossi P, Librenti MC, Menchini
U, Bandello F, Scialdone A, Brancato R, Brunetti P, Massi-Benedetti M, Santeusanio F, Fabietti PG. The effect of continuous insulin infusion as
compared with conventional insulin therapy in the evolution of diabetic retinal ischaemia. Two years report. Diabetes, Nutrition and Metabolism
- Clinical and Experimental 1989;2(3):209-18.
Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, Waugh N. Clinical and cost-effectiveness of continuous subcutaneous
infusion for diabetes: updating review. A technology assessment report commissioned by the HTA Programme on behalf of NICE. HTA
reference 06/61 [Internet]. London: National Institute for Health and Clinical Excellence, 2007 [accessed 8.7.14] Available from:
http://www.nice.org.uk/guidance/ta151/resources/diabetes-insulin-pump-therapy-assessment-report2
Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, Waugh N. Clinical effectiveness and cost-effectiveness of continuous
subcutaneous insulin infusion for diabetes: systematic review and economic evaluation. Health Technol Assess 2010;14(11):iii-iv, xi-xvi, 1-181.
Cyganek K, Hebda-Szydło A, Katra B, Klupa T, Kaim I, Skupien J, Reron A, Sieradzki J, Malecki MT. Efficacy and safety of continuous
Reason for
Exclusion
Outcomes
Study
design
Systematic
Review/Met
a-analysis
Intervention
Study
design
Intervention
Intervention
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Study
230
CONFIDENTIAL UNTIL PUBLISHED
Citation
subcutaneous insulin infusion therapy in pregnancy complicated by type 1 diabetes. Paper presented at 45th EASD Annual Meeting of the
European Association for the Study of Diabetes; 30 Sep-2 Oct 2009; Vienna: Austria. 2009.
Cyganek K, Hebda-Szydlo A, Katra B, Skupien J, Klupa T, Janas I, Kaim I, Sieradzki J, Reron A, Malecki MT. Glycemic control and selected
pregnancy outcomes in type 1 diabetes women on continuous subcutaneous insulin infusion and multiple daily injections: the significance of
pregnancy planning. Diabetes Technol Ther 2010;12(1):41-7.
Cyganek K, Hebda-Szydlo A, Katra B, Skupien J, Klupa T, Janas I, Kaim I, Sieradzki J, Reron A, Malecki MT. Pregnancy planning improves
glycemic control and pregnancy outcomes in type 1 diabetes women on CSII and MDI. Paper presented at 44th Annual Scientific Meeting of the
European Society for Clinical Investigation; 24-27 Feb 2010; Bari: Italy. Eur J Clin Invest 2010;40(Suppl 1):8.
Cypryk K, Kosinski M, Kaminska P, Kozdraj T, Lewinski A. Diabetes control and pregnancy outcomes in women with type 1 diabetes treated
during pregnancy with continuous subcutaneous insulin infusion or multiple daily insulin injections. Pol Arch Med Wewn 2008;118(6):339-44.
Dahl-Jorgensen K, Hanssen KF, Aagenaes O, Larsen S. [New methods for subcutaneous insulin administration. A year's experience with the
insulin pump and multiple insulin injection therapy]. Tidsskr Nor Laegeforen 1984;104(13):856-61.
Dahl-Jorgensen K, Hanssen KF, Kierulf P, Bjoro T, Sandvik L, Aagenaes O. Reduction of urinary albumin excretion after 4 years of continuous
subcutaneous insulin infusion in insulin-dependent diabetes mellitus. The Oslo Study. Acta Endocrinol (Copenh) 1988;117(1):19-25.
Dahl-Jorgensen K. Blood glucose control and progression of diabetic neuropathy: eight years results from the Oslo study. Paper presented at 28th
Annual Meeting of the European Association for the Study of Diabetes, EASD; 8-11 Sep 1992; Prague: Czechoslovakia. Diabetologia
1992;35(Suppl 1):A15.
Dahl-Jorgensen K. Near-normoglycemia and late diabetic complications. The Oslo Study. Acta Endocrinol Suppl (Copenh) 1987;284:1-38.
Damiano ER, McKeon K, El-Khatib FH, Zheng H, Nathan DM, Russell SJ. A comparative effectiveness analysis of three continuous glucose
monitors: the Navigator, G4 Platinum, and Enlite. J Diabetes Sci Technol 2014;pii:1932296814532203. [Epub ahead of print].
Danne T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, Blasig S, Wadien T, Zierow S, Hartmann R, Thomas A. [LGS
system cuts hypoglycaemia excursion frequency in children on SAP therapy]. Diabetes, Stoffwechsel und Herz 2012;21(3):157-63.
Danne T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, Blasig S, Wadien T, Zierow S, Hartmann R, Thomas A. Prevention
of hypoglycemia by using low glucose suspend function in sensor-augmented pump therapy. Diabetes Technol Ther 2011;13(11):1129-34.
Danne T, Kordonouri O, Remus K, Blasig S, Holder M, Wadien T, Haberland H, Golembowski S, Zierow S, Hartmann R, Thomas A. The Low
Glucose Suspend (LGS) function in sensor-augmented pump therapy prevents hypoglycaemia in children. Diabetes. Conference: 71st Scientific
Sessions of the American Diabetes Association San Diego, CA United States. Conference Start: 20110624 Conference End: 20110628.
Conference Publication: (var.pagings). 60 (pp A41), 2011. Date of Publication: July 2011. 2011.
Danne T, Kordonouri O, Remus K, Holder M, Wadien T, Haberland H, Golembowski S, Zierow S, Thomas A. Prevention of hypoglycaemia by
using low glucose suspend (LGS) function in sensor-augmented pump therapy. Diabetes Technology and Therapeutics. Conference: 4th
Reason for
Exclusion
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Study
design
Study
design
Not Found
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Not Found
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Study
design
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design
Study
design
Study
design
231
CONFIDENTIAL UNTIL PUBLISHED
Citation
International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2011 London United Kingdom. Conference Start:
20110216 Conference End: 20110219. Conference Publication: (var.pagings). 13 (2) (pp 217), 2011. Date of Publication: February 2011. 2011.
Danne T. Predictive low glucose management with sensor augmented CSII in response to exercise. Diabetes Technology and Therapeutics.
Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria. Conference
Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp A2), 2014. Date of Publication: February 2014. 2014.
Daskalaki E, Norgaard K, Prountzou A, Zuger T, Diem P, Mougiakakou S. Alarm system for the early warning of hypo- and hyperglycemic
events based on online adaptive models. Diabetes Technology and Therapeutics. Conference: 6th International Conference on Advanced
Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227 Conference End: 20130302. Conference
Publication: (var.pagings). 15 (pp A77-A78), 2013. Date of Publication: February 2013. 2013.
Dauber A, Corcia L, Safer J, Agus MSD, Einis S, Steil GM. Closed-loop insulin therapy improves glycemic control in children aged >7 years.
Diabetes Technol Ther 2014;16(Suppl 1):S23-S24.
Davies AG, Price DA, Houlton CA, Burn JL, Fielding BA, Postlethwaite RJ. Continuous subcutaneous insulin infusion in diabetes mellitus. A
year's prospective trial. Arch Dis Child 1984;59(11):1027-33.
Davis EA, Siafarikas A, Ratnam N, Loveday J, Baker V, Marangou D, Elliot J, Bulsara MK, Jones TW. The initiation of intensive pump therapy
at diagnosis of type 1 diabetes mellitus in adolescents: a randomised trial. Paper presented at 67th Annual Meeting of the American Diabetes
Association; 22-26 Jun 2007; Chicago: USA. Diabetes 2007;56:A53.
de Beaufort CE, Bruining GJ, Aarsen RS, den Boer NC, Grose WF. Does continuous subcutaneous insulin infusion (CSII) prolong the remission
phase of insulin-dependent diabetic children? Preliminary findings of a randomized prospective study. Neth J Med 1985;28 Suppl 1:53-4.
de Beaufort CE, Houtzagers CM, Bruining GJ, Aarsen RS, den Boer NC, Grose WF, van Strik R, de Visser JJ. Continuous subcutaneous insulin
infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: two-year follow-up of a randomized, prospective
trial. Diabet Med 1989;6(9):766-71.
De Bock MI, Dart J, George CE, Abraham M, Cooper M, Paramalingam N, Keenan B, Spital G, Roy A, Davis EA, Jones TW. Performance of a
predictive insulin pump suspension algorithm for prevention of overnight hypoglycaemia. Diabetes. Conference: 74th Scientific Sessions of the
American Diabetes Association San Francisco, CA United States. Conference Start: 20140613 Conference End: 20140617. Conference
Publication: (var.pagings). 63 (pp A240-A241), 2014. Date of Publication: June 2014. 2014.
De Portu S, Castaneda J, Hommel E, Olsen BS, Battelino T, Conget I, Schutz-Fuhrmann I, Hoogma R, Schierloh U, Sulli N, Bolinder J, Gough
H. The switch study: The impact of continuous glucose monitoring on health care resource utilization. Value in Health. Conference: ISPOR 15th
Annual European Congress Berlin Germany. Conference Start: 20121103 Conference End: 20121107. Conference Publication: (var.pagings). 15
(7) (pp A357), 2012. Date of Publication: November 2012. 2012.
Deiss D, Bolinder J, Riveline JP, Battelino T, Bosi E, Tubiana-Rufi N, Kerr D, Phillip M. Improved glycemic control in poorly controlled
Reason for
Exclusion
Study
design
Study
design
Study
design
Intervention
Intervention
Not Found
Not Found
Study
design
Outcomes
Intervention
232
CONFIDENTIAL UNTIL PUBLISHED
Citation
patients with type 1 diabetes using real-time continuous glucose monitoring. Diabetes Care 2006;29(12):2730-2.
Deiss D, Hartmann R, Schmidt J, Kordonouri O. Results of a randomized controlled cross-over trial on the effect of continuous subcutaneous
glucose monitoring (CGMS) on glycemic control in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes
2006;114(2):63-7.
DeLuca FC, Timoshin A, Bamji N, Ferraro G, Himel A, Noto J, Noto RA. The effect of insulin pump therapy on the diabetes control of children
and adolescents with IDDM-1. Paper presented at Annual Meeting of the Pediatric Academic Societies; 4 May 2004; San Francisco: USA.
Pediatr Res 2004;55(4):136A.
Derosa G, Maffioli P, D'Angelo A, Salvadeo SAT, Ferrari I, Fogari E, Mereu R, Gravina A, Palumbo I, Randazzo S, Cicero AFG. Effects of
insulin therapy with continuous subcutaneous insulin infusion (CSII) in diabetic patients: comparison with multi-daily insulin injections therapy
(MDI). Endocr J 2009;56(4):571-8.
DeSalvo DJ, Keith-Hynes P, Peyser T, Place J, Caswell K, Wilson DM, Harris B, Clinton P, Kovatchev B, Buckingham BA. Remote glucose
monitoring in cAMP setting reduces the risk of prolonged nocturnal hypoglycemia. Diabetes Technol Ther 2014;16(1):1-7.
DeVries JH. Health-economic comparison of continuous subcutaneous insulin infusion with multiple daily injection for the treatment of Type 1
diabetes in the UK (letter). Diabet Med 2006;23:709.
DexCom Inc. Effectiveness and Safety Study of the DexCom™ G4 Continuous Glucose Monitoring System in Children and Adolescents With
Type 1 Diabetes Mellitus. NCT01185496 2011.
DexCom Inc. Efficacy of Continuous Glucose Monitoring in Subjects With Type 1 Diabetes Mellitus on Multiple Daily Injections (MDI) or
Continuous Subcutaneous Insulin Infusion (CSII) Therapy. NCT01104142 2010.
Diabetes Research in Children Network Study Group, Weinzimer S, Xing D, Tansey M, Fiallo-Scharer R, Mauras N, Wysocki T, Beck R,
Tamborlane W, Ruedy K. Prolonged use of continuous glucose monitors in children with type 1 diabetes on continuous subcutaneous insulin
infusion or intensive multiple-daily injection therapy. Pediatr Diabetes 2009;10(2):91-6.
Diabetic retinopathy after two years of intensified insulin treatment. Follow-up of the Kroc Collaborative Study. The Kroc Collaborative Study
Group. JAMA 1988;260(1):37-41.
DiMeglio LA, Pottorff TM, Boyd SR, France L, Fineberg N, Eugster EA. A randomized, controlled study of insulin pump therapy in diabetic
preschoolers. J Pediatr 2004;145(3):380-4.
Edelmann E, Walter H, Biermann E, Schleicher E, Bachmann W, Mehnert H. Sustained normoglycemia and remission phase in newly diagnosed
type I diabetic subjects. Comparison between continuous subcutaneous insulin infusion and conventional therapy during a one year follow-up.
Horm Metab Res 1987;19(9):419-21.
Elleri D, Allen JM, Nodale M, Wilinska ME, Acerini CL, Dunger DB, Hovorka R. Suspended insulin infusion during overnight closed-loop
glucose control in children and adolescents with Type 1 diabetes. Diabet Med 2010;27(4):480-4.
Reason for
Exclusion
Intervention
Study
design
Population
Study
design
Outcomes
Outcomes
Study
design
Study
design
Intervention
Intervention
Intervention
Study
design
233
CONFIDENTIAL UNTIL PUBLISHED
Citation
Ellery B, Mundy L, Hiller JE. Closed-loop insulin delivery system ('artificial pancreas') for management of hypoglycaemia in type 1 diabetics.
Adelaide, South Australia: Adelaide Health Technology Assessment on behalf of National Horizon Scanning Unit, 2010
Emelyanov A, Kuraeva T, Peterkova V. CSII with real time continuous glucose monitoring versus raditional CSII: The comparative results.
Pediatric Diabetes. Conference: 35th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD Ljubljana
Slovenia. Conference Start: 20090902 Conference End: 20090905. Conference Publication: (var.pagings). 10 (pp 101), 2009. Date of
Publication: September 2009. 2009.
Emelyanov A, Kuraeva T, Peterkova V. CSII with real time continuous glucose monitoring vs. traditional CSII: Two year comparative results.
Hormone Research in Paediatrics. Conference: 49th Annual Meeting of the European Society for Paediatric Endocrinology, ESPE 2010 Prague
Czech Republic. Conference Start: 20100922 Conference End: 20100925. Conference Publication: (var.pagings). 74 (pp 57), 2010. Date of
Publication: September 2010. 2010.
Enander R, Adolfsson P, Bergdahl T, Forsander G, Gundevall C, Karlsson AK, Ludvigsson J, Wramner N, Tollig H, Hanas R. Intensive
subcutaneous insulin therapy and intravenous insulin infusion at onset of T1DM preserve beta-cell function equally well in children. Diabetes.
Conference: 71st Scientific Sessions of the American Diabetes Association San Diego, CA United States. Conference Start: 20110624
Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A336), 2011. Date of Publication: July 2011. 2011.
Enander R, Bergdahl T, Adolfsson P, Forsander G, Gundevall C, Karlsson AK, Ludvigsson J, Wramner N, Tollig H, Hanas R. Intensive
subcutaneous insulin therapy and intravenous insulin infusion at onset of diabetes preserve beta-cell function equally well in children. Pediatric
Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD Miami Beach, FL United
States. Conference Start: 20111019 Conference End: 20111022. Conference Publication: (var.pagings). 12 (pp 69-70), 2011. Date of Publication:
October 2011. 2011.
Erasmus Medical C, Netherlands: Ministry of Health W, Sports. Comparison Between Insulin Pump Treatment and Multiple Daily Insulin
Injections in Diabetic Type 1 Children. NCT00462371 2007.
Esvant A, Guilhem I, Jouve A, Leguerrier AM, Poirier JY. Real-time continuous monitoring in brittle diabetes: A 6-month observational study.
Diabetes Technology and Therapeutics. Conference: 6th International Conference on Advanced Technologies and Treatments for Diabetes,
ATTD 2013 Paris France. Conference Start: 20130227 Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A61), 2013.
Date of Publication: February 2013. 2013.
Eunice Kennedy Shriver National Institute of Child H, Human D, National Institute of D, Digestive, Kidney D. Randomized Trial to Assess
Efficacy and Safety of Continuous Glucose Monitoring in Children 4-<10 Years With T1DM. NCT00760526 2014.
Farrar D, Tuffnell DJ, West J. Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with
diabetes. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD005542. DOI: 10.1002/14651858.CD005542.pub2.
Reason for
Exclusion
Systematic
Review/Met
a-analysis
Study
design
Study
design
Intervention
Intervention
Outcomes
Study
design
Outcomes
Systematic
Review/Met
234
CONFIDENTIAL UNTIL PUBLISHED
Citation
Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM. Clinical review: Hypoglycemia with intensive insulin therapy: a
systematic review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections. J Clin
Endocrinol Metab 2009;94(3):729-40.
Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM. Hypoglycemia with intensive insulin therapy: a systematic
review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections. J Clin Endocrinol
Metab 2009;94(3):729-40.
Feldt-Rasmussen B, Mathiesen ER, Jensen T, Lauritzen T, Deckert T. Effect of improved metabolic control on loss of kidney function in type 1
(insulin-dependent) diabetic patients: an update of the Steno studies. Diabetologia 1991;34(3):164-70.
Fendler W, Baranowska AI, Mianowska B, Szadkowska A, Mlynarski W. Three-year comparison of subcutaneous insulin pump treatment with
multi-daily injections on HbA1c, its variability and hospital burden of children with type 1 diabetes. Acta Diabetol 2012;49(5):363-70.
Fiallo-Scharer R. Eight-point glucose testing Versus the continuous glucose monitoring system in evaluation of glycemic control in type 1
diabetes. J Clin Endocrinol Metab 2005;90(6):3387-91.
Flores d'Arcais A, Morandi F, Beccaria L, Meschi F, Chiumello G. Metabolic control in newly diagnosed type 1 diabetic children. Effect of
continuous subcutaneous infusion. Horm Res 1984;19(2):65-9.
Fortwaengler K, Rautenberg T, Caruso A. Short term health-economic outcomes of continuous subcutaneous insulin infusion (CSII) in type 1
diabetes: A cost comparison analysis. Value Health 2012;Conference: ISPOR 15th Annual European Congress Berlin Germany. Conference
Start: 20121103 Conference End: 20121107. Conference Publication:(var.pagings). 15 (7):A350.
Fox L, Englert K, Mauras N. Effects of continuous subcutaneous insulin infusion (CSII) in adolescents with newly-diagnosed type 1 diabetes
(T1D) on insulin resistance and s-cell function: A pilot study. Diabetes. Conference: 69th Annual Meeting of the American Diabetes Association
New Orleans, LA United States. Conference Start: 20090605 Conference End: 20090609. Conference Publication: (var.pagings). 58 , 2009. Date
of Publication: 2009. 2009.
Fox LA, Buckloh LM, Smith S, Wysocki T, Mauras N. A randomized trial of insulin pump therapy in toddlers and preschool age children with
type 1 diabetes (DM1). Paper presented at Annual Meeting of the Pediatric Academic Societies; 4 May 2004; San Francisco: USA. Pediatr Res
2004;55(4):136A.
Fox LA, Buckloh LM, Smith SD, Wysocki T, Mauras N. A randomized controlled trial of insulin pump therapy in young children with type 1
diabetes. Diabetes Care 2005;28(6):1277-81.
Fox LA, Wilkinson K, Buckloh L, Wysocki T, Mauras N. A randomized trial of insulin pump therapy in preschool age children with type 1
diabetes mellitus: preliminary results. Paper presented at 62nd Annual Meeting of the American Diabetes Association; 14-18 Jun 2002; San
Francisco: USA. Diabetes 2002;51(Suppl 2):A426.
Reason for
Exclusion
a-analysis
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Intervention
Intervention
Intervention
Intervention
Outcomes
Intervention
Intervention
Study
design
Outcomes
235
CONFIDENTIAL UNTIL PUBLISHED
Citation
Frandsen CSS, Kristensen PL, Beck-Nielsen H, Nørgaard K, Perrild H, Christiansen JS, Jensen T, Parving H-H, Thorsteinsson B, Tarnow L,
Pedersen-Bjergaard U. Patients with type 1 diabetes treated with insulin pumps do not experience a reduced risk of severe hypoglycaemia in a
real life setting. Paper presented at 49th Annual Meeting of the European Association for the Study of Diabetes, EASD 2013; 23-27 Sep 2013;
Barcelona: Spain. 2013.
Frias JP, Gottlieb PA, Mackenzie T, Chillara B, Ashley M, Garg SK. Better glycemic control and less severe hypoglycemia in pregnant women
with type 1 diabetes treated with continuous subcutaneous insulin infusion. Paper presented at 62nd Annual Meeting of the American Diabetes
Association; 14-18 Jun 2002; San Francisco: USA. Diabetes 2002;51(Suppl 2):A431.
Gane J, White B, Christie D, Viner R. Systematic review and meta-analysis of insulin pump therapy in children and adolescents with type 1
diabetes. Archives of Disease in Childhood. Conference: Royal College of Paediatrics and Child Health Annual Conference, RCPCH 2010
Coventry United Kingdom. Conference Start: 20100420 Conference End: 20100422. Conference Publication: (var.pagings). 95 (pp A94), 2010.
Date of Publication: April 2010. 2010.
Garg S, Bode BW, Bergenstal R, Klonoff DC, Mao M, Weiss R, Welsh JB. Characteristics and predictors of nocturnal hypoglycemia in the runin phase of the aspire in-home study. Diabetes. Conference: 74th Scientific Sessions of the American Diabetes Association San Francisco, CA
United States. Conference Start: 20140613 Conference End: 20140617. Conference Publication: (var.pagings). 63 (pp A242), 2014. Date of
Publication: June 2014. 2014.
Garg S, Brazg RL, Bailey TS, Buckingham BA, Klonoff DC, Shin J, Welsh JB, Kaufman FR. Automatic insulin pump suspension for induced
hypoglycemia: The ASPIRE study. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA
United States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A59), 2012. Date of
Publication: June 2012. 2012.
Garg S, Brazg RL, Bailey TS, Buckingham BA, Klonoff DC, Shin J, Welsh JB, Kaufman FR. The order effect of the in-clinic ASPIRE study:
Hypoglycemia begets hypoglycemia. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA
United States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A58-A59), 2012. Date of
Publication: June 2012. 2012.
Garg S, Brazg RL, Bailey TS, Buckingham BA, Slover RH, Klonoff DC, Shin J, Welsh JB, Kaufman FR. Reduction in duration of hypoglycemia
by automatic suspension of insulin delivery: the in-clinic ASPIRE study. Diabetes Technol Ther 2012;14(3):205-9.
Garg S, Brazg RL, Bailey TS, Buckingham BA, Slover RH, Klonoff DC, Shin J, Welsh JB, Kaufman FR. Reduction in duration of hypoglycemia
by automatic suspension of insulin delivery: the in-clinic ASPIRE study. Diabetes Technol Ther 2013;15(Suppl 1):S17-S18.
Garg S, Ellis SL, Beatson C, Gottlieb P, Gutin R, Bookout T, Figal C, Snyder B. Improved glycaemic control in intensively treated subjects with
type 1 diabetes using Accu-Chek* advisor insulin guidance software. Paper presented at 43rd Annual Meeting of the European Association for
the Study of Diabetes, EASD; 18-21 Sep 2007; Amsterdam: The Netherlands. Diabetologia 2007;50(Suppl 1):S116-S117.
Reason for
Exclusion
Study
design
Study
design
Systematic
Review/Met
a-analysis
Outcomes
Study
design
Study
design
Outcomes
Study
design
Intervention
236
CONFIDENTIAL UNTIL PUBLISHED
Citation
Garg SK, Brazg RL, Bailey TS, Buckingham BA, Klonoff DC, Shin J, Welsh JB, Kaufman FR. Reduction of hypoglycaemia with insulin pump
suspension and role of antecedent hypoglycaemia on future hypoglycaemic inductions: ASPIRE study. Diabetologia. Conference: 48th Annual
Meeting of the European Association for the Study of Diabetes, EASD 2012 Berlin Germany. Conference Start: 20121001 Conference End:
20121005. Conference Publication: (var.pagings). 55 (pp S258-S259), 2012. Date of Publication: October 2012. 2012.
Garg SK, Brazg RL, Bailey TS, Buckingham BA, Slover RH, Klonoff DC, Shin J, Welsh JB, Kaufman FR. Hypoglycemia begets hypoglycemia:
The order effect in the ASPIRE in-clinic study. Diabetes Technol Ther 2014;16(3):125-30.
Garg SK, Crew LB, Moser EG, Voelmle MK, Beatson CR. Effect of continuous glucose monitoring on glycemic control in subjects with type 1
diabetes (T1D) delivering insulin via pump or multiple daily injections (MDI): a prospective study. Paper presented at 70th Annual Meeting of
the American Diabetes Association; 25-29 Jun 2010; Orlando: USA. Diabetes 2010;59:A33-A34.
Garg SK, Voelmle MK, Beatson CR, Miller HA, Crew LB, Freson BJ, Hazenfield RM. Use of continuous glucose monitoring in subjects with
type 1 diabetes on multiple daily injections versus continuous subcutaneous insulin infusion therapy: a prospective 6-month study. Diabetes Care
2011;34(3):574-9.
Garg SK, Weiss R, Shah A, Mao M, Kaufman FR. Change in a1c and reduction in hypoglycemia with threshold suspend in the aspire in-home
study. Diabetes Technology and Therapeutics. Conference: 7th International Conference on Advanced Technologies and Treatments for
Diabetes, ATTD 2014 Vienna Austria. Conference Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp
A107), 2014. Date of Publication: February 2014. 2014.
Giacomet AC. [Efficacy of the monitoring of the glycemias and insulin pump in the control of diabetes mellitus type I]. Rev AMRIGS
1984;28(4):303-9.
Gimenez M, Conget I, Nicolau J, Pericot A, Levy I. Outcome of pregnancy in women with type 1 diabetes intensively treated with continuous
subcutaneous insulin infusion or conventional therapy. A case-control study. Acta Diabetol 2007;44(1):34-7.
Goicolea I, Hernández I, Fombellida J, Vázquez JA. Evolution of GFR and other renal function parameters in insulin-dependent diabetic patients
treated with subcutaneous insulin infusion. Comparison against an optimized standard therapy: 1year-followup effects. An Med Interna
1988;5(4):169-72.
Goicolea Opacua I, Hernandez Colau I, Vazquez Garcia JA. [Comparative study between the subcutaneous continuous insulin infusion pump and
optimized conventional treatment. Effects at 6 months]. Rev Clin Esp 1986;179(1):3-7.
Golden SH, Brown T, Yeh HC, Maruthur N, Ranasinghe P, Berger Z, Suh Y, Wilson LM, Haberl EB, Bass EB. Methods for insulin delivery and
glucose monitoring: comparative effectiveness [Internet]. Rockville, MD: Agency for Healthcare Research and Quality (US), 2012 [accessed
24.7.14]. Report No: 12-EHC036-EF
Gomez A, Alfonso-Cristancho R, Prieto-Salamanca D, Valencia JE, Lynch P, Roze S. Health economic benefits of sensor augmented insulin
pump therapy in Colombia. Value in Health. Conference: ISPOR 4th Latin America Conference Buenos Aires Argentina. Conference Start:
Reason for
Exclusion
Study
design
Study
design
Study
design
Study
design
Outcomes
Not Found
Study
design
Not Found
Intervention
Systematic
Review/Met
a-analysis
Outcomes
237
CONFIDENTIAL UNTIL PUBLISHED
Citation
20130912 Conference End: 20130914. Conference Publication: (var.pagings). 16 (7) (pp A690), 2013. Date of Publication: November 2013.
2013.
Gonzalez-Romero S, Gonzalez-Molero I, Fernandez-Abellan M, Dominguez-Lopez ME, Ruiz-de-Adana S, Olveira G, Soriguer F. Continuous
subcutaneous insulin infusion versus multiple daily injections in pregnant women with type 1 diabetes. Diabetes Technol Ther 2010;12(4):263-9.
Gottlieb PA, Crew LB, Moser EG, Voelmle MK, Beatson CR, Gutin RS, Garg SK. Effects of continuous glucose monitoring on glycaemic
control in subjects with type 1 diabetes delivering insulin via pump or multiple daily injections: A prospective study. Diabetologia. Conference:
46th Annual Meeting of the European Association for the Study of Diabetes, EASD 2010 Stockholm Sweden. Conference Start: 20100920
Conference End: 20100924. Conference Publication: (var.pagings). 53 (pp S25), 2010. Date of Publication: September 2010. 2010.
Gough H, Castaneda J, Hommel E, Olsen BS, Battelino T, Conget I, Schutz-Fuhrmann I, Hoogma R, Schierloh U, Sulli N, Bolinder J, De Portu
S. The switch study: The impact of continuous glucose monitoring on quality of life and treatment satisfaction. Value in Health. Conference:
ISPOR 15th Annual European Congress Berlin Germany. Conference Start: 20121103 Conference End: 20121107. Conference Publication:
(var.pagings). 15 (7) (pp A359), 2012. Date of Publication: November 2012. 2012.
Greene SA, Smith MA, Baum JD. Clinical application of insulin pumps in the management of insulin dependent diabetes. Arch Dis Child
1983;58(8):578-81.
Guerci B, Meyer L, Delbachian I, Kolopp M, Ziegler O, Drouin P. Blood glucose control on Sunday in IDDM patients: intensified conventional
insulin therapy versus continuous subcutaneous insulin infusion. Diabetes Res Clin Pract 1998;40(3):175-80.
Guilmin-Crepon S, Scornet E, Couque N, Sulmont V, Salmon AS, Le Tallec C, Coutant R, Dalla-Vale F, Stuckens C, Bony H, Crosnier H, Kurtz
F, Carel JC, Alberti C, Tubiana-Rufi N. Could clinical parameters at initiation of continuous glucose monitoring (CGM) predict efficacy on
HbA1c in type 1 diabetes (T1D) pediatric patients at 3 months? Preliminary results in a prospective study of 141 patients (Start-In!). Pediatric
Diabetes. Conference: 38th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD 2012 Istanbul Turkey.
Conference Start: 20121010 Conference End: 20121013. Conference Publication: (var.pagings). 13 (pp 117), 2012. Date of Publication: October
2012. 2012.
Haakens K, Hanssen KF, Dahl-Jorgensen K, Vaaler S, Aagenaes O, Mosand R. Continuous subcutaneous insulin infusion (CSII), multiple
injections (MI) and conventional insulin therapy (CT) in self-selecting insulin-dependent diabetic patients. A comparison of metabolic control,
acute complications and patient preferences. J Intern Med 1990;228(5):457-64.
Haardt MJ, Selam JL, Slama G, Bethoux JP, Dorange C, Mace B, Ramaniche ML, Bruzzo F. A cost-benefit comparison of intensive diabetes
management with implantable pumps versus multiple subcutaneous injections in patients with type I diabetes. Diabetes Care 1994;17(8):847-51.
Haidar A, Legault L, Dallaire M, Alkhateeb A, Coriati A, Messier V, Cheng P, Millette M, Boulet B, Rabasa-Lhoret R. Glucose-responsive
insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial. CMAJ
2013;185(4):297-305.
Reason for
Exclusion
Study
design
Study
design
Outcomes
Study
design
Outcomes
Study
design
Study
design
Study
design
Study
design
238
CONFIDENTIAL UNTIL PUBLISHED
Citation
Halvorson M, Carpenter S, Kaiserman K, Kaufman FR. A pilot trial in pediatrics with the sensor-augmented pump: combining real-time
continuous glucose monitoring with the insulin pump. J Pediatr 2007;150(1):103-105.e1.
Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily
injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the
Development of Pump Therapy in Diabetes. Diabetes Care 2000;23(9):1232-5.
Hanas R, Lindholm Olinder A, Olsson PO, Johansson UB, Jacobson S, Heintz E, Werko S, Persson M. CSII and SAP valuable tools in the
treatment of diabetes; A swedish health technology assesment. Diabetes Technology and Therapeutics. Conference: 7th International Conference
on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria. Conference Start: 20140205 Conference End: 20140208.
Conference Publication: (var.pagings). 16 (pp A56), 2014. Date of Publication: February 2014. 2014.
Hanssen KF, Dahl-Jorgensen K, Brinchmann-Hansen O. The influence of strict control on diabetic complications. Acta Endocrinol Suppl
(Copenh) 1985;272:57-60.
Haugstvedt A, Wentzel-Larsen T, Graue M, Sovik O, Rokne B. Fear of hypoglycaemia in mothers and fathers of children with Type 1 diabetes is
associated with poor glycaemic control and parental emotional distress: a population-based study. Diabet Med 2010;27(1):72-8.
Hayes Inc. MiniMed paradigm REAL-Time closed-loop continuous insulin infusion and blood glucose monitoring system (Medtronic MiniMed
Inc.). Hayes, Inc., 2010.
Health Quality Ontario. Continuous glucose monitoring for patients with diabetes: an evidence-based analysis. Ont Health Technol Assess Ser
2011;11(4):1-29.
Health Quality Ontario. Continuous subcutaneous insulin infusion (CSII) pumps for type 1 and type 2 adult diabetic populations: an evidencebased analysis. Ont Health Technol Assess Ser 2009;9(20):1-58.
Helve E, Koivisto VA, Lehtonen A, Pelkonen R, Huttunen JK, Nikkila EA. A crossover comparison of continuous insulin infusion and
conventional injection treatment of type I diabetes. Acta Med Scand 1987;221(4):385-93.
Helve E, Laatikainen L, Merenmies L, Koivisto VA. Continuous insulin infusion therapy and retinopathy in patients with type I diabetes. Acta
Endocrinol (Copenh) 1987;115(3):313-9.
Hermanides J, Devries JH. Sensor-augmented insulin pump more effective than multiple daily insulin injections for reducing HbA1C in people
with poorly controlled type 1 diabetes. Evid Based Med 2011;16(2):46-8.
Hermanides J, Norgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, Diem P, Fermon C, Wentholt IME, Hoekstra JBL, DeVries JH.
Sensor augmented pump therapy substantially lowers HbA1c; a randomized controlled trial. Diabetologia. Conference: 45th EASD Annual
Reason for
Exclusion
Study
design
Outcomes
Systematic
Review/Met
a-analysis
Not Found
Study
design
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Intervention
Not Found
Study
design
Study
design
239
CONFIDENTIAL UNTIL PUBLISHED
Citation
Meeting of the European Association for the Study of Diabetes Vienna Austria. Conference Start: 20090930 Conference End: 20091002.
Conference Publication: (var.pagings). 52 (S1) (pp S43), 2009. Date of Publication: 2009. 2009.
Hermanns N, Kulzer B, Gulde C, Eberle H, Pradler E, Patzelt-Bath A, Haak T. Short-term effects on patient satisfaction of continuous glucose
monitoring with the glucoday with real-time and retrospective access to glucose values: a crossover study. Diabetes Technol Ther
2009;11(5):275-81.
Hermansen K, Moller A, Christensen CK, Christiansen JS, Schmitz O, Orskov H, Alberti KG, Mogensen CE. Diurnal plasma profiles of
metabolite and hormone concentration in insulin-dependent diabetic patients during conventional insulin treatment and continuous subcutaneous
insulin infusion. A controlled study. Acta Endocrinol (Copenh) 1987;114(3):433-9.
Hermansen K, Schmitz O, Boye N, Christensen CK, Christiansen JS, Alberti KG, Orskov H, Mogensen CE. Glucagon responses to intravenous
arginine and oral glucose in insulin-dependent diabetic patients during six months conventional or continuous subcutaneous insulin infusion.
Metabolism 1988;37(7):640-4.
Hiéronimus S, Cupelli C, Bongain A, Durand-Réville M, Berthier F, Fénichel P. [Pregnancy in type 1 diabetes: insulin pump versus intensified
conventional therapy]. Gynecol Obstet Fertil 2005;33(6):389-94.
Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P, Santiago OM, Kolaczynski JW, Insulin Aspart CMDICSG. Continuous subcutaneous
insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously
treated with CSII. Diabetes Care 2005;28(3):533-8.
Hoeks L, Greven WL, de Valk HW. Real-time continuous glucose monitoring system for treatment of diabetes: a systematic review. Diabet Med
2011;28(4):386-94.
Hoffmann-La R. A Study Comparing Continuous Subcutaneous Insulin Infusion With Multiple Daily Injections With Insulin Lispro and
Glargine. NCT00468754 2014.
Hoffmann-La R. European, Open-label, Prospective, Multinational, Multicenter Study in Adult Subjects With Type 1 or Type 2 Diabetes
Previously on MDI or CSII Therapy. Subjects Home Setting is Considered Routine Practice. NCT02105103 2014.
Holder M, Kordonouri O, Haberland H, Golembowski S, Zierow S, Remus K, Blaesig S, Wadien T, Hartmann R, Thomas A, Danne T. The low
glucose suspend function in sensor-augmented pump therapy prevents hypoglycaemia in children. Diabetologia. Conference: 47th Annual
Meeting of the European Association for the Study of Diabetes, EASD 2011 Lisbon Portugal. Conference Start: 20110912 Conference End:
20110916. Conference Publication: (var.pagings). 54 (pp S400), 2011. Date of Publication: September 2011. 2011.
Hollander AS, White NH. Continuous subcutaneous insulin infusion (CSII) reduces severe hypoglycemia (SH) in children with type 1 diabetes
mellitus (T1DM) without compromising overall glycemic control. Paper presented at Pediatric Academic Societies and the American Academy
of Pediatrics joint meeting; 12-16 May 2000; Boston: USA. Pediatr Res 2000;47(4 Pt 2):132A.
Reason for
Exclusion
Study
design
Not Found
Intervention
Study
design
Study
design
Systematic
Review/Met
a-analysis
Outcomes
Study
design
Study
design
Study
design
240
CONFIDENTIAL UNTIL PUBLISHED
Citation
Home PD, Capaldo B, Burrin JM, Worth R, Alberti KG. A crossover comparison of continuous subcutaneous insulin infusion (CSII) against
multiple insulin injections in insulin-dependent diabetic subjects: improved control with CSII. Diabetes Care 1982;5(5):466-71.
Hommel E, Olsen B, Battelino T, Conget I, Schutz-Fuhrmann I, Hoogma R, Schierloh U, Sulli N, Gough H, Castaneda J, de Portu S, Bolinder J,
SWITCH Study Group. Impact of continuous glucose monitoring on quality of life, treatment satisfaction, and use of medical care resources:
analyses from the SWITCH study. Acta Diabetol 2014;51(5):845-51.
Hoogma R, Hoekstra JB, Michels BP, Levi M. Comparison between multiple daily insulin injection therapy (MDI) and continuous subcutaneous
insulin infusion therapy (CSII), results of the five nations study. Paper presented at International Symposium on New Technologies for Insulin
Replacement; 28 Apr-1 May 2005; Assisi: Italy. Diabetes Res Clin Pract 2006;74:S144-S147.
Hoogma R, Spijker AJM, van Doorn-Scheele M, van Doorn TT, Michels RPJ, van Doorn RG, Levi M, Hoekstra JB. Quality of life and
metabolic control in patients with diabetes mellitus type I treated by continuous subcutaneous insulin infusion or multiple daily insulin injections.
Neth J Med 2004;62(10):383-7.
Hoogma RP, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP, Wiefels KJ, de la Calle H, Schweitzer DH, Pfohl M, Torlone E,
Krinelke LG, Bolli GB, 5-Nations Study Group. Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based
multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial. Diabet Med 2006;23(2):141-7.
Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, Kollman C, Hovorka T, Larsen AMF, Nodale M, De Palma A, Wilinska ME,
Acerini CL, Dunger DB. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover
trial. Lancet 2010;375(9716):743-51.
Hovorka R, Elleri D, Thabit H, Allen JM, Leelarathna L, El-Khairi R, Kumareswaran K, Caldwell K, Calhoun P, Kollman C, Murphy HR,
Acerini CL, Wilinska ME, Nodale M, Dunger DB. Overnight closed-loop insulin delivery in young people with type 1 diabetes: a free-living,
randomized clinical trial. Diabetes Care 2014;37(5):1204-11.
Huang ES, O'Grady M, Basu A, Winn A, John P, Lee J, Meltzer D, Kollman C, Laffel L, Tamborlane W, Weinzimer S, Wysocki T. The costeffectiveness of continuous glucose monitoring in type 1 diabetes. Diabetes Care 2010;33(6):1269-1274.
Husted SE, Nielsen HK, Bak JF, Beck-Nielsen H. Antithrombin III activity, von Willebrand factor antigen and platelet function in young
diabetic patients treated with multiple insulin injections versus insulin pump treatment. Eur J Clin Invest 1989;19(1):90-4.
Ignatova N, Arbatskaya N, Melnikova E. Continuous subcutaneous insulin infusion (CSII) reduces the rate of hypoglycaemic episodes
throughout pregnancy. Diabetologia 2007;50(Suppl 1):S383-S384.
In Home Closed Loop Study G, National Institute of D, Digestive, Kidney D, Juvenile Diabetes Research F. Outpatient Reduction of Nocturnal
Hypoglycemia by Using Predictive Algorithms and Pump Suspension in Children. NCT01823341 2014.
In Home Closed Loop Study G, National Institute of D, Digestive, Kidney D. An Outpatient Pump Shutoff Pilot Feasibility and Safety Study.
NCT01736930 2014.
Reason for
Exclusion
Study
design
Outcomes
Study
design
Study
design
Intervention
Study
design
Study
design
Outcomes
Outcomes
Outcomes
Study
design
Study
design
241
CONFIDENTIAL UNTIL PUBLISHED
Citation
In Home Closed Loop Study G, National Institute of D, Digestive, Kidney D. Outpatient Pump Shutoff Pilot Feasibility and Efficacy Study.
NCT01591681 2014.
Indiana U, Juvenile Diabetes Research F. Prospective Study of the Impact of Insulin Pump Therapy in Young Children With Type 1 Diabetes.
NCT00727220 2012.
ISRCTN01687353. Standardized Procedure for the Assessment of new-to-market Continuous glucosE monitoring systems. 2012.
ISRCTN05450731. Paediatric onset study to assess the efficacy of insulin pump therapy using the MiniMed Paradigm® REAL-Time system
during the first year of diabetes in children and adolescents with type 1 diabetes. 2008.
ISRCTN28387915. Utility of continuous glucose monitoring (CGMS) in children with type I diabetes on intensive treatment regimens.
ISRCTN33678610. A randomised controlled trial (RCT) to compare minimally invasive glucose monitoring devices to conventional monitoring
in the management of insulin treated diabetes mellitus.
ISRCTN33678610. A randomised controlled trial (RCT) to compare minimally invasive glucose monitoring devices to conventional monitoring
in the management of insulin treated diabetes mellitus. 2003.
ISRCTN37153662. Comparison between continuous subcutaneous insulin infusion with multiple basal lispro infusion rates and multiple daily
insulin injection with lispro and glargine. 2007.
ISRCTN52164803. Prevention of recurrent severe hypoglycaemia: optimised multiple daily insulin injection (MDI) versus continuous
subcutaneous insulin infusion (CSII) with or without adjunctive real-time continuous glucose monitoring. 2009.
ISRCTN62034905. Comparison of two artificial pancreas systems for closed loop blood glucose control versus open loop control in patients with
type1 diabetes. 2011.
ISRCTN64351161. Comparison in metabolic control and treatment satisfaction with continuous subcutaneous insulin infusion and multiple daily
injections in children at onset of type 1 diabetes mellitus. 2007.
ISRCTN77773974. A randomised study of continuous subcutaneous insulin infusion (CSII) therapy compared to conventional bolus insulin
treatment in preschool aged children with Type 1 diabetes.
ISRCTN77773974. A randomised study of continuous subcutaneous insulin infusion (CSII) therapy compared to conventional bolus insulin
treatment in preschool aged children with Type 1 diabetes. 2003.
Jakisch BI, Wagner VM, Heidtmann B, Lepler R, Holterhus PM, Kapellen TM, Vogel C, Rosenbauer J, Holl RW, German/Austrian DPVI,
Working Group for Paediatric Pump T. Comparison of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in
paediatric Type 1 diabetes: a multicentre matched-pair cohort analysis over 3 years. Diabet Med 2008;25(1):80-5.
Jdrf Artificial Pancreas Project. Randomized Study of Real-Time Continuous Glucose Monitors (RT-CGM) in the Management of Type 1
Diabetes. NCT00406133 2010.
Reason for
Exclusion
Study
design
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design
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design
Study
design
Outcomes
Study
design
Intervention
Intervention
Outcomes
Study
design
Outcomes
Outcomes
Outcomes
Study
design
Outcomes
242
CONFIDENTIAL UNTIL PUBLISHED
Citation
Jeha GS, Karaviti LP, Anderson B, Smith EOB, Donaldson S, McGirk TS, Haymond MW. Insulin pump therapy in preschool children with type
1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia. Diabetes Technol Ther
2005;7(6):876-84.
Jeitler K, Horvath K, Berghold A, Gratzer TW, Neeser K, Pieber TR, Siebenhofer A. Continuous subcutaneous insulin infusion versus multiple
daily insulin injections in patients with diabetes mellitus: systematic review and meta-analysis. Diabetologia 2008;51(6):941-51.
Jenkins AJ, Krishnamurthy B, Best JD, Cameron FJ, Colman PG, Hamblin PS, O'Connell MA, Rodda C, Teede H, O'Neal DN. An algorithm
guiding patient responses to real-time-continuous glucose monitoring improves quality of life. Diabetes Technol Ther 2011;13(2):105-9.
Jennings AM, Lewis KS, Murdoch S, Talbot JF, Bradley C, Ward JD. Randomized trial comparing continuous subcutaneous insulin infusion and
conventional insulin therapy in type II diabetic patients poorly controlled with sulfonylureas. Diabetes Care 1991;14(8):738-44.
Jiang L, Jiang S, Ma Y, Zhang M, Feng X. Real-time continuous glucose monitoring vs conventional glucose monitoring in critically ill patients.
PROSPERO: CRD42014013488 [Internet]. 2014 [accessed 5.9.14].
Jimenez M, Hernaez R, Conget I, Alonso A, Yago G, Pericot A, Gonce A, Levy I. Metabolic control, maternal and perinatal outcomes in type 1
diabetic pregnancies intensively treated with conventional insulin therapy vs. continuous subcutaneous insulin infusion. Paper presented at 41st
Annual Meeting of the European Association for the Study of Diabetes, EASD; 10-15 Sep 2005; Athens: Greece. Diabetologia 2005;48(Suppl
1):A315.
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Group, Beck RW, Lawrence JM, Laffel L, Wysocki T, Xing D, Huang
ES, Ives B, Kollman C, Lee J, Ruedy KJ, Tamborlane WV. Quality-of-life measures in children and adults with type 1 diabetes: Juvenile
Diabetes Research Foundation Continuous Glucose Monitoring randomized trial. Diabetes Care 2010;33(10):2175-7.
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, Buckingham B,
Chase HP, Clemons R, Fiallo-Scharer R, Fox LA, Gilliam LK, Hirsch IB, Huang ES, Kollman C, Kowalski AJ, Laffel L, Lawrence JM, Lee J,
Mauras N, O'Grady M, Ruedy KJ, Tansey M, Tsalikian E, Weinzimer S, Wilson DM, Wolpert H, Wysocki T, Xing D. Continuous glucose
monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008;359(14):1464-76.
Kamble S, Perry BM, Shafiroff J, Schulman KA, Reed SD. The cost-effectiveness of initiating sensor-augmented pump therapy versus multiple
daily injections of insulin in adults with type 1 diabetes: Evaluating a technology in evolution. Value in Health. Conference: 16th Annual
International Meeting of the International Society for Pharmacoeconomics and Outcomes Research, ISPOR 2011 Baltimore, MD United States.
Conference Start: 20110521 Conference End: 20110525. Conference Publication: (var.pagings). 14 (3) (pp A82), 2011. Date of Publication: May
2011. 2011.
Kamble S, Schulman KA, Reed SD. Cost-effectiveness of sensor-augmented pump therapy in adults with type 1 diabetes in the United States.
Reason for
Exclusion
Study
design
Systematic
Review/Met
a-analysis
Intervention
Population
Systematic
Review/Met
a-analysis
Study
design
Intervention
Intervention
Outcomes
Outcomes
243
CONFIDENTIAL UNTIL PUBLISHED
Citation
Value Health 2012;15(5):632-8.
Kamble S, Weinfurt KP, Perry BM, Schulman KA, Reed SD. Patient time and indirect costs associated with sensor-augmented insulin pump
therapy in type 1 diabetes. Value in Health. Conference: 16th Annual International Meeting of the International Society for Pharmacoeconomics
and Outcomes Research, ISPOR 2011 Baltimore, MD United States. Conference Start: 20110521 Conference End: 20110525. Conference
Publication: (var.pagings). 14 (3) (pp A84), 2011. Date of Publication: May 2011. 2011.
Kamble S, Weinfurt KP, Schulman KA, Reed SD. Patient time costs associated with sensor-augmented insulin pump therapy for type 1 diabetes:
results from the STAR 3 randomized trial. Med Decis Making 2013;33(2):215-24.
Kapellen T, Kordonouri O, Pankowska E, Rami B, Coutant R, Hartmann R, Lange K, Danne T. Sensor-augmented pump therapy from the onset
of type 1 diabetes in children and adolescents - Results of the Pediatric ONSET Study after 12 months of treatment. Hormone Research in
Paediatrics. Conference: 49th Annual Meeting of the European Society for Paediatric Endocrinology, ESPE 2010 Prague Czech Republic.
Conference Start: 20100922 Conference End: 20100925. Conference Publication: (var.pagings). 74 (pp 58), 2010. Date of Publication:
September 2010. 2010.
Kaufman F, Shin J, Yang Q. Differences in measures of glycemic variability between the multiple daily injection therapy and sensor-augmented
pump therapy groups in the star 3 study. Diabetes Technology and Therapeutics. Conference: 4th International Conference on Advanced
Technologies and Treatments for Diabetes, ATTD 2011 London United Kingdom. Conference Start: 20110216 Conference End: 20110219.
Conference Publication: (var.pagings). 13 (2) (pp 186), 2011. Date of Publication: February 2011. 2011.
Kaufman FR, Agrawal P, Askari S, Kannard B, Welsh JB. Effectiveness of the low glucose suspend feature of the medtronic paradigm Veo
insulin pump in children and adolescents. Pediatric Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022. Conference Publication:
(var.pagings). 12 (pp 30-31), 2011. Date of Publication: October 2011. 2011.
Kaufman FR, Agrawal P, Lee SW, Kannard B. Characterization of the low glucose suspend feature of the medtronic minimed paradigm veo
insulin pump system and events preceding its activation. Diabetes. Conference: 71st Scientific Sessions of the American Diabetes Association
San Diego, CA United States. Conference Start: 20110624 Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A249),
2011. Date of Publication: July 2011. 2011.
Kaufman FR, Austin J, Neinstein A, Jeng L, Halvorson M, Devoe DJ, Pitukcheewanont P. Nocturnal hypoglycemia detected with the
Continuous Glucose Monitoring System in pediatric patients with type 1 diabetes. J Pediatr 2002;141(5):625-30.
Kaufman FR, Gibson LC, Halvorson M, Carpenter S, Fisher LK, Pitukcheewanont P. A pilot study of the continuous glucose monitoring system:
clinical decisions and glycemic control after its use in pediatric type 1 diabetic subjects. Diabetes Care 2001;24(12):2030-4.
Kaufman FR, Halvorson M, Kim C, Pitukcheewanont P. Use of insulin pump therapy at nighttime only for children 7-10 years of age with type 1
diabetes. Diabetes Care 2000;23(5):579-82.
Reason for
Exclusion
Outcomes
Outcomes
Study
design
Outcomes
Study
design
Study
design
Study
design
Study
design
Study
design
244
CONFIDENTIAL UNTIL PUBLISHED
Citation
Keenan DB, Cartaya R, Mastrototaro JJ. Accuracy of a new real-time continuous glucose monitoring algorithm. J Diabetes Sci Technol
2010;4(1):111-8.
Keenan DB, Mastrototaro JJ, Zisser H, Cooper KA, Raghavendhar G, Lee SW, Yusi J, Bailey TS, Brazg RL, Shah RV. Accuracy of the Enlite 6day glucose sensor with guardian and Veo calibration algorithms. Diabetes Technol Ther 2012;14(3):225-31.
Kernaghan D, Farrell T, Hammond P, Owen P. Fetal growth in women managed with insulin pump therapy compared to conventional insulin.
Eur J Obstet Gynecol Reprod Biol 2008;137(1):47-9.
Khalil S, Wright T, Field A, Hand J, Dyer P, Karamat MA. Does continuous subcutaneous insulin infusion (CSII) provide an effective method of
controlling diabetes in pregnant women with type 1 diabetes? Paper presented at Diabetes UK Professional Conference; 13-15 Mar 2013;
Manchester: UK. Diabet Med 2013;30(Suppl 1):170.
King Abdullah International Medical Research C, Reem Mohammad A. Incidence of Hypoglycemia During Ramadan in Patients With Type1
Diabetes on Insulin Pump Versus Multi Dose Injection. NCT01941238 2013.
Kordonouri O, Hartmann R, Lauterborn R, Barnekow C, Hoeffe J, Deiss D. Age-specific advantages of continuous subcutaneous insulin infusion
as compared with multiple daily injections in pediatric patients: one-year follow-up comparison by matched-pair analysis. Diabetes Care
2006;29(1):133-4.
Kordonouri O, Hartmann R, Pankowska E, Rami B, Kapellen T, Coutant R, Lange K, Danne T. Follow-up of patients with sensor-augmented
pump therapy during the first year of diabetes-pediatric onset study. Pediatric Diabetes. Conference: 37th Annual Meeting of the International
Society for Pediatric and Adolescent Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022.
Conference Publication: (var.pagings). 12 (pp 29), 2011. Date of Publication: October 2011. 2011.
Kordonouri O, Hartmann R, Pankowska E, Rami B, Kapellen T, Coutant R, Lange K, Danne T. Sensor augmented pump therapy from onset of
type 1 diabetes: Late follow-up results of the Pediatric ONSET Study. Diabetologia. Conference: 47th Annual Meeting of the European
Association for the Study of Diabetes, EASD 2011 Lisbon Portugal. Conference Start: 20110912 Conference End: 20110916. Conference
Publication: (var.pagings). 54 (pp S41), 2011. Date of Publication: September 2011. 2011.
Kordonouri O, Hartmann R, Pankowska E, Rami B, Kapellen T, Coutant R, Lange K, Danne T. Sensor augmented pump therapy from onset of
type 1 diabetes: late follow-up results of the Pediatric Onset Study. Pediatr Diabetes 2012;13(7):515-8.
Kordonouri O, Pankowska E, Rami B, Kapellen T, Coutant R, Hartmann R, Lange K, Knip M, Danne T. Sensor-augmented pump therapy from
the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia
2010;53(12):2487-95.
Kordonouri O. Pumps and sensors from the onset of diabetes. Pediatric Diabetes. Conference: 36th Annual Meeting of the International Society
for Pediatric and Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027 Conference End: 20101030. Conference
Publication: (var.pagings). 11 (pp 6), 2010. Date of Publication: October 2010. 2010.
Reason for
Exclusion
Study
design
Study
design
Intervention
Study
design
Study
design
Intervention
Study
design
Study
design
Study
design
Study
design
Study
design
245
CONFIDENTIAL UNTIL PUBLISHED
Citation
Kovatchev BP. Safety and efficacy of outpatient closed-loop control--results from randomized crossover trials of a wearable artificial pancreas.
Paper presented at 74th Scientific Sessions of the American Diabetes Association; 13-17 Jun 2014; San Francisco, CA: United States. 2014.
Kracht T, Kordonouri O, Datz N, Scarabello C, Walte K, Blaesig S, Geldmacher R, Von Dem Berge W, Hartmann R, Chico H, Matsubara H,
Balo AK, Danne T, Nakamura K. Reducing glycaemic variability and Hba1c with the Dexcom Seven.2 continuous glucose monitoring system in
children and young adults with type 1 diabetes (T1D). Pediatric Diabetes. Conference: 35th Annual Meeting of the International Society for
Pediatric and Adolescent Diabetes, ISPAD Ljubljana Slovenia. Conference Start: 20090902 Conference End: 20090905. Conference Publication:
(var.pagings). 10 (pp 104), 2009. Date of Publication: September 2009. 2009.
Kruger J, Brennan A. The cost of Type 1 diabetes mellitus in the United Kingdom: a review of cost-of-illness studies. Eur J Health Econ
2013;14(6):887-99.
Laatikainen L, Teramo K, Hieta-Heikurainen H, Koivisto V, Pelkonen R. A controlled study of the influence of continuous subcutaneous insulin
infusion treatment on diabetic retinopathy during pregnancy. Acta Med Scand 1987;221(4):367-76.
Laffel L, Buckingham B, Chase P, Bailey T, Liljenquist D, Daniels M, Price D, Nakamura K. Performance of a continuous glucose monitoring
system (CGM) and CGM glucose ranges in youth ages 2-17 yr old. Pediatric Diabetes. Conference: 39th Annual Conference of the International
Society for Pediatric and Adolescent Diabetes, ISPAD 2013 Gothenburg Sweden. Conference Start: 20131016 Conference End: 20131019.
Conference Publication: (var.pagings). 14 (pp 47-48), 2013. Date of Publication: October 2013. 2013.
Lagarde WH, Barrows FP, Davenport ML, Kang M, Guess HA, Calikoglu AS. Continuous subtaneous glucose monitoirng in children with type
1 diabetes mellitus: a single-blind, randomized, controlled trial. Pediatr Diabetes 2006;7(3):159-64.
Laguna AJ, Rossetti P, Ampudia-Blasco FJ, Vehi J, Bondia J. Postprandial performance of Dexcom SEVEN PLUS and Medtronic Paradigm
Veo: modeling and statistical analysis. Biomed Signal Process Control 2014;10:322-31.
Lange K, Coutant R, Danne T, Kapellen T, Pankowska E, Rami B, Aschemeier B, Blasig S, Hartmann R, Krug N, Marquardt E, Remus K,
Kordonouri O. High quality of life in children and psychological wellbeing in mothers 12 month after diabetes onset: Results of the paediatric
onset-trial of sensor-enhanced CSII. Pediatric Diabetes. Conference: 36th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027 Conference End: 20101030. Conference Publication:
(var.pagings). 11 (pp 101), 2010. Date of Publication: October 2010. 2010.
Langeland LB, Salvesen O, Selle H, Carlsen SM, Fougner KJ. Short-term continuous glucose monitoring: effects on glucose and treatment
satisfaction in patients with type 1 diabetes mellitus; a randomized controlled trial. Int J Clin Pract 2012;66(8):741-7.
Langendam M, Luijf YM, Hooft L, DeVries JH, Mudde AH, Scholten RJPM. Continuous glucose monitoring systems for type 1 diabetes
mellitus. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008101. DOI: 10.1002/14651858.CD008101.pub2.
Lapolla A, Dalfra MG, Masin M, Bruttomesso D, Piva I, Crepaldi C, Tortul C, Dalla Barba B, Fedele D. Analysis of outcome of pregnancy in
Reason for
Exclusion
Study
design
Intervention
Outcomes
Intervention
Intervention
Outcomes
Study
design
Study
design
Study
design
Systematic
Review/Met
a-analysis
Study
246
CONFIDENTIAL UNTIL PUBLISHED
Citation
type 1 diabetics treated with insulin pump or conventional insulin therapy. Acta Diabetol 2003;40(3):143-9.
Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T. Two-year experience with continuous subcutaneous insulin infusion in relation to
retinopathy and neuropathy. Diabetes 1985;34 Suppl 3:74-9.
Lawson ML, Bradley B, McAssey K, Clarson C, Kirsch S, Curtis JR, Richardson C, Courtney J, Cooper T. Timing of initiation of continuous
glucose monitoring in established pediatric diabetes: Recruitment and baseline characteristics in the CGM time trial. Diabetes Technology and
Therapeutics. Conference: 7th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria.
Conference Start: 20140205 Conference End: 20140208. Conference Publication: (var.pagings). 16 (pp A73-A74), 2014. Date of Publication:
February 2014. 2014.
Lawson ML, Olivier P, Huot C, Richardson C, Nakhla M, Romain J. Simultaneous vs delayed initiation of Real-Time Continuous Glucose
Monitoring (RT-CGM) in children and adolescents with established type 1 diabetes starting insulin pump therapy: A pilot study. Pediatric
Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD Miami Beach, FL United
States. Conference Start: 20111019 Conference End: 20111022. Conference Publication: (var.pagings). 12 (pp 126-127), 2011. Date of
Publication: October 2011. 2011.
Lawson ML, Richardson C, Muileboom J, Evans K, Landry A, Cormack L. Development of a standardized approach to initiating continuous
glucose monitoring in amulticentre pediatric study. Diabetes Technology and Therapeutics. Conference: 7th International Conference on
Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria. Conference Start: 20140205 Conference End: 20140208.
Conference Publication: (var.pagings). 16 (pp A73), 2014. Date of Publication: February 2014. 2014.
Lawson P, Home PD, Bergenstal R. Observations on blood lipid and intermediary metabolite concentrations during conventional insulin
treatment or CSII. Diabetes 1985;34 Suppl 3:27-30.
Lebenthal Y, Lazar L, Benzaquen H, Shalitin S, Phillip M. Patient perceptions of using OmniPod System compared with conventional insulin
pumps in young adults with type 1 diabetes. Pediatric Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022. Conference Publication:
(var.pagings). 12 (pp 131-132), 2011. Date of Publication: October 2011. 2011.
Lebenthal Y, Lazar L, Benzaquen H, Shalitin S, Phillip M. Patient perceptions of using the OmniPod system compared with conventional insulin
pumps in young adults with type 1 diabetes. Diabetes Technol Ther 2012;14(5):411-7.
Lecavalier L, Havrankova J, Hamet P, Chiasson JL. Effects of continuous subcutaneous insulin infusion versus multiple injections on insulin
receptors in insulin-dependent diabetics. Diabetes Care 1987;10(3):300-5.
Lee SW, Welsh JB, Green JB, Joyce C, Tamborlane WV, Kaufman FR. Successful transitions from MDI therapy to sensor-augmented pump
therapy in the STAR 3 study: System settings and behaviours. Diabetologia. Conference: 47th Annual Meeting of the European Association for
the Study of Diabetes, EASD 2011 Lisbon Portugal. Conference Start: 20110912 Conference End: 20110916. Conference Publication:
Reason for
Exclusion
design
Intervention
Outcomes
Outcomes
Outcomes
Intervention
Intervention
Intervention
Study
design
Outcomes
247
CONFIDENTIAL UNTIL PUBLISHED
Citation
(var.pagings). 54 (pp S395-S396), 2011. Date of Publication: September 2011. 2011.
Leelarathna L, Little SA, Walkinshaw E, Tan HK, Lubina-Solomon A, Kumareswaran K, Lane AP, Chadwick T, Marshall SM, Speight J,
Flanagan D, Heller SR, Shaw JAM, Evans ML. Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes:
hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial. Diabetes Care 2013;36(12):4063-70.
Legacy Health S, Juvenile Diabetes Research F, Oregon H, Science U. Sensor-Augmented Insulin Delivery: Insulin Plus Glucagon Versus
Insulin Alone. 2011. Available from: http://ClinicalTrials.gov/show/NCT00797823
Lepore G, Dodesini AR, Nosari I, Trevisan R. Both continuous subcutaneous insulin infusion and a multiple daily insulin injection regimen with
glargine as basal insulin are equally better than traditional multiple daily insulin injection treatment. Diabetes Care 2003;26(4):1321-2.
Lepore G, Dodesini AR, Nosari I, Trevisan R. Effect of continuous subcutaneous insulin infusion vs multiple daily insulin injection with glargine
as basal insulin: an open parallel long-term study. Diabetes Nutr Metab 2004;17(2):84-9.
Leveno KJ, Fortunato SJ, Raskin P, Williams ML, Whalley PJ. Continuous subcutaneous insulin infusion during pregnancy. Diabetes Res Clin
Pract 1988;4(4):257-68.
Li A, Tsang CH. The effectiveness of continuous subcutaneous insulin infusion on quality of life of families and glycaemic control among
children with type 1 diabetes: a systematic review. PROSPERO: CRD42012002029 [Internet]. 2012 [accessed 5.9.14].
Li XL. Multiple daily injections versus insulin pump therapy in patients with type 1 diabetes mellitus: a meta analysis. Journal of Clinical
Rehabilitative Tissue Engineering Research 2010;14(46):8722-5.
Lindholm Olinder A, Hanas R, Heintz E, Jacobson S, Johansson UB, Olsson PO, Persson M, Werko S. CGM and sap are valuable tools in the
treatment of diabetes; A swedish health technology assessment. Diabetes Technology and Therapeutics. Conference: 7th International
Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2014 Vienna Austria. Conference Start: 20140205 Conference End:
20140208. Conference Publication: (var.pagings). 16 (pp A74), 2014. Date of Publication: February 2014. 2014.
Liouri E, Koutsovasilis A, Kounenou K, Kamaratos A, Koukouli M-P, Nikolaou A, Iraklianou S, Damianaki D, Melidonis A. Intensified insulin
therapy vs CSII: the influence on family cohesion and adaptability of type 1 diabetics. Paper presented at 45th EASD Annual Meeting of the
European Association for the Study of Diabetes; 30 Sep-2 Oct 2009; Vienna: Austria. 2009.
Little S, Chadwick T, Choudhary P, Brennand C, Stickland J, Barendse S, Olateju T, Leelarathna L, Walkinshaw E, Tan HK, Marshall SM,
Thomas RM, Heller S, Evans M, Kerr D, Flanagan D, Speight J, Shaw JA. Comparison of Optimised MDI versus Pumps with or without Sensors
in Severe Hypoglycaemia (the Hypo COMPaSS trial). BMC Endocr Disord 2012;12:33.
Little SA, Leelarathna L, Walkinshaw E, Kai Tan H, Chapple O, Solomon AL, Barendse S, Chadwick T, Brennand C, Stocken D, Wood R,
Marshall SM, Begley J, Kerr D, Speight J, Flanagan D, Heller SR, Evans ML, Shaw JAM. A definitive multicenter rct to restore hypoglycemia
Reason for
Exclusion
Study
design
Study
design
Study
design
Not Found
Intervention
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Systematic
Review/Met
a-analysis
Outcomes
Outcomes
Outcomes
248
CONFIDENTIAL UNTIL PUBLISHED
Citation
awareness and prevent recurrent severe hypoglycemia in adults with long- standing type 1 diabetes: Results from the hypocompass trial.
Diabetes. Conference: 73rd Scientific Sessions of the American Diabetes Association Chicago, IL United States. Conference Start: 20130621
Conference End: 20130625. Conference Publication: (var.pagings). 62 (pp A98), 2013. Date of Publication: July 2013. 2013.
Little SA, Leelarathna L, Walkinshaw E, Tan HK, Chapple O, Lubina-Solomon A, Chadwick TJ, Barendse S, Stocken DD, Brennand C,
Marshall SM, Wood R, Speight J, Kerr D, Flanagan D, Heller SR, Evans ML, Shaw JAM. Recovery of hypoglycemia awareness in longstanding type 1 diabetes: a multicenter 2 × 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and
continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes Care 2014;37(8):2114-22.
Littlejohn E, Turksoy K, Quinn LT, Cinar A. Integrated multivariable artificial pancreas control systems work as well as operator controlled
systems. Paper presented at 74th Scientific Sessions of the American Diabetes Association; 13-17 Jun 2014; San Francisco: USA. 2014.
Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M. Insulin pump therapy in toddlers and preschool children with type 1 diabetes
mellitus. J Pediatr 2002;141(4):490-5.
Logtenberg SJ, Kleefstra N, Groenier KH, Gans RO, Bilo HJ. Use of short-term real-time continuous glucose monitoring in type 1 diabetes
patients on continuous intraperitoneal insulin infusion: a feasibility study. Diabetes Technol Ther 2009;11(5):293-9.
Ludvigsson J, Hanas R. Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a
controlled crossover study. Pediatrics 2003;111(5 Pt 1):933-8.
Luijf YM, De Vries JH, Mader JK, Doll W, Place J, Renard E, Bruttomesso D, Filippi A, Benesch C, Heinemann L. Accuracy and reliability of
current continuous glucose monitoring systems: A direct comparison. In: Journal of Diabetes Science and Technology. Conference: 12th Annual
Diabetes Technology Meeting Bethesda, MD United States. Conference Start: 20121108 Conference End: 20121110. Conference Publication:
(var.pagings). 7 (1) (pp A83), 2013. Date of Publication: January 2013., 2013.
Luijf YM, DeVries JH, Mader JK, Doll W, Place J, Renard E, Bruttomesso D, Avogaro A, Benesch C, Heinemann L. Accuracy and reliability of
current CGM systems: A direct comparison. Diabetes Technology and Therapeutics. Conference: 6th International Conference on Advanced
Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227 Conference End: 20130302. Conference
Publication: (var.pagings). 15 (pp A13-A14), 2013. Date of Publication: February 2013. 2013.
Luijf YM, DeVries JH, Zwinderman K, Leelarathna L, Nodale M, Caldwell K, Kumareswaran K, Elleri D, Allen JM, Wilinska ME, Evans ML,
Hovorka R, Doll W, Ellmerer M, Mader JK, Renard E, Place J, Farret A, Cobelli C, Del Favero S, Dalla Man C, Avogaro A, Bruttomesso D,
Filippi A, Scotton R, Magni L, Lanzola G, Di Palma F, Soru P, Toffanin C, De Nicolao G, Arnolds S, Benesch C, Heinemann L, Consortium
APh. Day and night closed-loop control in adults with type 1 diabetes: a comparison of two closed-loop algorithms driving continuous
subcutaneous insulin infusion versus patient self-management. Diabetes Care 2013;36(12):3882-7.
Luijf YM, Mader JK, Doll W, Pieber T, Farret A, Place J, Renard E, Bruttomesso D, Filippi A, Avogaro A, Arnolds S, Benesch C, Heinemann
L, DeVries JH, consortium APh. Accuracy and reliability of continuous glucose monitoring systems: a head-to-head comparison. Diabetes
Reason for
Exclusion
Outcomes
Intervention
Study
design
Intervention
Intervention
Outcomes
Outcomes
Study
design
Study
design
249
CONFIDENTIAL UNTIL PUBLISHED
Citation
Technol Ther 2013;15(8):721-6.
Ly TT, Keenan DB, Spital G, Roy A, Grosman B, Cantwell M, Davis EA, Jones TW. Portable glucose control with daytime treat-to-range and
overnight proportionalintegral-derivative control in adolescents with type 1 diabetes. Diabetes Technology and Therapeutics. Conference: 6th
International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227
Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A14), 2013. Date of Publication: February 2013. 2013.
Ly TT, Nicholas JA, Davis EA, Jones TW. Initial experience of automated low glucose insulin suspension using the medtronic paradigm veo
system. Diabetes. Conference: 71st Scientific Sessions of the American Diabetes Association San Diego, CA United States. Conference Start:
20110624 Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A112), 2011. Date of Publication: July 2011. 2011.
Ly TT, Nicholas JA, Retterath A, Davis EA, Jones TW. Analysis of glucose responses to automated insulin suspension with sensor-augmented
pump therapy. Diabetes Care 2012;35(7):1462-5.
Maahs DM, Calhoun P, Buckingham BA, Chase HP, Hramiak I, Lum J, Cameron F, Bequette BW, Aye T, Paul T, Slover R, Wadwa RP, Wilson
DM, Kollman C, Beck RW, In Home Closed Loop Study G. A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1
diabetes. Diabetes Care 2014;37(7):1885-91.
Maahs DM, Chase HP, Westfall E, Slover R, Huang S, Shin JJ, Kaufman FR, Pyle L, Snell-Bergeon JK. The effects of lowering nighttime and
breakfast glucose levels with sensor-augmented pump therapy on hemoglobin A1c levels in type 1 diabetes. Diabetes Technol Ther
2014;16(5):284-91.
Maiorino MI, Bellastella G, Petrizzo M, Improta MR, Brancario C, Castaldo F, Olita L, Giugliano D. Treatment satisfaction and glycemic
control in young Type 1 diabetic patients in transition from pediatric health care: CSII versus MDI. Endocrine 2014;46(2):256-62.
Manfrini S, Crino A, Fredrickson L, Pozzilli P. CSII versus intensive insulin therapy at onset of type 1 diabetes: the IMDIAB 8 two-year
randomised trial. Paper presented at 62nd Annual Meeting of the American Diabetes Association; 14-18 Jun 2002; San Francisco: USA. Diabetes
2002;51(Suppl 2):A4.
Maran A, Crazzolara D, Nicoletti M, Costa S, dal Pos M, Tiengo A, Avogaro A, Bruttomesso D. A randomized crossover study to compare
continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) in type 1 diabetic patients previously treated with CSII.
Paper presented at 41st Annual Meeting of the European Association for the Study of Diabetes, EASD; 10-15 Sep 2005; Athens: Greece.
Diabetologia 2005;48(Suppl 1):A328.
Mauras N, Beck R, Xing D, Ruedy K, Buckingham B, Tansey M, White N, Weinzimer SAW, Tamborlane W, Kollman C. A randomized
controlled trial (RCT) to assess the efficacy and safety of real-time continuous glucose monitoring (CGM) in the management of type 1 diabetes
(T1D) in young children. Pediatric Diabetes. Conference: 37th Annual Meeting of the International Society for Pediatric and Adolescent
Diabetes, ISPAD Miami Beach, FL United States. Conference Start: 20111019 Conference End: 20111022. Conference Publication:
(var.pagings). 12 (pp 30), 2011. Date of Publication: October 2011. 2011.
Reason for
Exclusion
Outcomes
Study
design
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Study
design
Study
design
Study
design
Study
design
Outcomes
Intervention
250
CONFIDENTIAL UNTIL PUBLISHED
Citation
Mauras N, Beck R, Xing D, Ruedy K, Buckingham B, Tansey M, White NH, Weinzimer SA, Tamborlane W, Kollman C. A randomized clinical
trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children aged 4
to < 10 years. Diabetes Technol Ther 2013;15(Suppl 1):S14-S15.
Mauras N, Beck R, Xing DY, Ruedy K, Buckingham B, Tansey M, White NH, Weinzimer SA, Tamborlane W, Kollman C. A randomized
clinical trial to assess the efficacy and safety of real-time continuous glucose monitoring in the management of type 1 diabetes in young children
aged 4 to <10 years. Diabetes Care 2012;35(2):204-10.
McCoy R, Smith S. Insulin pumps with a sensor and threshold-suspend reduced nocturnal hypoglycemia in type 1 diabetes. Ann Intern Med
2013;159(6):JC7.
McCoy R. Insulin pumps with a sensor and threshold-suspend reduced nocturnal hypoglycemia in type 1 diabetes. Ann Intern Med
2013;159(6):JC7.
Medtronic Diabetes. Feasibility Study for Training Pump Naïve Subjects To Use The Paradigm® System And Evaluate Effectiveness.
NCT00530023 2011.
Medtronic. SWITCH - Sensing With Insulin Pump Therapy to Control HbA1c. 2010. Available from:
http://ClinicalTrials.gov/show/NCT00598663
Melki V, Hanaire-Broutin H, Bessieres-Lacombe S, Tauber JP. CSII versus MDI in IDDM patients treated with insulin lispro: results of a
randomised, cross-over trial. Paper presented at 35th Annual meeting of the European Association for the Study of Diabetes; 28 Sep-2 Oct 1999;
Brussels: Belgium. Diabetologia 1999;42(Suppl 1):A17.
Mello G, Biagioni S, Ottanelli S, Nardini C, Tredici Z, Serena C, Marchi L, Mecacci F. Continuous subcutaneous insulin infusion (CSII) versus
multiple daily injections (MDI) of rapid-acting insulin analogues and detemir in type 1 diabetic (T1D) pregnant women. J Matern Fetal Neonatal
Med 2014:1-6.
Mello G, Parretti E, Tondi F, Riviello C, Borri P, Scarselli G. Impact of two treatment regimens with insulin lispro in post-prandial glucose
excursion patterns and fetal fat mass growth in type 1 diabetic pregnant women. Paper presented at 26th Annual Meeting of the Society for
Maternal-Fetal Medicine: The Pregnancy Meeting; 30 Jan-4 Feb 2006; Miami: USA. Am J Obstet Gynecol 2005;193(6 Suppl):S36.
Meschi F, Beccaria L, Vanini R, Szulc M, Chiumello G. Short-term subcutaneous insulin infusion in diabetic children. Comparison with three
daily insulin injections. Acta Diabetol Lat 1982;19(4371–5).
Meyer L, Boullu-Sanchis S, Boeckler P, Sibenaler A, Treger M, Pinget M, Jeandidier N. Comparison of glycemic control in 3 groups of type 1
diabetic patients treated with multiinjections and lispro (MDI), continuous subcutaneous insulin infusion with lispro (CSII) or continuous
peritoneal insulin infusion (CPII): data of continuous subcutaneous glucose sensing (CGMS). Paper presented at 62nd Annual Meeting of the
American Diabetes Association; 14-18 Jun 2002; San Francisco: USA. Diabetes 2002;51(Suppl 2):A124-A125.
Micossi P, Raggi U, Dosio F. Open-loop device microjet MC 2 improves unstable diabetes, lowers the daily insulin requirement and reduces the
Reason for
Exclusion
Study
design
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design
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design
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design
Intervention
Study
design
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Study
design
Outcomes
Not Found
Study
design
Intervention
251
CONFIDENTIAL UNTIL PUBLISHED
Citation
excursions of plasma free insulin levels: Comparison with a traditional intensive treatment. J Endocrinol Invest 1983;6(3):189-194.
Misso ML, Egberts KJ, Page M, O'Connor D, Shaw J. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for
type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005103. DOI:
10.1002/14651858.CD005103.pub2.
Moller A, Rasmussen L, Ledet T, Christiansen JS, Christensen CK, Mogensen CE, Hermansen K. Lipoprotein changes during continuous
subcutaneous insulin infusion in insulin-dependent diabetic patients. Scand J Clin Lab Invest 1986;46(5):471-5.
Monami M, Lamanna C, Marchionni N, Mannucci E. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 1
diabetes: a meta-analysis. Acta Diabetol 2010;47 Suppl 1:77-81.
Monnier LH, Rodier M, Gancel A, Crastes de Paulet P, Colette C, Piperno M, Crastes de Paulet J. Plasma lipid fatty acids and platelet function
during continuous subcutaneous insulin infusion in type I diabetes. Diabete Metab 1987;13(3):210-6.
Moreno-Fernandez J, Gomez FJ, Gazquez M, Pedroche M, Garcia-Manzanares A, Tenias JM, Benito P, Gomez IR. Real-time continuous
glucose monitoring or continuous subcutaneous insulin infusion, what goes first?: results of a pilot study. Diabetes Technol Ther
2013;15(7):596-600.
Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant
diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Am J Obstet Gynecol 2007;197(5):447-56.
Murphy HR, Kumareswaran K, Elleri D, Allen JM, Caldwell K, Biagioni M, Simmons D, Dunger DB, Nodale M, Wilinska ME, Amiel SA,
Hovorka R. Safety and efficacy of 24-h closed-loop insulin delivery in well-controlled pregnant women with type 1 diabetes: a randomized
crossover case series.[Erratum appears in Diabetes Care. 2012 Jan;35(1):191]. Diabetes Care 2011;34(12):2527-9.
Myers SJ, Uhrinak AN, Kaufman FR, Lee SW, Yusi J, Huang S, Agrawal P, Kannard B. Retrospective analysis of events preceding low glucose
suspend activation in pediatric subjects on the paradigm veo system. In: Journal of Diabetes Science and Technology. Conference: 11th Annual
Diabetes Technology Meeting San Francisco, CA United States. Conference Start: 20111027 Conference End: 20111029. Conference
Publication: (var.pagings). 6 (2) (pp A125), 2012. Date of Publication: March 2012., 2012.
Nabhan ZM, Kreher NC, Greene DM, Eugster EA, Kronenberger W, DiMeglio LA. A randomized prospective study of insulin pump vs. insulin
injection therapy in very young children with type 1 diabetes: 12-month glycemic, BMI, and neurocognitive outcomes. Pediatr Diabetes
2009;10(3):202-8.
Nahata L. Insulin therapy in pediatric patients with type I diabetes: continuous subcutaneous insulin infusion versus multiple daily injections.
Clin Pediatr (Phila) 2006;45(6):503-8.
Nathan DM, Lou P, Avruch J. Intensive conventional and insulin pump therapies in adult type I diabetes. A crossover study. Ann Intern Med
Reason for
Exclusion
Systematic
Review/Met
a-analysis
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Review/Met
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Review/Met
a-analysis
Study
design
Study
design
Intervention
Study
design
Study
252
CONFIDENTIAL UNTIL PUBLISHED
Citation
1982;97(1):31-6.
NCT00357890. Insulin Pump Therapy in Adolescents With Newly Diagnosed Type 1 Diabetes (T1D). 2006.
NCT00406133. Randomized Study of Real-Time Continuous Glucose Monitors (RT-CGM) in the Management of Type 1 Diabetes. 2006.
NCT00462371. Comparison Between Insulin Pump Treatment and Multiple Daily Insulin Injections in Diabetic Type 1 Children. 2007.
NCT00468754. A Study Comparing Continuous Subcutaneous Insulin Infusion With Multiple Daily Injections With Insulin Lispro and Glargine.
2007.
NCT00530023. Feasibility Study for Training Pump Naïve Subjects To Use The Paradigm® System And Evaluate Effectiveness. 2007.
NCT00571935. Efficacy and Safety of Insulin Aspart in MDI or CSII in Children Below 7 Years of Age With Type 1 Diabetes. 2007.
NCT00574405. Preservation of Pancreatic Beta Cell Function Through Insulin Pump Therapy. 2007.
NCT00598663. SWITCH - Sensing With Insulin Pump Therapy to Control HbA1c. 2007.
NCT00811317. Closed-loop Glucose Control for Automated Management of Type 1 Diabetes. 2008.
NCT00875290. The Effectiveness of Continuous Glucose Monitoring in Diabetes Treatment for Infants and Young Children. 2009.
NCT01185496. Effectiveness and Safety Study of the DexCom™ G4 Continuous Glucose Monitoring System in Children and Adolescents With
Type 1 Diabetes Mellitus. 2010.
NCT01454700. Effect of CSII and CGM on Progression of Late Diabetic Complications. 2011.
NCT01591681. Outpatient Pump Shutoff Pilot Feasibility and Efficacy Study. 2012.
NCT01667185. Effectiveness and Safety of the Dexcom™ G4 Continuous Glucose Monitoring System in Pediatric Subjects With Diabetes
Mellitus. 2012.
NCT01736930. An Outpatient Pump Shutoff Pilot Feasibility and Safety Study. 2012.
NCT01823341. Outpatient Reduction of Nocturnal Hypoglycemia by Using Predictive Algorithms and Pump Suspension in Children. 2013.
NCT02003898. Post Approval Study of the Threshold Suspend Feature With the Medtronic MiniMed® 530G Insulin Pump. 2013.
NCT02092051. CGM Treatment in Patients With Type 1 Diabetes Treated With Insulin Injections. 2014.
NCT02120794. Threshold Suspend in Pediatrics at Home. 2014.
NCT02153190. Hybrid Artificial Pancreas in Home Setting. 2014.
Reason for
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design
Population
Outcomes
Outcomes
Outcomes
Duplicate
Outcomes
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design
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Duplicate
Study
design
Duplicate
Study
design
Study
design
Study
design
Study
design
Study
design
Duplicate
Duplicate
Intervention
253
CONFIDENTIAL UNTIL PUBLISHED
Citation
NCT02179281. Prevention of Hypoglycaemia With Predictive Insulin Suspend Using Sensor Augmented Insulin Pump in Children. 2014.
Neeser K, Kocher S, Weber C, Heister F. CSII compared to MDI: A health economic analysis in the german health care setting. Value Health
2009;Conference: ISPOR 12th Annual European Congress Paris France. Conference Start: 20091024 Conference End: 20091027. Conference
Publication:(var.pagings). 12 (7):A407.
Neff K, McCarthy A, Forde R, Foley M, Coulter-Smith S, Daly S, Firth R, Byrne MM, Kinsley BT. Intensive glycaemic control in type 1
diabetic pregnancy: a comparison of continuous subcutaneous insulin infusion and multiple daily injection therapy. Paper presented at 46th
Annual Meeting of the European Association for the Study of Diabetes, EASD; 20-24 Sep 2010; Stockholm: Sweden. Diabetologia 2010;53(1
Suppl).
Nemours Children's C. Insulin Pump Therapy in Adolescents With Newly Diagnosed Type 1 Diabetes (T1D). NCT00357890 2012.
New J, Ajjan R, Pfeiffer AFH, Freckmann G. Impact of alarm functions with real time continuous glucose monitoring (CGM). Diabetes
Technology and Therapeutics. Conference: 6th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013
Paris France. Conference Start: 20130227 Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A8-A9), 2013. Date of
Publication: February 2013. 2013.
Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, Steed L, Manca A, Sculpher M, Barnard M, Kerr D, Weaver J, Ahlquist J,
Hurel SJ. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the
management of insulin-treated diabetes mellitus (MITRE). Health Technol Assess 2009;13(28):iii-iv, ix-xi, 1-194.
Neylon OM, O'Connell MA, Donath S, Cameron FJ. Can integrated technology improve self-care behavior in youth with type 1 diabetes? A
randomized crossover trial of automated pump function. Pediatric Diabetes. Conference: 39th Annual Conference of the International Society for
Pediatric and Adolescent Diabetes, ISPAD 2013 Gothenburg Sweden. Conference Start: 20131016 Conference End: 20131019. Conference
Publication: (var.pagings). 14 (pp 46), 2013. Date of Publication: October 2013. 2013.
Ng Tang Fui S, Pickup JC, Bending JJ, Collins AC, Keen H, Dalton N. Hypoglycemia and counterregulation in insulin-dependent diabetic
patients: a comparison of continuous subcutaneous insulin infusion and conventional insulin injection therapy. Diabetes Care 1986;9(3):221-7.
Nimri R, Miller S, Muller I, Atlas E, Fogel A, Bratina N, Kordonouri O, Battelino T, Danne T, Phillip M. The home use of MD-logic closed-loop
system during the nights significantly improves daytime glycemic control in subjects with type 1 diabetes. Diabetes. Conference: 74th Scientific
Sessions of the American Diabetes Association San Francisco, CA United States. Conference Start: 20140613 Conference End: 20140617.
Conference Publication: (var.pagings). 63 (pp A243), 2014. Date of Publication: June 2014. 2014.
Nimri R, Muller I, Atlas E, Miller S, Fogel A, Bratina N, Kordonouri O, Battelino T, Danne T, Phillip M. MD-Logic overnight control for 6
weeks of home use in patients with type 1 diabetes: randomized crossover trial. Diabetes Care 2014;37(11):3025-32.
Nixon R, Pickup JC. Fear of hypoglycemia in type 1 diabetes managed by continuous subcutaneous insulin infusion: is it associated with poor
Reason for
Exclusion
Study
design
Outcomes
Study
design
Population
Outcomes
Intervention
Outcomes
Study
design
Intervention
Intervention
Study
254
CONFIDENTIAL UNTIL PUBLISHED
Citation
glycemic control? Diabetes Technol Ther 2011;13(2):93-8.
Norgaard K, Sohlberg A, Goodall G. [Cost-effectiveness of continuous subcutaneous insulin infusion therapy for type 1 diabetes]. Ugeskr Laeger
2010;172(27):2020-5.
NTR863. Randomized, controlled, multinational, multi-center, clinical trial to examine whether HbA1c can improve in type 1 diabetes patients
who continuously use the Paradigm® REAL-Time system with alarm function as compared to patients on multiple injection therapy receiving
one six-day period of continuous glucose monitoring - without alarm function (Guardian® REAL-Time Clinical). 2007.
Nuboer R, Borsboom GJJM, Zoethout JA, Koot HM, Bruining J. Effects of insulin pump vs. injection treatment on quality of life and impact of
disease in children with type 1 diabetes mellitus in a randomized, prospective comparison. Pediatr Diabetes 2008;9(4 Pt 1):291-6.
O'Connell R, Oroszlan G, Hamer G, Yusi J, Kaufman F, Welsh J, Mihalakis M, Lee S. Efficacy of low glucose suspend and low predictive alert:
Data analysis using the medtronic carelink therapy management software database. Diabetes Technology and Therapeutics. Conference: 4th
International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2011 London United Kingdom. Conference Start:
20110216 Conference End: 20110219. Conference Publication: (var.pagings). 13 (2) (pp 244), 2011. Date of Publication: February 2011. 2011.
O'Grady MJ, Retterath AJ, Keenan DB, Kurtz N, Cantwell M, Spital G, Kremliovsky MN, Roy A, Davis EA, Jones TW, Ly TT. The use of an
automated, portable glucose control system for overnight glucose control in adolescents and young adults with type 1 diabetes. Diabetes Care
2012;35(11):2182-7.
Olivier P, Lawson ML, Huot C, Richardson C, Nakhla M, Romain J. Lessons learned from a pilot RCT of simultaneous versus delayed initiation
of continuous glucose monitoring in children and adolescents with type 1 diabetes starting insulin pump therapy. J Diabetes Sci Technol
2014;8(3):523-8.
Opipari-Arrigan L, Fredericks EM, Burkhart N, Dale L, Hodge M, Foster C. Continuous subcutaneous insulin infusion benefits quality of life in
preschool-age children with type 1 diabetes mellitus. Pediatr Diabetes 2007;8(6):377-83.
Pankowska E, Blazik M, Dziechciarz P, Szypowska A, Szajewska H. Continuous subcutaneous insulin infusion vs. multiple daily injections in
children with type 1 diabetes: a systematic review and meta-analysis of randomized control trials. Pediatr Diabetes 2009;10(1):52-8.
Patrakeeva EM, Zalevskaya AG, Shlyakhto EV. Fear of hypoglycemia in relatives of young type 1 diabetes mellitus (T1DM) patients on MDI
and CSII therapy. Paper presented at 74th Scientific Sessions of the American Diabetes Association; 13-17 Jun 2014; San Francisco: USA. 2014.
Perkins BA, Halpern EM, Orszag A, Weisman A, Houlden RL, Bergenstal RM, Joyce C. Sensor-augmented pump and multiple daily injection
therapy in the United States and Canada: post-hoc analysis of a randomized controlled trial. [Epub ahead of print]. Can J Diabetes
2014;pii:S1499-2671(14)00151-8.
Petkova E, Petkova V, Konstantinova M, Petrova G. Economic evaluation of continuous subcutaneous insulin infusion for children with diabetes
- a pilot study: CSII application for children - economic evaluation. BMC Pediatr 2013;13:155.
Reason for
Exclusion
design
Not Found
Intervention
Intervention
Study
design
Study
design
Outcomes
Intervention
Systematic
Review/Met
a-analysis
Study
design
Outcomes
Outcomes
255
CONFIDENTIAL UNTIL PUBLISHED
Citation
Petkova E, Petkova V, Konstantinova M, Petrova G. Economic Evaluation of Continuous Subcutaneous Insulin Infusion for Children with
Diabetes--Part II. Modern Economy 2013;4(10A):9-13.
Petkova V, Petrova G, Petkova E. Compa rative analysis of the cost and metabolic control in diabetic children using insulin pumps. Value Health
2013;Conference: ISPOR 16th Annual European Congress Dublin Ireland. Conference Start: 20131102 Conference End: 20131106. Conference
Publication:(var.pagings). 16 (7):A437.
Petrovski G, Jovanovska B, Bitovska I, Ahmeti I. Constant or intermittent glucose monitoring: Evaluation on pregnancy and glycemic outcome
in type 1 diabetics on insulin pump. Diabetes. Conference: 73rd Scientific Sessions of the American Diabetes Association Chicago, IL United
States. Conference Start: 20130621 Conference End: 20130625. Conference Publication: (var.pagings). 62 (pp A684), 2013. Date of Publication:
July 2013. 2013.
Phillip M, Battelino T, Atlas E, Kordonouri O, Bratina N, Miller S, Biester T, Stefanija MA, Muller I, Nimri R, Danne T. Nocturnal glucose
control with an artificial pancreas at a diabetes camp. N Engl J Med 2013;368(9):824-33.
Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self
monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ 2011;343:d3805.
Pickup JC. The evidence base for diabetes technology: appropriate and inappropriate meta-analysis. J Diabetes Sci Technol 2013;7(6):1567-74.
Poolsup N, Suksomboon N, Kyaw AM. Systematic review and meta-analysis of the effectiveness of continuous glucose monitoring (CGM) on
glucose control in diabetes. Diabetol Metab Syndr 2013;5:39.
Pozzilli P, Crino A, Schiaffini R, Manfrini S, Fioriti E, Coppolino G, Pitocco D, Visalli N, Corbi S, Spera S, Suraci C, Cervoni M, Matteoli MC,
Patera IP, Ghirlanda G, Group I. A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with
newly diagnosed type 1 diabetes (IMDIAB 8). Diabetes Technol Ther 2003;5(6):965-74.
Price D, Nakamura K, Christiansen M, Bailey T, Watkins E, Liljenquist D, Peyser T. Accuracy and reliability of a next generation continuous
glucose monitoring system: The Dexcom G4 platinum pivotal trial results. Diabetes Technology and Therapeutics. Conference: 6th International
Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227 Conference End:
20130302. Conference Publication: (var.pagings). 15 (pp A70-A71), 2013. Date of Publication: February 2013. 2013.
Price DA, Peyser T, Simpson P, Nakamura K, Mahalingam A. Impact of study design and analytic techniques on the reported accuracy of
Continuous Glucose Monitoring (CGM) systems. Diabetes. Conference: 72nd Scientific Sessions of the American Diabetes Association
Philadelphia, PA United States. Conference Start: 20120608 Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A1),
2012. Date of Publication: June 2012. 2012.
Price DA, Peyser TA, Graham C. Challenges with systematic reviews and meta-analyses of real-time continuous glucose monitoring (CGM).
Reason for
Exclusion
Outcomes
Outcomes
Intervention
Study
design
Systematic
Review/Met
a-analysis
Background
Systematic
Review/Met
a-analysis
Intervention
Study
design
Background
Background
256
CONFIDENTIAL UNTIL PUBLISHED
Citation
Reason for
Exclusion
Diabetes. Conference: 73rd Scientific Sessions of the American Diabetes Association Chicago, IL United States. Conference Start: 20130621
Conference End: 20130625. Conference Publication: (var.pagings). 62 (pp A644), 2013. Date of Publication: July 2013. 2013.
Quiroz M, Machado F, Shafiroff J, Gill M, Molina M, Gonzalez P. Insulin pump cost-utility analysis compared to multiple daily injection in type
Outcomes
1 diabetic patients in the Mexican social security institute, 21st century hospital. Value Health 2012;Conference: 17th Annual International
Meeting of the International Society for Pharmacoeconomics and Outcomes Research, ISPOR 2012 Washington, DC United States. Conference
Start: 20120602 Conference End: 20120606. Conference Publication:(var.pagings). 15 (4):A69.
Rabin Medical C. Treatment Satisfaction of Using OmniPod System Compared With Conventional Insulin Pump in Adults With Type 1
Intervention
Diabetes. 2012. Available from: http://ClinicalTrials.gov/show/NCT00935129
Radermecker RP, Saint Remy A, Scheen AJ, Bringer J, Renard E. Continuous glucose monitoring reduces both hypoglycaemia and HbA1c in
Outcomes
hypoglycaemia-prone type 1 diabetic patients treated with a portable pump. Diabetes Metab 2010;36(5):409-13.
Ranasinghe P, Maruthur N, Yeh HC, Brown T, Suh Y, Wilson L, Berger Z, Bass E, Golden S. Comparative effectiveness of continuous
Systematic
subcutaneous insulin infusion with multiple daily injections among pregnant women with diabetes mellitus: A systematic review. In: Journal of
Review/Met
Hospital Medicine. Conference: 2012 Annual Meeting of the Society of Hospital Medicine, SHM 2012 San Diego, CA United States.
a-analysis
Conference Start: 20120401 Conference End: 20120404. Conference Publication: (var.pagings). 7 (pp S52), 2012. Date of Publication: March
2012., 2012.
Reid SM, Lawson ML. Comparison of continuous subcutaneous insulin infusion versus conventional treatment of Type 1 diabetes with respect to Intervention
metabolic control, quality of life and treatment satisfaction. Paper presented at Pediatric Academic Societies' annual meeting; 4-7 May 2002;
Baltimore: USA. Pediatr Res 2002;51(4 Suppl):122A-123A.
Riveline J-P, Schaepelynck P, Chaillous L, Renard E, Sola-Gazagnes A, Penfornis A, Tubiana-Rufi N, Sulmont V, Catargi B, Lukas C,
Intervention
Radermecker RP, Thivolet C, Moreau F, Benhamou P-Y, Guerci B, Leguerrier A-M, Millot L, Sachon C, Charpentier G, Hanaire H, Group ESS.
Assessment of patient-led or physician-driven continuous glucose monitoring in patients with poorly controlled type 1 diabetes using basal-bolus
insulin regimens: a 1-year multicenter study. Diabetes Care 2012;35(5):965-71.
Robinson-Vincent KA. Systematic review of the effects of continuous glucose monitoring on metabolic control in children and adolescents with
Systematic
type 1 diabetes. In: Canadian Journal of Diabetes. Conference: 16th Annual Canadian Diabetes Association/Canadian Society of Endocrinology
Review/Met
and Metabolism Professional Conference and Annual Meetings Montreal, QC Canada. Conference Start: 20131017 Conference End: 20131019.
a-analysis
Conference Publication: (var.pagings). 37 (pp S21), 2013. Date of Publication: October 2013., 2013.
Roy A, Kaufman FR, Spital G, Clark B, Grosman B, Parikh N, Mastrototaro J, Keenan B. An in-silico study of predictive low glucose
Study
management algorithm for minimizing hypoglycemia. Diabetes Technology and Therapeutics. Conference: 6th International Conference on
design
Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France. Conference Start: 20130227 Conference End: 20130302.
Conference Publication: (var.pagings). 15 (pp A81-A82), 2013. Date of Publication: February 2013. 2013.
257
CONFIDENTIAL UNTIL PUBLISHED
Citation
Roze S, Demessinov A, Zeityn M, Toktarova N, Abduakhassova G, Sissemaliev R, Karamalis M, Dunne N, Muratalina A, Klots M, Lynch P.
Health-economic comparison of continuous subcutaneous insulin infusion versus multiple daily injections for the treatment of type 1 diabetes in
Kazakhstan children. Value Health 2013;Conference: ISPOR 16th Annual European Congress Dublin Ireland. Conference Start: 20131102
Conference End: 20131106. Conference Publication:(var.pagings). 16 (7):A439-A440.
Roze S, Lynch P, Cook M. Projection of long term health-economic benefits of Continuous Glucose Monitoring (CGM) versus self monitoring
of blood glucose in type 1 diabetes, a UK perspective. Diabetologia 2012;Conference: 48th Annual Meeting of the European Association for the
Study of Diabetes, EASD 2012 Berlin Germany. Conference Start: 20121001 Conference End: 20121005. Conference Publication: (var.pagings).
55:S427.
Roze S, Valentine WJ, Zakrzewska KE, Palmer AJ. Health-economic comparison of continuous subcutaneous insulin infusion with multiple
daily injection for the treatment of Type 1 diabetes in the UK. Diabet Med 2005;22(9):1239-45.
Rubin RR, Peyrot M. Patient-reported outcomes in the sensor-augmented pump therapy (SAPT) for A1c reduction (STAR) 3 trial. Diabetes.
Conference: 71st Scientific Sessions of the American Diabetes Association San Diego, CA United States. Conference Start: 20110624
Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A82), 2011. Date of Publication: July 2011. 2011.
Rys PM, Mucha A, Koprowski M, Nowicki M, Malecki MT. Efficacy and safety of continuous glucose monitoring systems vs. self-monitoring
blood glucose in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. Diabetes. Conference: 71st Scientific Sessions of
the American Diabetes Association San Diego, CA United States. Conference Start: 20110624 Conference End: 20110628. Conference
Publication: (var.pagings). 60 (pp A244), 2011. Date of Publication: July 2011. 2011.
Sadri H, Bereza BG, Longo CJ. Cost-consequence analysis of CSII vs. MDI: A Canadian perspective. Value Health 2010;Conference: ISPOR
13th Annual European Congress Prague Czech Republic. Conference Start: 20101106 Conference End: 20101109. Conference
Publication:(var.pagings). 13 (7):A290.
Sahin SB, Cetinkalp S, Ozgen AG, Saygili F, Yilmaz C. The importance of anti-insulin antibody in patients with type 1 diabetes mellitus treated
with continuous subcutaneous insulin infusion or multiple daily insulin injections therapy. Acta Diabetol 2010;47(4):325-30.
Saigí I, Chico A, Santos L, Aulinas A, Adelantado J, Ginovart G, Garcia-Patterson A, Corcoy R. Glycaemic control and perinatal outcomes of
pregnancies complicated by type 1 diabetes: multiple daily injections vs continuous subcutaneous insulin infusion. Paper presented at 45th
EASD Annual Meeting of the European Association for the Study of Diabetes; 30 Sep-2 Oct 2009; Vienna: Austria. 2009.
Saigi I, Chico A, Santos L, Aulinas A, Adelantado J, Ginovart G, Garcia-Patterson A, Corcoy R. Glycaemic control and perinatal outcomes of
pregnancies complicated by type 1 diabetes: multiple daily injections vs continuous subcutaneous insulin infusion. Paper presented at 45th
Annual Meeting of the European Association for the Study of Diabetes, EASD; 29 Sep-2 Oct 2009; Vienna: Austria. Diabetologia
2009;52(Suppl 1):S46.
Saraiva J, Paiva S, Ruas L, Barros L, Baptista C, Melo M, Alves M, Gouveia S, Moreno C, Guelho D, Marta E, Gomes L, Moura P, Carrilho F.
Reason for
Exclusion
Outcomes
Outcomes
Outcomes
Outcomes
Not Found
Outcomes
Study
design
Outcomes
Study
design
Study
258
CONFIDENTIAL UNTIL PUBLISHED
Citation
Type 1 diabetes and pregnancy: continuous subcutaneous insulin infusion systems versus multiple daily injection therapy. Paper presented at
49th Annual Meeting of the European Association for the Study of Diabetes, EASD 2013; 23-27 Sep 2013; Barcelona: Spain. 2013.
Saurbrey N, Arnold-Larsen S, Moller-Jensen B, Kuhl C. Comparison of continuous subcutaneous insulin infusion with multiple insulin injections
using the NovoPen. Diabet Med 1988;5(2):150-3.
Scaramuzza A, De Angelis L, Bosetti A, Gazzarri A, Platerote F, Redaelli F, Macedoni M, Mazzantini S, Marchi O, Maio D, De Palma A, Peio
F, Zuccotti GV. Evaluation of three bolus calculators in children with type 1 diabetes using insulin pump therapy. Pediatric Diabetes.
Conference: 37th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes, ISPAD Miami Beach, FL United States.
Conference Start: 20111019 Conference End: 20111022. Conference Publication: (var.pagings). 12 (pp 128), 2011. Date of Publication: October
2011. 2011.
Scaramuzza AE, De Angelis L, Gazzarri A, Bosetti A, Platerote F, Redaelli F, MacEdoni M, Mazzantini S, Marchi O, Maio D, De Palma A,
Zuccotti G. Evaluation of 3 bolus calculators in children and adolescents with type 1 diabetes using insulin pump therapy. Diabetologia.
Conference: 47th Annual Meeting of the European Association for the Study of Diabetes, EASD 2011 Lisbon Portugal. Conference Start:
20110912 Conference End: 20110916. Conference Publication: (var.pagings). 54 (pp S352), 2011. Date of Publication: September 2011. 2011.
Schaepelynck P, Rocher L, Hanaire H, Chaillous L, Renard E, Sola A, Penfornis A, Tubiana-Rufi N, Sulmont V, Radermecker R, Charpentier G,
Riveline JP. Patient- or physician-driven continuous glucose monitoring (CGM) improves control and quality of life (QoL) in poorly-controlled
type 1 diabetic patients on intensified insulin therapy: A one-year multicenter study. Diabetes. Conference: 71st Scientific Sessions of the
American Diabetes Association San Diego, CA United States. Conference Start: 20110624 Conference End: 20110628. Conference Publication:
(var.pagings). 60 (pp A65), 2011. Date of Publication: July 2011. 2011.
Schaepelynck-Belicar P, Vague P, Simonin G, Lassmann-Vague V. Improved metabolic control in diabetic adolescents using the continuous
glucose monitoring system (CGMS). Diabetes Metab 2003;29(6):608-12.
Schiaffini R, Patera PI, Bizzarri C, Ciampalini P, Cappa M. Basal insulin supplementation in Type 1 diabetic children: a long-term comparative
observational study between continuous subcutaneous insulin infusion and glargine insulin. J Endocrinol Invest 2007;30(7):572-7.
Schiel R, Burgard D, Bambauer R, Perenthaler T, Kramer G. [Differences between intensified insulin therapy using multiple insulin injections
(ICT) or continuous subcutaneous insulin infusion using pumps (CSII) in children and adolescents with type 1 diabetes mellitus]. Diabetol
Stoffwechs 2013;8(5):380-6.
Schiffrin A, Belmonte MM. Comparison between continuous subcutaneous insulin infusion and multiple injections of insulin. A one-year
prospective study. Diabetes 1982;31(3):255-64.
Schiffrin A, Desrosiers M, Moffatt M, Belmonte MM. Feasibility of strict diabetes control in insulin-dependent diabetic adolescents. J Pediatr
1983;103(4):522-7.
Schiffrin AD, Desrosiers M, Aleyassine H, Belmonte MM. Intensified insulin therapy in the type I diabetic adolescent: a controlled trial.
Reason for
Exclusion
design
Not Found
Study
design
Study
design
Outcomes
Study
design
Intervention
Not Found
Study
design
Outcomes
Outcomes
259
CONFIDENTIAL UNTIL PUBLISHED
Citation
Diabetes Care 1984;7(2):107-13.
Schmidt S, Norgaard K. Long-Term effects of sensor-augmented pump therapy in type 1 diabetes: A 3-year follow-up study. Diabetes.
Conference: 72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA United States. Conference Start: 20120608
Conference End: 20120612. Conference Publication: (var.pagings). 61 (pp A3), 2012. Date of Publication: June 2012. 2012.
Schmidt S, Norgaard K. Sensor-augmented pump therapy at 36 months. Diabetes Technol Ther 2012;14(12):1174-7.
Schmitz A, Christiansen JS, Christensen CK, Hermansen K, Mogensen CE. Effect of pump versus pen treatment on glycaemic control and
kidney function in long-term uncomplicated insulin-dependent diabetes mellitus (IDDM). Dan Med Bull 1989;36(2):176-8.
Schottenfeld-Naor Y, Galatzer A, Karp M. Comparison of metabolic and psychological parameters during continuous subcutaneous insulin
infusion and intensified conventional insulin treatment in type I diabetic patients. Isr J Med Sci 1985;21(10):822-8.
Secher AL, Ringholm L, Andersen HU, Damm P, Mathiesen ER. The effect of real-time continuous glucose monitoring in pregnant women with
diabetes: a randomized controlled trial. Diabetes Care 2013;36(7):1877-83.
Selam JL, Haardt MJ, Slama G, Bethoux JP. A randomized cross-over cost-benefits comparison of intensive insulin therapy with intraperitoneal
infusion via implantable pumps vs multiple subcutaneous injections in patients with type-I diabetes. Paper presented at 54th Annual Meeting of
the American Diabetes Association; 11-14 Jun 1994; New Orleans: USA. Diabetes 1994;43(Suppl 1):A167.
Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by
intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care
1992;15(1):53-8.
Self-monitoring of blood glucose. Int J Clin Pract 2012;66(s175):2-93.
Sequeira PA, Montoya L, Ruelas V, Xing D, Chen V, Beck R, Peters AL. Continuous glucose monitoring pilot in low-income type 1 diabetes
patients. Diabetes Technol Ther 2013;15(10):855-8.
Shehadeh N, Battelino T, Galatzer A, Naveh T, Hadash A, de Vries L, Phillip M. Insulin pump therapy for 1-6 year old children with type 1
diabetes. Isr Med Assoc J 2004;6(5):284-6.
Sherr J, Carria LR, Weyman K, Zgorski M, Steffen AT, Tichy EM, Collazo MMP, Cengiz E, Michaud C, Tamborlane WV, Weinzimer S. Effect
of 2-hr suspensions of basal insulin on elevating nighttime sensor glucose concentrations. Diabetes. Conference: 73rd Scientific Sessions of the
American Diabetes Association Chicago, IL United States. Conference Start: 20130621 Conference End: 20130625. Conference Publication:
(var.pagings). 62 (pp A249), 2013. Date of Publication: July 2013. 2013.
Sherr J, Paula Collazo M, Caria L, Steffen A, Weyman K, Zgorski M, Tichy E, Cengiz E, Tamborlane WV, Weinzimer SA. Safety of nighttime
2-hour suspension of basal insulin in pump-treated type 1 diabetes (T1D) even in absence of low glucose. Diabetes Technology and
Reason for
Exclusion
Study
design
Study
design
Outcomes
Not Found
Intervention
Outcomes
Intervention
Study
design
Outcomes
Study
design
Study
design
Study
design
260
CONFIDENTIAL UNTIL PUBLISHED
Citation
Therapeutics. Conference: 6th International Conference on Advanced Technologies and Treatments for Diabetes, ATTD 2013 Paris France.
Conference Start: 20130227 Conference End: 20130302. Conference Publication: (var.pagings). 15 (pp A22), 2013. Date of Publication:
February 2013. 2013.
Sherr JL, Collazo MMP, Carria LR, Steffen AT, Zgorski M, Weyman K, Tichy EM, Cengiz E, Tamborlane WV, Weinzimer SA. Safety of
nighttime 2-hour suspensions of basal insulin in pump-treated Type 1 Diabetes (T1D) even in absence of low glucose. Diabetes. Conference:
72nd Scientific Sessions of the American Diabetes Association Philadelphia, PA United States. Conference Start: 20120608 Conference End:
20120612. Conference Publication: (var.pagings). 61 (pp A226-A227), 2012. Date of Publication: June 2012. 2012.
Sherr JL, Palau Collazo M, Cengiz E, Michaud C, Carria L, Steffen AT, Weyman K, Zgorski M, Tichy E, Tamborlane WV, Weinzimer SA.
Safety of nighttime 2-hour suspension of Basal insulin in pump-treated type 1 diabetes even in the absence of low glucose. Diabetes Care
2014;37(3):773-9.
Skogsberg L, Fors H, Hanas R, Chaplin JE, Lindman E, Skogsberg J. Improved treatment satisfaction but no difference in metabolic control
when using continuous subcutaneous insulin infusion vs. multiple daily injections in children at onset of type 1 diabetes mellitus. Pediatr
Diabetes 2008;9(5):472-9.
Skogsberg L, Skogsberg J, Fors H. Improved treatment satisfaction using continuous subcutaneous insulin infusion compared to multiple daily
injections in children at onset of type 1 diabetes mellitus - A five-year follow-up study. Pediatric Diabetes. Conference: 36th Annual Meeting of
the International Society for Pediatric and Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027 Conference End:
20101030. Conference Publication: (var.pagings). 11 (pp 99), 2010. Date of Publication: October 2010. 2010.
Slover R, Daniels MW, Foster CM, Wood MA, Kaufman FR, Welsh JB, Shin J, Weinzimer SA, Willi SM. Insulin pump adjustments and
glycemic outcomes in the pediatric cohort of the STAR 3 study. Diabetes. Conference: 71st Scientific Sessions of the American Diabetes
Association San Diego, CA United States. Conference Start: 20110624 Conference End: 20110628. Conference Publication: (var.pagings). 60
(pp A254), 2011. Date of Publication: July 2011. 2011.
Slover RH, Buckingham BA, Garg S, Brazg RL, Bailey TS, Klonoff DC, Shin JJ, Welsh JB, Kaufman FR. Efficacy of automatic insulin pump
suspension in youth with type 1 diabetes. Pediatric Diabetes. Conference: 38th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD 2012 Istanbul Turkey. Conference Start: 20121010 Conference End: 20121013. Conference Publication:
(var.pagings). 13 (pp 40-41), 2012. Date of Publication: October 2012. 2012.
Slover RH, Tamborlane WV, Battelino T, Criego A, Daniels M, Foster C, McEvoy RC, Orlowski C, Weinzimer S, White NH, Willi S, Wood
MA. Glucose excursions in children and adolescents in the STAR 3 study: A 1-year randomized controlled trial comparing sensor-augmented
pump therapy to multiple daily injections. Pediatric Diabetes. Conference: 36th Annual Meeting of the International Society for Pediatric and
Adolescent Diabetes, ISPAD Buenos Aires Argentina. Conference Start: 20101027 Conference End: 20101030. Conference Publication:
(var.pagings). 11 (pp 33), 2010. Date of Publication: October 2010. 2010.
Reason for
Exclusion
Study
design
Study
design
Intervention
Outcomes
Outcomes
Study
design
Outcomes
261
CONFIDENTIAL UNTIL PUBLISHED
Citation
St Charles M, Lynch P, Graham C, Minshall ME. A cost-effectiveness analysis of continuous subcutaneous insulin injection versus multiple
daily injections in type 1 diabetes patients: a third-party US payer perspective. Value Health 2009;12(5):674-86.
St Charles ME, Sadri H, Minshall ME, Tunis SL. Health economic comparison between continuous subcutaneous insulin infusion and multiple
daily injections of insulin for the treatment of adult type 1 diabetes in Canada. Clin Ther 2009;31(3):657-67.
Szypowska A, Dżygało K, Ramotowska A, Lipka M, Procner-Czaplińska M, Trippenbach-Dulska H. The benefits of continuous subcutaneous
insulin infusion in children with type 1 diabetes mellitus started at diabetes recognition. A 7 year follow-up. Paper presented at 46th Annual
Meeting of the European Association for the Study of Diabetes, EASD; 20-24 Sep 2010; Stockholm: Sweden. 2010.
Szypowska A, Ramotowska A, Dzygalo K, Golicki D. Beneficial effect of real-time continuous glucose monitoring system on glycemic control
in type 1 diabetic patients: systematic review and meta-analysis of randomized trials. Eur J Endocrinol 2012;166(4):567-74.
Tamborlane W, Buse J, Slover R, Green J, Kaufman F, Shin J. Comparison of insulin pump settings and insulin usage patterns in adult and
pediatric subjects in the star 3 study. Diabetes Technology and Therapeutics. Conference: 4th International Conference on Advanced
Technologies and Treatments for Diabetes, ATTD 2011 London United Kingdom. Conference Start: 20110216 Conference End: 20110219.
Conference Publication: (var.pagings). 13 (2) (pp 196), 2011. Date of Publication: February 2011. 2011.
Tamborlane WV, Batas SE, Rudolf MC. Comparison of continuous subcutaneous insulin infusion versus multiple daily injections in adolescents
with insulin-dependent diabetes. Adv Diabetol 1989;2(Suppl 1):24-7.
Tamborlane WV, Ruedy KJ, Wysocki T, O'Grady M, Kollman C, Block J, Chase HP, Hirsch I, Huang E, Beck RW, Wilson D, Lawrence J,
Laffel L. JDRF randomized clinical trial to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 diabetes:
research design and methods. Diabetes Technol Ther 2008;10(4):310-21.
Tanenberg R, Bode B, Lane W, Levetan C, Mestman J, Harmel AP, Tobian J, Gross T, Mastrototaro J. Use of the Continuous Glucose
Monitoring System to guide therapy in patients with insulin-treated diabetes: a randomized controlled trial. Mayo Clin Proc 2004;79(12):1521-6.
Tanenberg RJ, Houlden RL, Tildesley HD, Kaufman FR, Welsh JB, Shin J. Insulin pump adjustments and glycemic outcomes in the adult cohort
of the STAR 3 study. Diabetes. Conference: 71st Scientific Sessions of the American Diabetes Association San Diego, CA United States.
Conference Start: 20110624 Conference End: 20110628. Conference Publication: (var.pagings). 60 (pp A253-A254), 2011. Date of Publication:
July 2011. 2011.
Tanenberg RJ, Welsh JB. Patient behaviors associated with optimum glycemic outcomes with sensor-augmented pump therapy: insights from the
STAR 3 study. Endocr Pract 2014:1-16 [Epub ahead of print].
Thabit H, Lubina-Solomon A, Stadler M, Leelarathna L, Walkinshaw E, Pernet A, Allen JM, Iqbal A, Choudhary P, Kumareswaran K, Nodale
M, Nisbet C, Wilinska ME, Barnard KD, Dunger DB, Heller SR, Amiel SA, Evans ML, Hovorka R. Home use of closed-loop insulin delivery
for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study. Lancet Diabetes Endocrinol.
Reason for
Exclusion
Outcomes
Outcomes
Study
design
Systematic
Review/Met
a-analysis
Outcomes
Not Found
Intervention
Intervention
Outcomes
Outcomes
Study
design
262
CONFIDENTIAL UNTIL PUBLISHED
Citation
2014;2(9):701-9.
Thabit H, Lubina-Solomon A, Stadler M, Leelarathna LT, Walkinshaw E, Pernet A, Allen JM, Iqbal A, Choudhary P, Kumareswaran K, Nodale
M, Nesbit C, Wilinska ME, Dunger DB, Heller SR, Amiel SA, Evans ML, Hovorka R. Four weeks' home use of overnight closed-loop insulin
delivery in adults with type 1 diabetes: A multicentre, randomised, crossover study. Diabetes. Conference: 74th Scientific Sessions of the
American Diabetes Association San Francisco, CA United States. Conference Start: 20140613 Conference End: 20140617. Conference
Publication: (var.pagings). 63 (pp A61), 2014. Date of Publication: June 2014. 2014.
Thomas LE, Kane MP, Bakst G, Busch RS, Hamilton RA, Abelseth JM. A glucose meter accuracy and precision comparison: the freestyle flash
versus the Accu-Chek Advantage, Accu-Chek Compact Plus, Ascensia Contour, and the BD Logic. Diabetes Technol Ther 2008;10(2):102-10.
Trossarelli GF, Cavallo-Perin P, Meriggi E, Menato G, Dolfin G, Carta Q, et al. Metabolic and obstetrical results in Type 1 (insulin-dependent)
diabetic pregnancy: pump versus optimized conventional insulin therapy. Diabetologia 1984;27(2):340A.
Tsioli C, Remus K, Blaesig S, Datz N, Schnell K, Marquardt E, Grosser U, Aschemeier B, Kordonouri O, Danne T. The predictive low glucose
management system in youth with type 1 diabetes during exercise-data from the Pilgrim study. Pediatric Diabetes. Conference: 39th Annual
Conference of the International Society for Pediatric and Adolescent Diabetes, ISPAD 2013 Gothenburg Sweden. Conference Start: 20131016
Conference End: 20131019. Conference Publication: (var.pagings). 14 (pp 48), 2013. Date of Publication: October 2013. 2013.
Tumminia A, Crimi S, Sciacca L, Buscema M, Frittitta L, Squatrito S, Vigneri R, Tomaselli L. Efficacy of REAL-Time continuous glucose
monitoring on glycaemic control and glucose variability in Type 1 diabetic patients treated with either insulin pumps or multiple insulin injection
therapy: a randomised controlled cross-over trial. Diabetes Metab Res Rev 2014:[Epub ahead of print].
Uhrinak AN, Myers SJ, Kaufman FR, Lee SW, Yusi J, Huang S, Agrawal P, Kannard B. Retrospective analysis of events preceding low glucose
suspend activation in adult subjects on the paradigm veo system. In: Journal of Diabetes Science and Technology. Conference: 11th Annual
Diabetes Technology Meeting San Francisco, CA United States. Conference Start: 20111027 Conference End: 20111029. Conference
Publication: (var.pagings). 6 (2) (pp A182), 2012. Date of Publication: March 2012., 2012.
Ulf S, Ragnar H, Arne WP, Johnny L. Do high blood glucose peaks contribute to higher HbA1c? Results from repeated continuous glucose
measurements in children. World J Pediatr 2008;4(3):215-21.
University of Ljubljana FoM. Prevention of Hypoglycaemia With Predictive Insulin Suspend Using Sensor Augmented Insulin Pump in
Children. NCT02179281 2014.
US Food and Drug Administration. Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring System - P120005/S002 [Internet]. US
Food and Drug Administration, 2014 [accessed 5.9.14]. Available from:
http://www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recently-approveddevices/ucm386985.htm
US Food and Drug Administration. Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring System. FDA Summary of Safety and
Effectiveness Data [Internet]: US Food and Drug Administration, 2014 [accessed 5.9.14] Available from:
Reason for
Exclusion
Intervention
Intervention
Not Found
Study
design
Outcomes
Study
design
Intervention
Study
design
Study
design
Study
design
263
CONFIDENTIAL UNTIL PUBLISHED
Citation
http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120005S002b.pdf
US Food and Drug Administration. MiniMed 530G System - P120010 [Internet]. US Food and Drug Administration, 2014 [accessed 5.9.14].
Available from: http://www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recentlyapproveddevices/ucm372176.htm
Volpe L, Pancani F, Aragona M, Lencioni C, Battini L, Ghio A, Resi V, Bertolotto A, Del Prato S, Di Cianni G. Continuous subcutaneous
insulin infusion and multiple dose insulin injections in Type 1 diabetic pregnant women: a case-control study. Gynecol Endocrinol
2010;26(3):193-6.
von Hagen C, Bechtold S, Temme K, Tremml S, Wex S, Schwarz HP. [Metabolic control and quality of life in adolescents with type 1 diabetes:
Insulin pump therapy versus multiple daily injections]. Diabetol Stoffwechs 2007;2(4):238-47.
Voormolen DN, Devries JH, Evers IM, Mol BWJ, Franx A. The efficacy and effectiveness of continuous glucose monitoring during pregnancy:
a systematic review. Obstet Gynecol Surv 2013;68(11):753-63.
Weinstock RS, Bergenstal RM, Garg S, Bailey TS, Thrasher J, Mao M, Shin J. Reduction in hypoglycemia across a range of definitions in the
aspire in-home study. Diabetes. Conference: 74th Scientific Sessions of the American Diabetes Association San Francisco, CA United States.
Conference Start: 20140613 Conference End: 20140617. Conference Publication: (var.pagings). 63 (pp A240), 2014. Date of Publication: June
2014. 2014.
Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, Dickerman Z, Phillip M. Comparison of continuous subcutaneous insulin
infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Paper presented at 62nd
Annual Meeting of the American Diabetes Association; 14-18 Jun 2002; San Francisco: USA. Diabetes 2002;51(Suppl 2):A479.
Weintrob N, Schechter A, Benzaquen H, Shalitin S, Lilos P, Galatzer A, Phillip M. Glycemic patterns detected by continuous subcutaneous
glucose sensing in children and adolescents with type 1 diabetes mellitus treated by multiple daily injections vs continuous subcutaneous insulin
infusion. Arch Pediatr Adolesc Med 2004;158(7):677-84.
Weintrob N, Schechter A, Bezaquen H, Shalitin S, Lilos P, Galatzer A, et al. Glycemic patterns detected by continuous subcutaneous glucose
sensing in children with type 1 diabetes treated by MDI or CSII. Diabetes 2003;52(Suppl 1):A100.
Weinzimer SA, Ahern JH, Doyle EA, Vincent MR, Dziura J, Steffen AT, Tamborlane WV. Persistence of benefits of continuous subcutaneous
insulin infusion in very young children with type 1 diabetes: a follow-up report. Pediatrics 2004;114(6):1601-5.
Weiss R, Bailey TS, Schwartz FL, Garg S, Ahmann AJ, Thrasher J, Huang S, Lee SW. Time spent (%) in hypoglycemia following automatic
threshold suspend activation in the aspire in-home study. Diabetes. Conference: 74th Scientific Sessions of the American Diabetes Association
San Francisco, CA United States. Conference Start: 20140613 Conference End: 20140617. Conference Publication: (var.pagings). 63 (pp A241),
2014. Date of Publication: June 2014. 2014.
Reason for
Exclusion
Study
design
Study
design
Not Found
Systematic
Review/Met
a-analysis
Outcomes
Outcomes
Study
design
Outcomes
Study
design
Outcomes
264
CONFIDENTIAL UNTIL PUBLISHED
Citation
Weiss R, Schwartz FL, Weinstock RS, Bode BW, Bailey TS, Ahmann AJ, Kaufman FR. Bolus insulin dosing and nocturnal hypoglycemia in the
aspire in-home study. Diabetes. Conference: 74th Scientific Sessions of the American Diabetes Association San Francisco, CA United States.
Conference Start: 20140613 Conference End: 20140617. Conference Publication: (var.pagings). 63 (pp A601), 2014. Date of Publication: June
2014. 2014.
Wender-Ozegowska E, Zawiejska A, Ozegowska K, Wroblewska-Seniuk K, Iciek R, Mantaj U, Olejniczak D, Brazert J. Multiple daily
injections of insulin versus continuous subcutaneous insulin infusion for pregnant women with type 1 diabetes. Aust N Z J Obstet Gynaecol
2013;53(2):130-5.
Wilson DC, Halliday HL, Reid M, McClure G, Dodge JA. Continuous insulin infusion in hyperglycaemic extremely low birthweight infants? A
randomized trial. Paper presented at 14th European Congress of Perinatal Medicine; 5-8 Jun 1994; Helsinki: Finland. In: Proceedings of 14th
European Congress of Perinatal Medicine, 1994: 581.
Wilson DM, Buckingham BA, Kunselman EL, Sullivan MM, Paguntalan HU, Gitelman SE. A two-center randomized controlled feasibility trial
of insulin pump therapy in young children with diabetes. Diabetes Care 2005;28(1):15-9.
Wiseman MJ, Saunders AJ, Keen H, Viberti G. Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulindependent diabetes. N Engl J Med 1985;312(10):617-21.
Wojciechowski P, Rys P, Lipowska A, Gaweska M, Malecki MT. Efficacy and safety comparison of continuous glucose monitoring and selfmonitoring of blood glucose in type 1 diabetes: systematic review and meta-analysis. Pol Arch Med Wewn 2011;121(10):333-43.
Yates K, Hasnat Milton A, Dear K, Ambler G. Continuous glucose monitoring-guided insulin adjustment in children and adolescents on nearphysiological insulin regimens: a randomized controlled trial. Diabetes Care 2006;29(7):1512-7.
Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, Wilson LM, Haberl EB, Brick J, Bass EB, Golden SH. Comparative
effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann
Intern Med 2012;157(5):336-47.
Yogev Y, Chen R, Ben-Haroush A, Phillip M, Jovanovic L, Hod M. Continuous glucose monitoring for the evaluation of gravid women with
type 1 diabetes mellitus. Obstet Gynecol 2003;101(4):633-8.
Ziegler D, Dannehl K, Koschinsky T, Toeller M, Gries FA. Comparison of continuous subcutaneous insulin infusion and intensified
conventional therapy in the treatment of Type I diabetes: a two-year randomized study. Diabetes, Nutrition and Metabolism - Clinical and
Experimental 1990;3(3):203-13.
Zisser HC, Dassau E, Bevier W, Harvey RA, Jovanovic L, Doyle III. FJ. Clinical evaluation of a fully-automated artificial pancreas using zonemodel predictive control with health monitoring system. Paper presented at 72nd Scientific Sessions of the American Diabetes Association; 8-12
Jun 2012; Philadelphia: USA. 2012.
Reason for
Exclusion
Outcomes
Study
design
Not Found
Intervention
Intervention
Systematic
Review/Met
a-analysis
Outcomes
Systematic
Review/Met
a-analysis
Study
design
Intervention
Study
design
265
CONFIDENTIAL UNTIL PUBLISHED
Citation
Zucchini S, Scipione M, Maltoni G, Rollo A, Balsamo C, Zanotti M, Cicognani A. Comparison between sensor-augmented insulin therapy with
either insulin pump (CSII) or multiple daily injections (MDI) in everyday life: Analysis of glucose variability and sensor reliability. Hormone
Research in Paediatrics. Conference: 50th Annual Meeting of the European Society for Paediatric Endocrinology, ESPE 2011 Glasgow United
Kingdom. Conference Start: 20110925 Conference End: 20110928. Conference Publication: (var.pagings). 76 (pp 157-158), 2011. Date of
Publication: October 2011. 2011.
Reason for
Exclusion
Study
design
266
CONFIDENTIAL UNTIL PUBLISHED
Appendix 5: Conversion Tables for HbA1c and Glucose Values
Table 86: HbA1c Conversion Table - Older DCCT-aligned (%) and newer IFCCstandardised (mmol/mol) concentrations (IFCC-standardised values are rounded to the nearest
whole number)
HbA1c conversion table
Definitions
Old unit
= DCCT unit
=%
New unit
= IFCC unit
= mmol/mol
Conversion formulas
Old
= 0,0915 New + 2,15%
New
= 10,93 Old – 23,5 mmol/mol
HbA1c Old
HbA1c New
HbA1c Old
HbA1c New
4,0
20
9,1
76
4,1
21
9,2
77
4,2
22
9,3
78
4,3
23
9,4
79
4,4
25
9,5
80
4,5
26
9,6
81
4,6
27
9,7
83
4,7
28
9,8
84
4,8
29
9,9
85
4,9
30
10,0
86
5,0
31
10,1
87
5,1
32
10,2
88
5,2
33
10,3
89
5,3
34
10,4
90
5,4
36
10,5
91
5,5
37
10,6
92
5,6
38
10,7
93
5,7
39
10,8
95
5,8
40
10,9
96
5,9
41
11,0
97
6,0
42
11,1
98
6,1
43
11,2
99
6,2
44
11,3
100
6,3
45
11,4
101
6,4
46
11,5
102
6,5
48
11,6
103
6,6
49
11,7
104
6,7
50
11,8
105
6,8
51
11,9
107
6,9
52
12,0
108
7,0
53
13.0
119
7,1
54
13.1
120
7,2
55
13.2
121
7,3
56
13.3
122
7,4
57
13.4
123
7,5
58
13.5
124
7,6
60
13.6
125
7,7
61
13.7
126
7,8
62
13.8
127
7,9
63
13.9
128
8,0
64
14.0
130
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HbA1c Old
HbA1c New
HbA1c Old
HbA1c New
8,1
65
14.1
131
8,2
66
14.2
132
8,3
67
14.3
133
8,4
68
14.4
134
8,5
69
14.5
135
8,6
70
14.6
136
8,7
72
14.7
137
8,8
73
14.8
138
8,9
74
14.9
139
9,0
75
DCCT=Diabetes Control and Complications Trial; IFCC=International Federation of Clinical
Chemistry
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Table 87: Glucose Values Conversion Table (mg/dl - mmol/l)
Glucose Values Conversion Table
Conversion formulas:
mg/dl x 0.0555 = mmol/l
mmol/l x 18.018 = mg/dl
mg/dl => mmol/l
40 ~ 2.2
mmol/l => mg/dl
2.0 ~ 36
45 ~ 2.5
2.5 ~ 45
50 ~ 2.8
3.0 ~ 54
55 ~ 3.1
3.5 ~ 63
60 ~ 3.3
4.0 ~ 72
65 ~ 3.6
4.5 ~ 81
70 ~ 3.9
5.0 ~ 90
75 ~ 4.2
5.5 ~ 99
80 ~ 4.4
6.0 ~ 108
85 ~ 4.7
6.5 ~ 117
90 ~ 5.0
95 ~ 5.3
7.0 ~ 126
7.5 ~ 135
100 ~ 5.6
8.0 ~ 144
110 ~ 6.2
120 ~ 6.7
8.5 ~ 153
9.0 ~ 162
130 ~ 7.2
9.5 ~ 171
140 ~ 7.8
10.0 ~ 180
150 ~ 8.3
10.5 ~ 189
160 ~ 8.9
11.0 ~ 198
170 ~ 9.4
11.5 ~ 207
180 ~ 10.0
12.0 ~ 216
190 ~ 10.6
200 ~ 11.1
12.5 ~ 225
13.0 ~ 234
220 ~ 12.2
13.5 ~ 243
240 ~ 13.3
14.0 ~ 252
mg/dl => mmol/l
260 ~ 14.4
mmol/l => mg/dl
14.5 ~ 261
280 ~ 15.5
15.0 ~ 270
300 ~ 16.7
16.0 ~ 288
320 ~ 17.8
340 ~ 18.9
17.0 ~ 306
18.0 ~ 324
360 ~ 20.0
19.0 ~ 342
380 ~ 21.1
20.0 ~ 360
400 ~ 22.2
420 ~ 23.3
21.0 ~ 378
22.0 ~ 396
440 ~ 24.4
23.0 ~ 414
460 ~ 25.5
24.0 ~ 432
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CONFIDENTIAL UNTIL PUBLISHED
Appendix 6: Detailed description of IMS CDM
The IMS CDM is a multilayer internet application linked to a mathematical calculation model
and structured query language (SQL) database sited on a central server. Online access to the
IMS CDM Software is available under license from IMS, the developers of the model. The
structure is based on four separate elements: the user interface, the input databases, the data
processor, and the output databases. Figure 24 outlines the overview of the IMS CDM
software structure.
Figure 24: IMS CDM software model structure.
Complication Submodels
The Myocardial Infarction (MI) Submodel: The MI submodel is made up of three states:
no history of MI, history of MI and death following MI. Transition probabilities between the
states can be taken from UKPDS risk engine,144 Framingham88 or UKPDS Outcomes model.86
In our calculations, Framingham is chosen as it is the only one that is based on T1DM only.
Unstable Angina Submodel: Unstable Angina submodel is made up of two states: no history
of Angina, history of angina. Transition probabilities between the states are derived from
Framingham.88 They are adjusted according to HbA1c and renal function.
Congestive Heart Failure (CHF) Submodel: CHF submodel is composed of three states: no
CHF, history of CHF and death following CHF. A logistic regression based on
Framingham145 generates the risk profile and includes the following risk factors: age, sex, left
ventricular hyperthrophy (LVH), heart rate, systolic blood pressure, congenital heart disease,
valve disease, presence of diabetes, BMI, presence of diabetes and valve disease jointly.
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CONFIDENTIAL UNTIL PUBLISHED
Stroke Submodel: Stroke submodel is composed of three states: no stroke, history of stroke
and death following stroke. Transition probabilities between the states can be taken from
UKPDS risk engine,146 Framingham147 or UKPDS Outcomes model.86 In our calculations,
Framingham is chosen as it is the only one that is based on T1DM only.
Peripheral Vascular Disease (PVD) Submodel: PVD submodel is made up of two states: no
PVD and PVD. Transition probabilities are the same as T1DM and T2DM. A logistic
regression based on Framingham148 is used to generate the risk for PVD, including the
following risk factors: age, sex, blood pressure (normal-high), stage-1 hypertension (yes/no),
stage-2 hypertension (yes/no), presence of diabetes, no of cigarettes per day, cholesterol level
and heart failure history.
Neuropathy Submodel: Neuropathy submodel is made up of two states: no neuropathy and
neuropathy. Transition probabilities for T1DM are derived from DCCT.87 Transition
probabilities are indexed by diabetes duration and are adjusted for HbA1c, SBP and ACEI
use.
Foot Ulcer/Amputation Submodel: This submodel consists of nine states: 1) No foot ulcer
2) Uninfected ulcer 3) Infected ulcer 4) Healed ulcer 5) Uninfected recurrent ulcer 6) Infected
recurrent ulcer 7) Gangrene 8) History of amputation and 9) Death resulting from foot ulcer.
Transition probabilities are the same for T1DM and T2DM. Different from other sub-models,
this sub-model runs in monthly cycles. Therefore, patients may have multiple foot ulcers in a
single year.
Diabetic Retinopathy Submodel: This submodel is composed of 10 states: 1) No
retinopathy & not screened 2) No retinopathy & screened 3) Background diabetic retinopathy
(BDR) & not screened 4) BDR & screened 5) BDR & wrongly diagnosed as proliferative 6)
Diabetic retinopathy and laser (retinal photocoagulation) treated 7) Proliferative diabetic
retinopathy (PDR) & not screened&no laser treatment 8) PDR & screened & detected & laser
treated 9) PDR & screened & not detected 10) Severe vision loss.
Severe vision loss is a terminal state. Transition probabilities for T1DM are derived from
DCCT,87 and are adjusted for HbA1c, SBP and ACEI use.
Macular Oedema Submodel: Macular Oedema submodel consists of six states: 1) No
macular oedema & not screened 2) No macular oedema & screened 3) Macular oedema & not
screened & no laser treatment 4) Macular oedema & screened & not detected 5) Macular
oedema & screened & detected & laser treated 6) Severe vision loss
Severe vision loss is a terminal state. Transition probabilities for T1DM are derived from
DCCT,87 and are adjusted for HbA1c, SBP and ACEI use.
Cataract Submodel: Cataract submodel is composed of three states: no cataract, first cataract
with operation and 2nd cataract with operation. Transition probabilities are the same for
T1DM and T2DM and are taken from a study in diabetes outpatients in the UK published by
Janghorbani et al.149
Nephropathy Submodel: This submodel is composed of 13 states: 1) No renal complications
& no treatment with ACEI 2) No renal complications & treated with ACEI 3) No renal
complications after ACEI side effects 4) Microalbuminuira & no treatment with ACEI 5)
Microalbuminuira & screened & detected & treated with ACEI 6) Microalbuminuira after
ACEI side effects 7) Gross proteinuria & no treatment with ACEI 8) Gross proteinuria &
screened & detected & treated with ACEI 9) Gross proteinuria after ACEI side effects 10)
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CONFIDENTIAL UNTIL PUBLISHED
End-stage renal disease, treated with hemodialysis 11) End-stage renal disease, treated with
peritoneal dialysis 12) End-stage renal disease, treated with renal transplant 13) End-stage
renal disease death.
Data on the cumulative incidence of progression of microalbuminuria and gross proteinuria
were taken from the DCCT,87 probabilities for the progression from gross proteinuria to endstage renal disease are based on cumulative incidence data for T2DM patients in the
Rochester population.150 It is assumed that the probability of progression from gross
proteinuria to end-stage renal disease is the same for T1DM and T2DM. The probability of
progression from end-stage renal disease states to death is dependent on treatment and ethnic
group (Wolfe et al. 1999).151 Transition probabilities are adjusted according to patient HbA1c
levels, SBP and concomitant ACE inhibitor treatment
Hypoglycaemia Submodel: Hypoglycemia submodel is a state in which the minor and
severe hypoglycaemic episodes are counted. Minor hypoglycaemic events are calculated on a
daily basis (cycle length = 1 day). For the simulation of severe hypoglycaemic events, the
sub-model runs four times for each year of simulation. All rates (defined as number of events
per 100 patient years) are adjusted to the 1 day or 3-month cycle length, respectively.
Therefore, patients can have multiple hypoglycaemic episodes in a single year. The patients
may die after a severe hypoglycaemic episode. The definition of severe and minor
hypoglycaemia can be refined by the user according to the available data. In our analysis,
hypoglycaemic episode rates are treatment specific and any hypoglycaemic episode that
required assistance from a third party is considered as severe. Note that in our base case
analysis the probability of death due to a severe hypoglycaemic episode was assumed to be 0.
Ketoacidosis Submodel: Ketoacidosis submodel has two states: alive and dead (due to
ketoacidosis). There are no probability adjustments in the ketoacidosis submodel.
Depression Submodel: Depression submodel has three states: no depression, depression
receiving anti-depression program and depression not receiving anti-depression program. The
onset probability of depression is same for T1DM and T2DM and dependent on gender.
Lactic Acidosis Submodel: This sub-model is relevant for T2DM only.
Peripheral Oedema Submodel: This sub-model is relevant for T2DM only.
Non-Specific Mortality Submodel: This sub-model consists of 2 states: alive or dead. The
transition probabilities are indexed by age, sex and race and reflect the UK life tables.
272
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Appendix 7: Disease natural history parameters and transition probabilities
The parameters that will determine the natural course of the disease and their corresponding
sources can be seen in Table 88. We considered the same values as in the updated CG15.3
Table 88: Disease natural history parameters.
Parameter
HbA1c adjustments
Risk reduction of background diabetic retinopathy
with 10% lower HbA1c
Risk reduction of proliferative diabetic retinopathy
with 10% lower HbA1c
Risk reduction of sever vision loss
with 10% lower HbA1c
Risk reduction of macular oedema
with 10% lower HbA1c
Risk reduction of microalbuminuria
with 10% lower HbA1c
Risk reduction of gross proteinuria
with 10% lower HbA1c GPR
Risk reduction of end stage renal disease
with 10% lower HbA1c
Risk reduction of neuropathy
with 10% lower HbA1c
Risk reduction of myocardial infarction
with 1% lower HbA1c
Risk reduction of cataract
with 1% lower HbA1c
Risk reduction of heart failure
with 1% lower HbA1c
Risk reduction of stroke
with 1% lower HbA1c
Risk reduction of angina
with 1% lower HbA1c
Risk reduction of haemodialysis mortality
with 1% lower HbA1c
Risk reduction of peritoneal dialysis mortality
with 1% lower HbA1c
Risk reduction of renal transplant mortality
with 1% lower HbA1c
Risk reduction of first ulcer
with 1% lower HbA1c
Systolic blood pressure (SBP) adjustments
Risk reduction of microalbuminuria
with 10mmHg lower SBP
Risk reduction of severe vision loss
with 10mmHg lower SBP
Myocardial infarction (MI) adjustments
Proportion with MI
having an initial CHD event, female
Proportion with MI
having an initial CHD event, male
Proportion with MI
Mean
value
Source
39%
DCCT87
43%
0%
No data
13%
Klein et al 2009152
28%
DCCT87
37%
21%
Rosolowsky et al
2011153
32%
DCCT87
20%
0%
Grauslund et al
2011154
23%
Lind et al 2011155
20%
DCCT87
20%
12%
12%
0%
17%
Morioka et al
2001156
Wiesbauer et al
2010157
Monami et al
2009158
13%
Adler et al 2000159
0%
No data
0.361
0.522
D’Agostino et al
2000160
0.474
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CONFIDENTIAL UNTIL PUBLISHED
Parameter
having a subsequent CHD event MI, female
Proportion with MI
having a subsequent CHD event MI, male
Relative risk of MI
if microalbuminuria is present
Relative risk of MI
if gross proteinuria is present
Relative risk of MI
if end stage renal disease is present
Relative risk of recurrent MI
if DIGAMI intensive control is used
Relative risk of MI mortality
if DIGAMI intensive control is used
Relative risk of MI
if aspirin used for primary prevention
Relative risk of MI
if aspirin used for secondary prevention
Relative risk of MI
if statins used for primary prevention
Relative risk of MI
if statins used for secondary prevention
Relative risk of MI
if ACE-inhibitors used for primary prevention
Relative risk of MI
if ACE-inhibitors used for secondary prevention
MI mortality
Probability of sudden death
after first MI, male
Probability of sudden death
after first MI, female
Probability of sudden death
after recurrent MI, male
Probability of sudden death
after recurrent MI, female
Relative risk 12 month mortality
after MI conventional treatment
Relative risk mortality
first year after MI aspirin treatment
Relative risk mortality
each subsequent year after MI aspirin treatment
Relative risk mortality
first year after MI statins treatment
Relative risk mortality
each subsequent year after MI statins treatment
Relative risk of sudden death
after MI aspirin treatment
Relative risk of sudden death
after MI statins treatment
Relative risk of sudden death
after MI ACE-inhibitors treatment
Mean
value
Source
0.451
1
1
1
No data
1
1
0.82
0.80
0.70
0.81
0.78
0.78
Baigent et al
2009161
Brugts et al
2009162
Shepherd et al
2002163
HOPE Study
Investigators
2000164
D’Agostino et al
2000160
0.393
0.364
0.393
Sonke et al
1996165
0.364
1.45
0.88
0.88
0.75
Malmberg et al
1995166
Antiplatelet
Trialists'
Collaboration
1994167
Stenestrand et al
2001168
1.00
No data
1.00
No data
1.00
Briel et al 2006169
1.00
No data
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Parameter
Relative risk long-term mortality
after MI using ACE-inhibitors
Relative risk 12 month mortality
after MI using ACE-inhibitors
Stroke
Relative risk stroke with microalbuminuria
Relative risk stroke with gross proteinuria
Relative risk stroke with end stage renal disease
Relative risk of first stroke if aspirin used
Relative risk of second stroke if aspirin used
Mean
value
0.64
0.64
1.00
1.00
1.00
0.86
0.78
Relative risk of first stroke if statins used
0.81
Relative risk of second stroke if statins used
0.84
Relative risk of first stroke if ACE-inhibitors used
0.67
Relative risk of recurrent stroke if ACE-inhibitors used
0.72
Stroke mortality
Probability 30-day death after first stroke
Probability 30-day death after recurrent stroke
0.124
0.422
Relative risk mortality after stroke if aspirin used
0.84
Relative risk mortality if statins used
1.00
Relative risk sudden death after stroke if aspirin used
0.95
Relative risk sudden death after stroke if statins used
Relative risk sudden death after stroke if ACE-inhibitors
used
Relative risk long-term mortality
after stroke using ACE-inhibitors
Relative risk 12 month mortality
after stroke using ACE-inhibitors
Angina adjustments
Proportion with angina
having initial CHD event, female
Proportion with angina
having initial CHD event, male
Proportion with angina
having subsequent CHD event, female
1.00
0.49
1.000
1.000
Source
Gustafsson et al
1999170
Sonke et al
1996165
No data
No data
No data
Baigent et al
2009161
Brugts et al
2009162
The Stroke
Prevention by
Aggressive
Reduction in
Cholesterol Levels
(SPARCL)
Investigators
2006171
HOPE Study
Investigators
2000164
PROGRESS
Collaborative
Group 2001172
Eriksson et al
2001173
Antiplatelet
Trialists'
Collaboration167
Manktelow et al
2009174
Sandercock et al
2008175
Briel et al 2006169
Chitravas et al
2007176
Asberg et al
2010177
Eriksson et al
2001173
0.621
0.420
D’Agostino et al
2000160
0.359
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CONFIDENTIAL UNTIL PUBLISHED
Parameter
Proportion with angina
having subsequent CHD event, male
Relative risk angina with microalbuminuria
Relative risk angina with gross proteinuria
Relative risk angina with end stage renal disease
Congestive heart failure adjustments
Relative risk of heart failure
with microalbuminuria
Relative risk of heart failure
with gross proteinuria
Relative risk of heart failure
with end stage renal disease
Relative risk of heart failure if aspirin used
Relative risk of heart failure if statins used
Mean
value
Source
0.301
1.00
1.00
1.00
No data
No data
No data
1.00
1.00
No data
1.00
1.00
1.00
Relative risk of heart failure if ACE-inhibitors used
0.80
Relative risk of heart failure death if ACE-inhibitors used
0.80
Relative risk of heart failure death diabetic male
Relative risk of heart failure death diabetic female
ACE inhibitor adjustments for micro-vascular
complications
Relative risk of background diabetic retinopathy
if ACE-inhibitors used
Relative risk of proliferative diabetic retinopathy
if ACE-inhibitors used
Relative risk of macular oedema
if ACE-inhibitors used
Relative risk of severe vision loss
if ACE-inhibitors used
Relative risk of worsening microalbuminuria
if ACE-inhibitors used, no complications
Relative risk of worsening gross proteinuria
if ACE-inhibitors used, with microalbuminuria
Relative risk of worsening end stage renal disease
if ACE-inhibitors used, with gross proteinuria
Relative risk of neuropathy
if ACE-inhibitors used
Side effects of ACE-inhibitors
Probability stopping ACE-inhibitors
due to side effects first year
Probability stopping ACE-inhibitors
due to side effects each subsequent year
Adverse events
Probability death from severe hypoglycaemic event
1.00
1.70
Probability death from severe ketoacidosis event
0.027
Relative risk of hypo events with ACE-inhibitors
Foot ulcer and amputation
1.00
0.75
0.19
HOPE Study
Investigators
2000164
Ascencao et al
2008178
Ho et al 1993179
Chaturvedi et al
1998180
1.00
No data
1.00
0.79
0.41
Penno et al
1998181
0.63
Lewis et al
1993182
1.00
No data
0
Assumption
0
0
Assumption
MacIsaac et al
2002183
No data
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CONFIDENTIAL UNTIL PUBLISHED
Probability gangrene to amputation
Probability gangrene to healed amputation
Probability death following onset gangrene
Probability death with history amputation
Probability death following healed ulcer
Probability developing recurrent uninfected ulcer
Probability amputation following infected ulcer
Probability infected ulcer after amputation healed
Probability of death from infected ulcer
Probability of gangrene from infected ulcer
Probability of infected ulcer from uninfected ulcer
Mean
value
0.181800
0.308200
0.009800
0.004000
0.004000
0.039300
0.003700
0.044500
0.009800
0.007500
0.139700
Probability of recurrent amputation
0.008451
Borkosky et al
2012185
Probability of death from uninfected ulcer
Probability of uninfected ulcer from infected ulcer
Probability of healed ulcer from uninfected ulcer
Probability developing ulcer
with neither neuropathy or peripheral vascular disease
Probability developing ulcer
with either neuropathy or peripheral vascular disease
Probability developing ulcer
with both neuropathy or peripheral vascular disease
Depression
0.004000
0.047300
0.078700
Persson et al
2000184
Parameter
0.000250
0.006092
0.006092
Source
Persson et al
2000184
Ragnarson et al
2001186
Persson et al
2000184
Relative risk for all cause death if depression
1.33
Relative risk for congestive heart failure if depression
Relative risk for myocardial infarction if depression
1.00
1.00
Relative risk for depression if neuropathy
3.10
Relative risk for depression if stroke
6.30
Relative risk for depression if amputation
Other
Probability of severe vision loss
from background diabetic retinopathy
Probability of reversal of neuropathy
1.00
Egede et al
2005187
No data
No data
Yoshida et al
2009188
Whyte et al
2004189
No data
0.015
CORE default77
0.000
No data
Transition probabilities values were provided by the IMS CDM developers and were not
changed in our analyses given the high degree of validation of the model. These were UK
specific whenever possible and based on relevant sources (e.g. DCCT trial). In Table 89 we
report these sources. We do not report the complete set of probabilities as we believe this
would be too extensive and little informative due to the complexity of the model.
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CONFIDENTIAL UNTIL PUBLISHED
Table 89: Transition probabilities dependencies and sources
Parameter
Dependent on
Renal disease
Duration of
Probability onset microalbuminuria
diabetes
Probability worsening from microalbuminuria to
Duration of
gross proteinuria
diabetes
Probability worsening from gross proteinuria to
Duration of gross
end stage renal disease
proteinuria
Proportion end stage renal disease with
haemodialysis, peritoneal dialysis or renal
transplant
Current age
Probability death end stage renal disease under
haemodialysis, peritoneal dialysis or renal
transplant
Current age
Eye disease
Probability onset background diabetic retinopathy,
proliferative diabetic retinopathy, macular oedema Duration of
or severe vision loss
diabetes
Probability onset of cataract extraction - male,
female
Current age
Probability recurrent cataract extraction - male,
female
Current age
Neuropathy
Duration of
Probability onset neuropathy
diabetes
heart failure
Probability heart failure long-term mortality, per
Time since onset of
gender and age range
heart failure
myocardial infarction
Probability death within 12 month after
first/recurrent myocardial infarction - male, female Current age
Time since first
Probability post myocardial infarction long-term
myocardial
mortality - male, female
infarction
Stroke
Probability death within 12 month after
first/recurrent stroke - male, female
Current age
Probability post stroke long-term mortality - male, Time since first
female
stroke
Time since first
Probability recurrent stroke - male, female
stroke
Depression
Probability onset depression - male, female
Time of simulation
Probability depression reversal for patients
receiving/not receiving anti-depression program
Time of simulation
Non specific mortality
Probability non-specific mortality per race and
gender
Current age
Physiological parameter progression tables
HbA1c progression
Time of simulation
BMI, haemodialysis, LDL, systolic blood pressure, Time of simulation
Source
DCCT87
DCCT87
Rosolowsky et
al.153
US Renal Data
System, USRDS
2010190
US Renal Data
System, USRDS
2010190
DCCT87
Janghorbani et
al149
Janghorbani et
al149
DCCT87
Ho et al179
Malmberg et al166
Malmberg et al166
Eriksson et al173
Eriksson et al173
Eriksson et al173
Golden et al191
Valenstein et al192
UK life-tables89
DCCT87
CORE default77
278
CONFIDENTIAL UNTIL PUBLISHED
T-Chol, Triglycerides progression
Other adjustment factors
Quality of life adjustment based on current BMI
BMI
Age adjustment for myocardial infarction mortality Current age
Bagust et al193
Herlitz et al194
279
CONFIDENTIAL UNTIL PUBLISHED
Appendix 8: Results (full incremental and intervention versus comparator) of base case
and scenario analyses
Table 90: Base case model results (all technologies) probabilistic simulation
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146 £64,563
CSII+SMBG
11.9756 £90,436
0.561
£25,873
£46,123
Extendedly dominated†
MiniMed Veo system
12.0412 £138,357
by CSII+CGM standalone
CSII+CGM stand-alone 12.0604 £146,476
0.0849
£56,039
£660,376
dominated by
Integrated CSII+CGM
12.0604 £147,150
CSII+CGM stand(Vibe)
alone
† An extendedly dominated strategy has an ICER higher than that of the next most effective strategy
Table 91: Base case model results (intervention versus comparator
simulation
Intervention
Comparator
Incr. QALY
MiniMed Veo system
MDI+SMBG
0.6266
MiniMed Veo system
CSII+SMBG
0.0656
MiniMed Veo system
CSII+CGM stand-alone
-0.0192
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0849
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
only) probabilistic
Incr. Cost
£73,794
£47,921
-£8,119
£82,587
£56,713
£674
ICER
£117,769
£730,501
£422,849
£127,883
£668,789
undefined
Superseded –
see Erratum
Table 92: Base case model results (all technologies) deterministic simulation
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
12.145 £66,585
CSII+SMBG
12.7258 £93,433
0.5808
£26,847
£46,225
Extendedly dominated
MiniMed Veo system 12.8087 £143,309
by CSII+CGM standalone
CSII+CGM
stand12.8223 £151,671
0.0965
£58,238
£603,495
alone
Integrated CSII+CGM
Dominated by CSII+
12.8223 £152,372
(Vibe)
CGM stand-alone
Table 93: Base case model results (intervention versus comparator only) deterministic
simulation
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6637
£76,723
£115,600
MiniMed Veo system
CSII+SMBG
0.0829
£49,876
£601,639
MiniMed Veo system
CSII+CGM stand-alone
-0.0136
-£8,363
£614,910
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6773
£85,787
£126,660
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0965
£58,939
£610,772
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£701
undefined
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Table 94: Model results (all technologies), scenario with different baseline population
characteristics
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
9.6117 £68,049
CSII+SMBG
10.0991 £91,189
0.4874
£23,140
£47,476
Extendedly
dominated by
MiniMed Veo system
10.1474 £132,149
CSII+CGM standalone
CSII+CGM stand-alone
10.164 £139,157
0.0649
£47,967
£738,593
dominated by
Integrated CSII+CGM
10.164 £139,733
CSII+CGM stand(Vibe)
alone
Table 95: Model results (intervention versus comparator only), scenario with different
baseline population characteristics
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.5357
£64,100
£119,657
MiniMed Veo system
CSII+SMBG
0.0483
£40,960
£848,028
MiniMed Veo system
CSII+CGM stand-alone
-0.0166
-£7,008
£422,148
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.5523
£71,684
£129,791
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0649
£48,543
£747,971
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£576
undefined
Superseded –
see Erratum
Table 96: Model results (all technologies), scenario with two (CGM) versus eight (SMBG)
blood glucose testing per day
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146 £71,973
CSII+SMBG
11.9756 £98,034
0.561
£26,061
£46,459
Extendedly
dominated by
MiniMed Veo system
12.0412 £138,357
CSII+CGM standalone
CSII+CGM stand-alone
12.0604 £146,476
0.0849
£48,441
£570,844
dominated by
Integrated CSII+CGM
12.0604 £147,150
CSII+CGM stand(Vibe)
alone
Table 97: Model results (intervention versus comparator only), scenario with two (CGM)
versus eight (SMBG) blood glucose testing per day
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6266
£66,385
£105,944
MiniMed Veo system
CSII+SMBG
0.0656
£40,323
£614,683
MiniMed Veo system
CSII+CGM stand-alone
-0.0192
-£8,119
£422,849
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
£75,177
£116,409
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0849
£49,116
£579,194
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£674
undefined
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Table 98: Model results (all technologies), scenario with increased amount of daily insulin
for MDI
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146 £65,627
£24,810
£44,228
CSII+SMBG
11.9756 £90,437
0.5610
MiniMed Veo system
12.0412
£138,358
0.0657
£47,921
CSII+CGM stand-alone
12.0604
£146,476
0.0849
£56,040
Integrated CSII+CGM
(Vibe)
12.0604
£147,150
0
£674
Extendedly
dominated by
CSII+CGM standalone
£660,376
dominated by
CSII+CGM standalone
Table 99: Model results (intervention versus comparator only), scenario with increased
amount of daily insulin for MDI
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6266
£72,731
£116,072
MiniMed Veo system
CSII+SMBG
0.0656
£47,921
£730,501
MiniMed Veo system
CSII+CGM stand-alone
-0.0192
-£8,119
£422,849
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
£81,523
£126,236
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0848
£56,713
£668,789
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£674
undefined
Superseded –
see Erratum
Table 100: Model results (all technologies), scenario with no HbA1c progression
QALYs
Cost
Incr. QALY Incr. Cost
MDI+SMBG
11.8715
£62,127
CSII+SMBG
12.4558
£88,663
0.5843
£26,536
MiniMed Veo system
12.5228
£137,739
0.0669
£49,076
CSII+CGM stand-alone
12.5398
£146,076
0.0840
£57,414
Integrated CSII+CGM
(Vibe)
12.5398
£146,767
0
£690
ICER
£45,413
Extendedly
dominated by
CSII+CGM
stand-alone
£683,889
Dominated by
CSII+CGM
stand-alone
Table 101: Model results (intervention versus comparator only), scenario with no HbA1c
progression
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6513
£75,612
£116,094
MiniMed Veo system
CSII+SMBG
0.067
£49,076
£732,483
MiniMed Veo system
CSII+CGM stand-alone
-0.017
-£8,337
£490,424
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6683
£84,640
£126,650
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.084
£58,104
£691,715
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£690
undefined
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Table 102: Cost-effectiveness results when no treatment effect (in terms of HbA1c change)
in the first year is assumed (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
CSII+CGM
standDominated by
12.0006
£146,632
alone
MDI+SMBG
Integrated
Dominated by
12.0006
£147,304
CSII+CGM (Vibe)
MDI+SMBG
MDI+SMBG
12.0016
£60,539
CSII+SMBG
12.016
£90,178
0.0144
£29,638
£2,057,175
MiniMed Veo system
12.026
£138,538
0.0099
£48,360
£4,871,356
Table 103: Cost-effectiveness results when no treatment effect (in terms of HbA1c change)
in the first year is assumed (intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.0244
£77,999
£3,196,686
MiniMed Veo system
CSII+SMBG
0.0099
£48,360
£4,871,356
MiniMed Veo system
CSII+CGM stand-alone
0.0254
-£8,093
-£318,634
Integrated CSII+CGM (Vibe)
MDI+SMBG
-0.0009
£86,764 -£86,764,430
Integrated CSII+CGM (Vibe)
CSII+SMBG
-0.0154
£57,126
-£3,709,460
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£672
undefined
Superseded –
see Erratum
Table 104: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (all technologies)
Hypo MiniMed Veo
QALYs
Cost
Incr. QALY Incr. Cost
ICER
system RR=0.125
MDI+SMBG
11.412
£64,323
CSII+SMBG
11.9597 £91,195
0.5477
£26,871
£49,059
Extendedly
dominated by
MiniMed Veo system
12.0453 £138,333
CSII+CGM standalone
CSII+CGM stand-alone
12.0604 £146,476
0.1007
£55,281
£549,080
Dominated by
Integrated CSII+CGM
12.0604 £147,150
CSII+CGM stand(Vibe)
alone
Table 105: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6333
£74,010
£116,863
MiniMed Veo system
CSII+SMBG
0.0856
£47,138
£550,675
MiniMed Veo system
CSII+CGM stand-alone
-0.0151
-£8,143
£539,295
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6484
£82,827
£127,740
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.1007
£55,955
£555,659
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£674
undefined
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Table 106: Cost-effectiveness results mortality due to severe hypoglycaemia scenario (all
technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.1041
£61,924
Dominated by
CSII+CGM stand-alone
11.7701
£142,215
CSII+SMBG
Integrated CSII+CGM
Dominated by
11.7701
£142,872
(Vibe)
CSII+SMBG
CSII+SMBG
11.8781
£89,475
0.774
£27,551
£35,596
MiniMed Veo system
12.0071
£137,801
0.129
£8,326
£374,531
Table 107: Cost-effectiveness results mortality due to severe hypoglycaemia scenario
(intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.9029
£75,878
£84,029
MiniMed Veo system
CSII+SMBG
0.1290
£48,327
£374,626
MiniMed Veo system
CSII+CGM stand-alone
0.2369
-£4,413
-£18,622
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6659
£80,948
£121,544
Integrated CSII+CGM (Vibe)
CSII+SMBG
-0.1079
£53,397
-£494,418
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£ 657
undefined
Superseded –
see Erratum
Table 108: Cost-effectiveness results minimum QALY estimation method scenario (all
technologies)
QALYs
Cost
Incr. QALY
Incr. Cost
ICER
MDI+SMBG
12.1327
£64,563
CSII+SMBG
12.5861
£90,436
0.4534
£25,873
£57,062
MiniMed Veo
12.6408
£138,357
0.0546
£47,920
£876,987
system
CSII+CGM stand12.6462
£146,476
0.0601
£56,039
£932,305
alone
Dominated by
Integrated
12.6462
£147,150
0
£674
CSII+CGM standCSII+CGM (Vibe)
alone
Table 109: Cost-effectiveness results minimum QALY estimation method scenario
(intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.5081
£73,794
£145,235
MiniMed Veo system
CSII+SMBG
0.0547
£47,921
£876,067
MiniMed Veo system
CSII+CGM stand-alone
-0.0054
-£8,119
£1,503,465
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.5135
£82,587
£160,831
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0601
£56,713
£943,649
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
£674
undefined
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Table 110: Four year time horizon scenario (all technologies)
QALYs
Cost
Incr. QALY
2.7718
£7,437
MDI+SMBG
CSII+CGM stand2.7882
£24,803
alone
Integrated
2.7886
£24,939
CSII+CGM (Vibe)
CSII+SMBG
2.7906
£13,365
0.0188
MiniMed
Veo
2.7928
£23,144
0.0022
system
Incr. Cost
ICER
£5,927
Dominated by
CSII+SMBG
Dominated by
CSII+SMBG
£314,826
£9,778
£4,461,063
Table 111: Four year time horizon scenario (intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
MiniMed Veo system
MDI+SMBG
0.0210
£15,707
MiniMed Veo system
CSII+SMBG
0.0022
£9779
MiniMed Veo system
CSII+CGM stand-alone
0.0046
-£1659
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.0168
£17,502
Integrated CSII+CGM (Vibe)
CSII+SMBG
-0.0020
£11,574
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0.0004
£136
ICER
£747,952
£4,445,000
-£360,652
£1,041,786
-£5,787,000
£340,000
Superseded –
see Erratum
Table 112: Cost-effectiveness results fear of hypoglycaemia scenario (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146
£64,563
CSII+SMBG
11.9756
£90,436
0.5610
£25,873
£46,123
Extendedly
dominated by
CSII+CGM stand-alone 12.0604
£146,476
MiniMed Veo
system
MiniMed Veo system
12.6224
£138,357
0.6468
£47,920
£74,088
Integrated CSII+CGM
12.6429
£147,150
0.0205
£8,792
£428,595
(Vibe)
Table 113: Cost-effectiveness results fear of hypoglycaemia scenario (intervention vsersus
comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
1.2077
£73,794
£61,100
MiniMed Veo system
CSII+SMBG
0.6468
£47,921
£74,088
MiniMed Veo system
CSII+CGM stand-alone
0.5619
-£8,119
-£14,448
Integrated CSII+CGM (Vibe)
MDI+SMBG
1.2282
£82,587
£67,238
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.6468
£47,921
£74,089
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0.5824
£674
£1,157
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Table 114: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
ICER
MDI+SMBG
11.4146 £ 64,564.00
CSII+SMBG
11.9756 £ 92,272.00
0.561
£27,708
£49,395
Extendedly
dominated by
CSII+CGM stand-alone
MiniMed Veo
12.0412 £138,358.00
system
MiniMed Veo system
12.0604 £147,150.00
0.0849
£54,878
£646,692
Dominated by
Integrated CSII+CGM
MiniMed Veo
(Vibe)
12.0604 £150,063.00
0
£2,912
system
Table 115: Cost-effectiveness results cost of stand-alone CSII+CGM without market
scenario (intervention versus comparator only)
Intervention
Comparator
Incr. QALY Incr. Cost
MiniMed Veo system
MDI+SMBG
0.6266
£73,794
MiniMed Veo system
CSII+SMBG
0.0656
£46,086
MiniMed Veo system
CSII+CGM stand-alone
-0.0192
-£11,705
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
£82,586
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0848
£54,878
Integrated CSII+CGM (Vibe) CSII+CGM stand-alone
0
-£2,913
share
ICER
£117,769
£702,530
£609,635
£127,882
£647,146
undefined
Superseded –
see Erratum
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Appendix 9: Guidance relevant to the treatment of type 1 diabetes
Published NICE guidance
Diabetes. NICE Pathway. (2013). Available from:
http://pathways.nice.org.uk/pathways/diabetes
Preventing type 2 diabetes. NICE Pathway. June 2013. Available from:
http://pathways.nice.org.uk/pathways/preventing-type-2-diabetes
Diagnosis and management of type 1 diabetes in children, young people and adults: NICE
clinical guideline CG15 (2004). Available from: http://www.nice.org.uk/CG15 Date for
review: Reviewed in August 2011 and decision was made to update the guideline. Update
scheduled to be published in
Diabetic foot – inpatient management of people with diabetic foot ulcers and infection: NICE
clinical guideline CG119 (2011). Available from: http://guidance.nice.org.uk/CG119. Date
for review: TBC
Type 2 diabetes: the management of type 2 diabetes (update): NICE clinical guideline CG66
(2008). Available from: http://guidance.nice.org.uk/CG66. Date for review: Following a
review in 2011 an update of this guideline is currently in the process of being scheduled into
the work programme.
Type 2 diabetes: prevention and management of foot problems: NICE clinical guideline
CG10 (2004). Available from: http://guidance.nice.org.uk/CG10. Date for review: An update
of this guideline is underway to coincide with publication of the four diabetes guidelines
currently being updated.
Type 2 Diabetes - newer agents (partial update of CG66) (CG87): NICE clinical guideline
CG87 (2009). Available from: http://guidance.nice.org.uk/CG87 Date for review: Following
the recent review recommendation, an update of this guideline is in progress
Diabetes in pregnancy: management of diabetes and its complications from pre-conception to
the postnatal period: NICE clinical guideline (2008). Available from:
http://guidance.nice.org.uk/CG63 Date for review: This guideline is currently being updated.
Further information can be found on the Diabetes in pregnancy guideline in development
page.
Neuropathic pain - pharmacological management: the pharmacological management of
neuropathic pain in adults in non-specialist settings: NICE clinical guideline CG173 (2013).
Available from: http://guidance.nice.org.uk/CG173 Date for Review: TBC
Hyperglycaemia in acute coronary syndrome: NICE clinical guideline CG130 (2011)
Available from: http://www.nice.org.uk/guidance/CG130 Date for review: TBC
The clinical effectiveness and cost effectiveness of long acting insulin analogues for diabetes:
NICE technology appraisal guidance TA53 (2002). Available from:
http://www.nice.org.uk/guidance/TA53 Date for review: The recommendations in this
technology appraisal relating to type 2 diabetes have been replaced by recommendations in
the Diabetes - type 2 (update) clinical guideline published in May 2008. Please note that the
recommendations in this technology appraisal relating to type 1 diabetes have not changed.
287
CONFIDENTIAL UNTIL PUBLISHED
Continuous subcutaneous insulin infusion for the treatment of diabetes (review). NICE
technology appraisal guidance TA151 (2008). Available from:
http://guidance.nice.org.uk/TA151 Date for review: TBC
Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after
an inadequate response to prior therapy (rapid review of technology appraisal guidance 271):
NICE technology appraisal guidance TA301 (2013). Available from:
http://guidance.nice.org.uk/TA301 Date for review: TBC
Dapagliflozin in combination therapy for treating type 2 diabetes: NICE technology appraisal
guidance TA288 (2013). Available from: http://guidance.nice.org.uk/TA288 Date for review:
TBC
Ranibizumab for the treatment of diabetic macular oedema (rapid review of TA237): NICE
technology appraisal guidance TA274 (2013). Available from:
http://guidance.nice.org.uk/TA274 Date for review: TBC
Exenatide prolonged-release suspension for injection in combination with oral antidiabetic
therapy for the treatment of type 2 diabetes: NICE technology appraisal guidance TA248
(2012). Available from: http://guidance.nice.org.uk/TA248 Date for review: TBC
Liraglutide for the treatment of type 2 diabetes mellitus: NICE technology appraisal guidance
TA203 (2010) Available from: http://guidance.nice.org.uk/TA203 Date for review: TBC
The clinical effectiveness and cost effectiveness of patient education models for diabetes:
NICE technology appraisal guidance TA60 (2003) Available from:
http://guidance.nice.org.uk/TA60 Date for review: In December 2005, following consultation,
the Institute proposed that the guidance be updated as part of the reviews of the guidelines on
type 1 and type 2 diabetes. The recommendations in this technology appraisal relating to type
2 diabetes have been replaced by recommendations in the Diabetes - type 2 (update) clinical
guideline published in May 2008. Please note that the recommendations in this technology
appraisal relating to type 1diabetes have not changed.
Dapagliflozin in combination therapy for treating type 2 diabetes: NICE technology appraisal
TA288 (2013). Available from: http://guidance.nice.org.uk/TA288 Date for review: TBC
Fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular
oedema after an inadequate response to prior therapy. NICE Technology Appraisal, TA271
(2013). Available from: http://guidance.nice.org.uk/TA271 Date for review: TBC
Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus: NICE
interventional procedure IPG257 (2008). Available from: http://guidance.nice.org.uk/IPG257
Date for review: TBC
Autologous pancreatic islet cell transplantation for improved glycaemic control after
pancreatectomy: NICE interventional procedure IPG274 (2008). Available from:
http://guidance.nice.org.uk/IPG274 Date for review: TBC
Extracorporeal albumin dialysis for acute liver failure: NICE interventional procedure
IPG316 (2009) Available from: http://guidance.nice.org.uk/IPG316 Date for review: TBC
Preventing type 2 diabetes: risk identification and interventions for individuals at high risk.
NICE Public Health Guidance PH38 (2012). Available from:
http://guidance.nice.org.uk/PH38 Date for review: TBC
288
CONFIDENTIAL UNTIL PUBLISHED
Preventing type 2 diabetes: population and community-level interventions in high-risk groups
and the general population. NICE Public Health Guidance PH35 (2011). Available from:
http://www.nice.org.uk/guidance/PH35 Date for review: May 2014
Type 2 diabetes: alogliptin: NICE Evidence summaries: new medicines ESNM20 (2013)
Available from: http://publications.nice.org.uk/esnm20-type-2-diabetes-alogliptin-esnm20
Date for review: TBC
Type 2 diabetes: lixisenatide: NICE Evidence summaries: new medicines ESNM26 (2013)
Available from: http://publications.nice.org.uk/esnm26type-2-diabetes-lixisenatide-esnm26
Date for review: TBC
Type 1 diabetes: insulin degludec. NICE Evidence summaries: new medicines, ESNM5
(2012). Available from:
http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM5.jsp Date for review:
TBC
Type 2 diabetes: insulin degludec. NICE Evidence summaries: new medicines, ESNM4
(2012). Available from:
http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM4.jsp Date for review:
TBC
Diabetes in adults: NICE Quality Standard QS6 (2011) Available from:
http://guidance.nice.org.uk/QS6 Date for review: TBC “Quality statement 14:
Hypoglycaemia People with diabetes who have experienced hypoglycaemia requiring medical
attention are referred to a specialist diabetes team.”
Patient education programme for people with type 2 diabetes. NICE Commissioning Guide
(2009). Available from:
http://www.nice.org.uk/usingguidance/commissioningguides/type2diabetes/patienteducationp
rogrammeforpeoplewithtype2diabetes-mainpage.jsp Date for review: TBC
NICE guidance under development
Diabetes in children and young people (update) NICE clinical guideline (publication expected
August 2015)
Type 1 diabetes (update) NICE clinical guideline (publication expected August 2015)
Type 2 diabetes (update) NICE clinical guideline (publication expected August 2015)
Diabetes in pregnancy (update) NICE clinical guideline (publication expected February
2015)
Diabetic foot problems (update) NICE clinical guideline (publication expected June 2015)
NICE pathways
The guidance: “Type 1 diabetes: Integrated sensor-augmented pump therapy systems for
managing blood glucose levels (The MiniMed Paradigm Veo System and the Vibe and G4
PLATINUM CGM system)” will be included in the NICE diabetes pathway.
Relevant guidance from other organisations
Management of diabetes. Scottish Intercollegiate guidelines Network guideline 116 (2010).
Available from: http://www.sign.ac.uk/guidelines/fulltext/116/
Diabetes UK (2010) The hospital management of hypoglycaemia in adults with diabetes
mellitus
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CONFIDENTIAL UNTIL PUBLISHED
Diabetes UK (2013) State of the nation: England 2013
Diabetes UK (2012) Use of analogue insulins
Diabetes UK (2012) End of life diabetes care
Diabetes UK (2005) Recommendations for the provision of services in primary care for
people with diabetes
Joint Royal Colleges Ambulance Liaison Committee (2006) Glycaemic emergencies in
children
National Metabolic Biochemistry Network (2012) Guidelines for the investigation of
hypoglycaemia in infants and children
British Inherited Metabolic Diseases Group (2013) Recurrent hypoglycaemia
British Inherited Metabolic Diseases Group (2008) Ketotic hypoglycaemia
British Inherited Metabolic Diseases Group (2008) Management of surgery in children at risk
of hypoglycaemia
Joint Royal Colleges Ambulance Liaison Committee (2006) Glycaemic emergencies in adults
Driver and vehicle licensing agency (2013) DVLA’s current medical guidelines for
professionals – conditions D to F
Driver and vehicle licensing agency (2013) DVLA’s current medical guidelines for
professionals – conditions G to I
Royal College of Nursing (2013) Children and young people with diabetes: RCN guidance for
newly-appointed nurse specialists
Royal College of Nursing (2013) Supporting children and young people with diabetes
Royal College of Nursing (2006) Specialist nursing services for children and young people
with diabetes
Royal College of Nursing (2012) Starting injectable treatment in adults with type 2 diabetes
290
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Appendix 10: PRISMA check list
# Checklist item
Reported on
page #
1 Identify the report as a systematic review, meta-analysis, or both.
1, 2 and 3
2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility
criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and
implications of key findings; systematic review registration number.
13
Rationale
3 Describe the rationale for the review in the context of what is already known.
18 to 22
Objectives
4 Provide an explicit statement of questions being addressed with reference to participants, interventions,
comparisons, outcomes, and study design (PICOS).
23 to 25
Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide
registration information including registration number.
NICE website
Eligibility criteria
6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale.
24 to 25
Information sources
7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify
additional studies) in the search and date last searched.
25 to 26, and
appendix 1
Search
8 Present full electronic search strategy for at least one database, including any limits used, such that it could be
repeated.
Appendix 1
Study selection
9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis).
27
Section/topic
TITLE
Title
ABSTRACT
Structured summary
INTRODUCTION
METHODS
Data collection process
10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any
processes for obtaining and confirming data from investigators.
27
291
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Section/topic
# Checklist item
Reported on
page #
Data items
11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and
simplifications made.
27
Risk of bias in individual
studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was
done at the study or outcome level), and how this information is to be used in any data synthesis.
27 to 28
Summary measures
13 State the principal summary measures (e.g., risk ratio, difference in means).
28 to 29
Synthesis of results
14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency
(e.g., I2) for each meta-analysis.
28 to 29
Risk of bias across studies
15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective
reporting within studies).
27 to 28
Additional analyses
16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done,
indicating which were pre-specified.
29
Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions
at each stage, ideally with a flow diagram.
29 to 30
Study characteristics
18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period)
and provide the citations.
31 to 33, and
appendix 3
Risk of bias within studies
19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
31, and app. 2
Results of individual studies
20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each
intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
33 to 53, and
appendix 3
Synthesis of results
21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.
36 to 53
Risk of bias across studies
22 Present results of any assessment of risk of bias across studies (see Item 15).
117 to 119
Additional analysis
23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
49 to 53
RESULTS
DISCUSSION
292
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Section/topic
# Checklist item
Reported on
page #
Summary of evidence
24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance
to key groups (e.g., healthcare providers, users, and policy makers).
115 to 116
Limitations
25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of
identified research, reporting bias).
117 to 119
Conclusions
26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
121
27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for
the systematic review.
2
FUNDING
Funding
293
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in collaboration with:
ERRATUM TO
Type 1 diabetes: Integrated sensor-augmented pump therapy
systems for managing blood glucose levels (The MiniMed Paradigm
Veo System and the Vibe and G4 PLATINUM CGM system)
CONFIDENTIAL UNTIL PUBLISHED
1. Page 17: the ICER of CSII+SMBG compared to MDI+SMBG (£46,123) and the
probability that MDI+SMBG is cost-effective (95%) quoted in the first paragraph are
incorrect. They should be £52,381 and 98%, respectively.
A corrected page 17 is copied below.
2. Page 29 and 30: In the methods section it was mentioned that we would use the
random effects method in all analyses. In fact we used the fixed effect method in all
analyses unless heterogeneity was too high (I2>50%).
Corrected pages 29 and 30 are copied below.
3. Page 33: Table 3 reported HbA1c levels without describing the unit of measurement
(% or mmol/mol). This was % - HbA1c.
A corrected page 33 is copied below.
4. Page 35: Table 5 reported HbA1c levels without describing the unit of measurement
(% or mmol/mol). This was % - HbA1c.
A corrected page 35 is copied below.
5. Pages 40 and 41: Table 10 reported HbA1c levels without describing the unit of
measurement (% or mmol/mol). This was % - HbA1c.
Corrected pages 40 and 41 are copied below.
6. Page 42: the text in all three paragraphs refers to the integrated CSII+CGM system
being compared to CSII+SMBG, this should have read the integrated CSII+CGM
system compared to MDI+SMBG.
A corrected page 42 is copied below and we have also added references to the studies.
7. Page 47: Table 15 reported HbA1c levels without describing the unit of measurement
(% or mmol/mol). This was % - HbA1c.
A corrected page 47 is copied below.
8. Page 49: Table 18 and 19 the comparator is listed as MDI+SMBG in the table. The
comparator should have been listed as CSII+SMBG.
A corrected page 49 is copied below.
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9. Page 84: Table 38: insulin costs for MDI+CGM and MDI+SMBG in the table are
incorrect. Outpatient costs for all treatments are incorrect (they should match those in
Table 37). Total costs for all treatments are incorrect.
A corrected page 84 is copied below.
10. Page 91: Table 46: the rates reported in scenarios 2, 3 and 4 for MDI+SMBG
correspond to MiniMed Veo system and vice versa.
A corrected page 91 is copied below.
11. Page 94: cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 48 are incorrect. The ICER of CSII+SMBG compared to
MDI+SMBG quoted in the first paragraph below Table 48 is incorrect.
A corrected page 94 is copied below.
12. Page 95: incremental costs and ICER of MiniMed Veo system vs. MDI+SMBG and
integrated CSII+CGM (Vibe) vs. MDI+SMBG in Table 49 are incorrect. The first
sentence after Table 49 has been amended according to the figures reported in the
corrected Table 49. Cost of MDI+SMBG, incremental costs and ICER of
CSII+SMBG vs. MDI+SMBG, incremental QALY, incremental costs and ICER of
MiniMed Veo system vs. CSII+SMBG, incremental QALY, incremental costs and
ICER of CSII+CGM stand-alone vs. MiniMed Veo system in Table 50 are incorrect.
Incremental costs and ICER of MiniMed Veo system vs. MDI+SMBG and integrated
CSII+CGM (Vibe) vs. MDI+SMBG in Table 51 are incorrect.
A corrected page 95 is copied below.
13. Page 96: the percentage that treatment costs represents for MDI+SMBG and Figure
11 are incorrect.
A corrected page 96 is copied below.
14. Page 97: Figure 12 and the ceiling ratio value reported for MDI+SMBG in the
paragraph below Figure 12 are incorrect.
A corrected page 97 is copied below.
15. Page 98: Figure 13 is incorrect.
A corrected page 98 is copied below.
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16. Page 100: cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 52 are incorrect. The ICER of CSII+SMBG compared to
MDI+SMBG quoted in the first paragraph below Table 52 is incorrect.
A corrected page 100 is copied below.
17. Page 101: cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 53 are incorrect. The ICER of CSII+SMBG compared to
MDI+SMBG quoted in the first paragraph below Table 53 is incorrect.
A corrected page 101 is copied below.
18. Page 102: cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 54 are incorrect. The ICER of CSII+SMBG compared to
MDI+SMBG quoted in the first paragraph below Table 54 is incorrect. Cost of
MDI+SMBG, incremental costs and ICER of CSII+SMBG vs. MDI+SMBG in Table
55 are incorrect.
A corrected page 102 is copied below.
19. Page 103: Figure 16 is incorrect. Cost of MDI+SMBG, incremental costs and ICER of
CSII+SMBG vs. MDI+SMBG in Table 56 are incorrect.
A corrected page 103 is copied below.
20. Page 104: Cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 57 are incorrect. The ICER of CSII+SMBG compared to
MDI+SMBG quoted in the first paragraph below Table 57 is incorrect.
A corrected page 104 is copied below.
21. Page 105: Table 58 and 59: Cost of MDI+SMBG, incremental costs and ICER of
CSII+SMBG vs. MDI+SMBG in Table 58 and Table 59 are incorrect.
A corrected page 105 is copied below.
22. Page 106: Figure 18 and 19 are incorrect.
A corrected page 106 is copied below.
23. Page 107: Cost of MDI+SMBG, incremental costs and ICER of CSII+SMBG vs.
MDI+SMBG in Table 60 are incorrect. The value at which the probability of being
cost-effective for CSII+SMBG starts decreasing quoted in the last paragraph of the
page is incorrect.
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A corrected page 107 is copied below.
24. Page 108: Figure 20 is incorrect.
A corrected page 108 is copied below.
25. Page 109: Table 61: Cost of MDI+SMBG, incremental costs and ICER of
CSII+SMBG vs. MDI+SMBG in Table 61 are incorrect. Figure 22 is incorrect.
A corrected page 109 is copied below.
26. Page 117: The ICER of CSII+SMBG compared to MDI+SMBG quoted in the last but
one paragraph is incorrect.
A corrected page 117 is copied below.
27. Pages 284 - 290: Appendix 8: this appendix is summary of all cost-effectiveness
results and includes Table 90 to Table 115. Costs of MDI+SMBG, incremental costs
and ICERs of any treatment compared to MDI+SMBG in all tables are incorrect.
Corrected pages 284 – 290 are copied below.
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PAGE 17:
stand-alone compared to the next most effective choice, CSII+SMBG, is £660,376 and the ICER of
CSII+SMBG compared to the least effective choice, MDI+SMBG, is £52,381. Thus, assuming the
common threshold of £30,000 per QALY gained, MDI+SMBG, whilst being the least effective,
would be considered the optimal choice. When uncertainty is taken into account we see that at that
threshold MDI+SMBG would have a 98% probability of being the optimal choice.
That CSII+CGM is more effective than Minimed Paradigm Veo might appear to contradict the
clinical effectiveness conclusions, but this is explained by effectiveness being affected by both
difference in hypoglycaemic event rate and HbA1c level. Whilst the evidence shows that Minimed
Paradigm Veo is probably better in terms of hypoglycaemic event rate it does show a small albeit not
statistically significant disadvantage in terms of HbA1c. Even this small difference seems to be
sufficient, through the consequences of hyperglycaemia, to outweigh the difference in the relatively
rare hypoglycaemia with generally less severe consequences. However, note that all of these results
should be interpreted with caution as some studies on which effect estimates were based included all
type 1 patients, whereas others included patients who had been on a pump for at least six months
already and others included patients without pump experience but with poor glycaemic control at
baseline.
These results remained largely unchanged in scenario analyses, used to assess the potential impact of
various input parameters on the model outcomes. Even when a large array of scenarios is considered,
in all of them MDI+SMBG would be considered the optimal choice assuming a threshold of £30,000
per QALY gained.
1.5 Conclusions
Overall, the evidence seems to suggest that the MiniMed Paradigm Veo system reduces
hypoglycaemic events in comparison with other treatments, without any differences in other
outcomes, including change in HbA1c. In addition we found significant results in favour of the
integrated CSII+CGM system in comparison with MDI+SMBG for HbA1c and quality of life.
However, the evidence base was poor. The quality of included studies was generally low and often
there was only one study to compare treatments in a specific population and at a specific follow-up
time. In particular, the evidence for the two interventions of interest was limited, with only one study
comparing the MiniMed Paradigm Veo system with an integrated CSII+CGM system and one study
in a mixed population comparing the MiniMed Paradigm Veo system with CSII+SMBG.
Cost-effectiveness analyses indicated that MDI+SMBG is the option most likely to be cost-effective,
given the current threshold of £30,000 per QALY gained, whereas integrated CSII+CGM systems and
MiniMed Paradigm Veo are dominated and extendedly dominated, respectively, by CSII+CGM standalone. Scenario analyses, used to assess the potential impact of changing various input parameters, did
not alter these conclusions. No cost-effectiveness modelling was conducted for children and pregnant
women.
1.6 Suggested research priorities
In adults, a trial comparing the MiniMed Paradigm Veo system with CSII+SMBG is warranted.
Similarly a trial comparing the Vibe and G4 PLATINUM CGM system or any integrated CSII+CGM
system with CSII+SMBG is warranted. In children, a trial comparing the MiniMed Paradigm Veo
system with the Vibe and G4 PLATINUM CGM system or any integrated CSII+CGM system is
warranted, as is a trial comparing an integrated CSII+CGM system with CSII+SMBG. For pregnant
women, trials comparing the MiniMed Paradigm Veo
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PAGES 29 and 30:
Domain
Other sources of bias
Item
Was the study
apparently free of
other problems that
could put it at a high
risk of bias?
Description
inclusions in analyses.
Overall, the study should be free from
any important concerns about bias (i.e.
bias from other sources not previously
addressed by the other items).
Each study was awarded a ‘yes’, ‘no’ or ‘unclear/unknown’ rating for each individual item in the
checklist. Any additional clarifications or comments were also recorded.
Quality assessment was carried out independently by two reviewers. Any disagreements were
resolved by consensus. The results of the quality assessment were used for descriptive purposes to
provide an evaluation of the overall quality of the included studies and to provide a transparent
method of recommendation for design of any future studies. Based on the findings of the quality
assessment, recommendations are made for the conduct of future studies.
4.1.5 Methods of analysis/synthesis
Where meta-analysis was considered unsuitable for some or all of the data identified (e.g. due to the
heterogeneity and/or small numbers of studies), we employed a narrative synthesis. Typically, this
involves the use of text and tables to summarise data. These allow the reader to consider any
outcomes in the light of differences in study designs and potential sources of bias for each of the
studies being reviewed. Studies were organised by comparison.
The methods used to synthesise the data were dependent on the types of outcome data included and
the clinical and statistical similarity of the studies. Possible methods include the following types of
analysis.
Dichotomous outcomes
Dichotomous data were analysed by calculating the relative risk (RR) for each trial using the fixed
effect method or DerSimonian and Laird random effects method and the corresponding 95%
confidence intervals (CIs).34
Continuous outcomes
Continuous data were analysed by calculating the weighted mean difference (WMD) between groups
and the corresponding 95% CI. If the standard deviations and means were not determinable, they
were estimated from the data that was provided or using a representative value from other studies.
Systematic differences between studies (heterogeneity) are likely; therefore, the random-effects model
was used for the calculation of relative risks or weighted mean differences if heterogeneity was
moderate or high (I2>50%). Heterogeneity was initially assessed by measuring the degree of
inconsistency in the studies' results (I2). This measure (I2) describes the percentage of total variation
across studies that was due to heterogeneity rather than the play of chance. The value of I2 can lie
between 0% and 100%. Low, moderate and high I2 values correspond to 25%, 50%, and 75%.
If important heterogeneity was identified, we planned to formally investigate this using metaregression. In particular, a model was planned to be used to explore the possible modifying effects of
the following pre-specified factors: methodological quality of the primary studies, underlying illness,
and different age groups. The coefficient describing the predictive value of each factor and the
overall effect on the main outcome would be modelled, using a fixed-effect model. However, due to
the limited number of studies for each comparison this was not possible.
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A funnel plot (plots of logarithm of the RR for efficacy against the precision of the logarithm of the
RR) was planned in order to estimate potential asymmetry, which would be indicative of small study
effects. HbA1c was chosen as an outcome since this is likely to be reported by the majority of
included studies. In addition, the Egger regression asymmetry test was planned in order to facilitate
the prediction of potential publication biases. This test detects funnel plot asymmetry by determining
whether the intercept deviates significantly from zero in a regression of the standardised effect
estimates against their precision. However, due to the limited number of studies for each comparison
this was not possible.
Network meta-analysis methods
In the absence of RCTs directly comparing the MiniMed Veo System or the integrated CSII+CGM
system (such as Animas Vibe Pump with Dexcom G4 CGM) with the comparators (i.e.
CSII+CGM/SMBG or MDI+CGM/SMBG), indirect treatment comparisons were performed, where
possible. As only limited networks could be formed a mixed treatment comparison was not possible.
However, where it was possible indirect comparisons were made. Although ‘head-to-head’
comparisons are preferred to indirect methods in health technology assessment they are generally
considered acceptable and all methods need to be applied with consideration for the basic assumptions
of homogeneity, similarity, and consistency as reported in Song 2009.35 For this appraisal, where
‘head-to-head’ trials (i.e. A versus B) of the MiniMed Paradigm Veo with CGM System versus the
comparators (CSII+ CGM/SMBG or MDI+CGM/SMBG) were missing, the effect sizes (RR or MD)
for A versus B were estimated using ‘indirect’ methods e.g. from A versus C and B versus C, where C
is a common control group (e.g. CSII+CGM (i.e. CSII with a stand-alone CGM)). All indirect
comparisons were consistent with ISPOR taskforce recommendations for the conduct of direct and
indirect meta-analysis and used the Bucher method.36 A practical issue for indirect comparisons
concerns the limitations in availability of the same outcomes in the studies of interventions that are
candidates for an indirect comparison. Only studies that provide the same outcome measures at the
same follow-up time can be compared with each other which may limit the availability of suitable
trial networks. Dependent on the data available, separate network analyses were performed for each of
the subgroups specified in this protocol. Indirect meta-analysis were performed using Microsoft Excel
2007 according to the method developed by Bucher 1997.36 Effect sizes with 95% CIs were calculated
using results from the direct head-to-head meta-analysis. Direct head-to-head meta-analyses were
performed using fixed effect models in STATA (STATA™ for Windows, version 13, Stata Corp;
College Station, TX), unless significant heterogeneity was present, in which case we used random
effects models.
4.2 Results of the assessment of clinical effectiveness
4.2.1 Results of literature searches
The literature searches of bibliographic databases identified 9,870 references. After initial screening
of titles and abstracts, 555 were considered to be potentially relevant and ordered for full paper
screening. Of the total of 555 publications considered potentially relevant, 29 could not be obtained
within the time scale of this assessment. Most of these 29 unobtainable studies were older (pre-2000)
or conference abstracts; only four were possibly relevant trials published after 2000, based on their
abstracts it was unclear whether they fulfilled the inclusion criteria. Figure 1 shows the flow of studies
through the review process, and
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PAGE 33:
Table 3: Characteristics of included studies
Study ID
Population
Baseline
(Age
Age,
range)
Mean (SD)
ASPIRE inA (16-70)
43 (13)
37
home
Ly 201338
M (4-50)
19 (12)
M (12-72)
Hirsch 20084
A (18-72)
33 (16)
C (12-17)
O'Connell 20095
M (13-40)
23 (8.4)
RealTrend6
M (2-65)
28 (16)
Eurythmics7
A (18-65)
38 (11)
8
Lee 2007
A (NR)
NR
Peyrot 20099
A (NR)
47 (13)
M (7-70)
32 (17)
STAR-310
A (19-70)
41 (12)
C (7-18)
12 (3)
39
Bolli 2009
A (18-70)
40 (11)
DeVries 200240
A (18-70)
37 (10)
Nosadini 198841
? (A)
34 (6)
42
OSLO
A (18-45)
26 (21)
Thomas 200743
A (NR)
43 (10)
Tsui 200144
A (18-60)
36 (11)
Weintrob 200345
C (8-14)
12 (1.5)
Thrailkill 201146
C (8-18)
12 (3)
Doyle 200447
C (8-21)
13 (3)
Nosari 199348
P (NR)
26 (2.4)
Baseline
HbA1c (%)
Mean, SD
7.2 (0.7)
Pump
use
Follow-up
(months)
>6m
3m
7.5 (0.8)
M 8.4 (0.7)
A 8.3 (0.6)
C 8.7 (0.9)
7.4 (0.7)
9.2 (1)
8.6 (0.9)
9 (0.9)
8.6 (1)
>6m
6m
>6m
6m
>3m
NR
Naive
Naive
NR
3m
6m
6m
3.5m
3.7m
8.3 (0.5)
Naive
12m
7.7 (0.7)
9.4 (1.4)
NR
8.5 (NR)
8.5 (1.5)
8 (0.6)
8 (1)
11.5 (2.4)
8.1 (1.2)
NR
Naive
Naive
NR
NR
NR
Naive
NR
Naive
Naive
Naive
6m
3.7m
12m
3, 6, 12, 24m
4, 6m
9m
3.5m
6, 12m
3.7m
9m
A=Adults, C=Children, M=Mixed, P=Pregnant women; NR=Not reported; m=months.
Table 4 shows the inclusion criteria regarding HbA1c and hypoglycaemic events used in the
included studies. Further details of the characteristics of study participants and the
interventions, comparators and results are reported in the data extraction tables presented in
Appendix 3. It is clear from Table 3 that most studies include patients who have never used a
pump before. However, the two studies looking at the MiniMed Veo system (ASPIRE and Ly
2013), both include patients who have at least 6 months experience using an insulin pump. In
addition, baseline HbA1c differs considerably between studies. DeVries et al (2002) included
patients with poor control at baseline who are pump-naive. The two studies looking at the
MiniMed Veo system included patients with relatively good glycaemic control at baseline,
but that might be as a result of using an insulin pump for at least six months. Other studies,
such as Bolli et al (2009), included patients with relatively good glycaemic control at baseline
without any previous pump experience. Therefore, there is considerable heterogeneity
between study populations.
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PAGE 35:
Table 5: Included studies for adults
Study ID
Veo
Integrated
CSII+CGM
ASPIRE in-home37
Hirsch 20084
Eurythmics7
Lee 20078
Peyrot 20099
STAR-310
Bolli 200939
DeVries 200240
Nosadini 198841
OSLO42
Thomas 200743
Tsui 200144







CSII+
SMBG
MDI+
SMBG
Baseline Age,
Mean (SD), Range
Baseline HbA1c
(%), Mean, SD
Pump
use
Follow-up
(months)










43 (13), 16-70
33 (16), 18-72
38 (11), 18-65
NR
47 (13), NR
41 (12), 19-70
40 (11), 18-70
37 (10), 18-70
34 (6), NR
26 (21), 18-45
43 (10), NR
36 (11), 18-60
7.2 (0.7)
8.3 (0.6)
8.6 (0.9)
9 (0.9)
8.6 (1)
8.3 (0.5)
7.7 (0.7)
9.4 (1.4)
NR
8.5 (NR)
8.5 (1.5)
8 (0.6)
>6m
>6m
Naive
Naive
NR
Naive
Naive
Naive
NR
NR
NR
Naive
3m
6m
6m
3.5m
3.7m
12m
6m
3.7m
12m
3, 6, 12, 24m
4, 6m
9m



1



1) Nosadini 1988 was a three arm study that compared two different versions of CSII+SMBG versus MDI+SMBG
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PAGES 40 and 41:
Table 10: Results for the integrated CSII+CGM system versus MDI+SMBG at 3, 6 and 12 months follow-up in adults
Integrated CSII+CGM
MDI+SMBG
Baseline
3
months
Baseline
3 months
3 months follow-up
Change in HbA1c (%):
- Peyrot 2009 (n=27)
8.87 (0.89), n=14
7.16 (0.75)
8.32 (1.05), n=13
7.30 (0.92)
- Lee 2007 (n=16)
9.45 (0.55), n=8
7.40 (0.66)
8.58 (1.30), n=8
7.50 (1.01)
Hypoglycaemic events (patients with events/ total
patients):
- Peyrot 2009 (n=27), nr of severe events
0/14
3/13
- Lee 2007 (n=16), proportion of patients
0/8
1/8
DKA
- Peyrot 2009 (n=27)
0/14
1/13
- Lee 2007 (n=16)
0/8
1/8
Serious AE
0/8
1/8
Integrated CSII+CGM (n=41)
MDI+SMBG (n=36)
Baseline
6m follow-up
Baseline
6m follow-up
6 months follow-up
Change in HbA1c (%)
8.46 (0.95)
7.23 (0.65)
8.59 (0.82)
8.46 (1.04)
Proportion achieving HbA1c ≤7%
14/41
0/36
Hypoglycaemic events
0.7 (SD 0.7)
0.6 (SD 0.7)
(Mean number per day, glucose <
4.0 mmol/L)
Hyperglycaemic events
2.1 (SD 0.8)
2.2 (SD 0.7)
(Mean number per day, glucose >
11.1 mmol/L)
Insulin Use (total daily dose)
46.7 (16.5)
57.8 (18.1)
QoL:
SF-36 General Health
55.5 (20.3)
67.7 (21.6)
59.8 (22.3)
63.1 (19.1)
Difference at 3m
-0.69, p=0.071
-0.97, p=0.02
NS
NS
NS
NS
NS
Difference at 6m
-1.1 (95% CI -1.47, -0.73)
p<0.001
0.1 (95% CI -0.2, 0.5)
-0.2 (95% CI -0.5, 0.2)
-11.0 units per day; 95% CI -16.1 to 5.9, p< 0.001
7.9 (95% CI 0.5, 15.3), p=0.04
CONFIDENTIAL UNTIL PUBLISHED
12 months follow-up
Change in HbA1c (%)
Proportion achieving HbA1c ≤7%
Severe hypoglycaemia
(patients with events/ total patients)
Severe hypoglycaemic event rate
(per 100 person-year; HbA1c <50
mg.dL)
Hypoglycaemic AUC
(Threshold <70 mg/dL)
Hyperglycaemic AUC
( >250 mg/dL)
Patients with DKA
QoL: SF-36 General Health
HFS
Integrated CSII+CGM (n=169)
Baseline
12m follow-up
8.3 (0.5)
7.3 (NR)
57/166
17/169
MDI+SMBG (n=167)
Baseline
12m follow-up
8.3 (0.5)
7.9 (NR)
19/163
13/167
Difference at 12m
-0.6 (95% CI -0.8, -0.4), p<0.001
p<0.001
NS
15.31/169
17.62/167
p=0.66
0.25 (0.44)
0.29 (0.55)
p=0.63
3.74 (5.01)
7.38 (8.62)
p<0.001
2/169
Change: +2.7 (8.07)
Change: -9 (16.04)
0/167
Change: -0.3
(7.13)
Change: -2.4
(15.88)
NS
3 (SD 7.75;
95% CI 1.36, 4.64)
-6.5 (SD 16.0;
95% CI -9.76, -3.27)
DKA = Diabetic ketoacidosis; HFS=Hypoglycaemia Fear Survey; NS=Not significant
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PAGE 42:
At three months follow-up, results were available from two small RCTs, with 279 and 168
adult respondents respectively. Change in HbA1c favoured the integrated CSII+CGM system
over MDI+SMBG, but this was not significant in one of the trials. There were more
hypoglycaemic events, DKA and serious adverse events for MDI+SMBG at three months.
None of these results were significant; however, study sizes were small and the number of
events was limited.
At six months follow-up, results were available from one small RCT with 77 adult
respondents.7 This trial showed a significant difference in HbA1c change scores in favour of
the integrated CSII+CGM system and a significantly higher number of patients achieving
HbA1c ≤7%. Insulin use was significantly less in the integrated CSII+CGM group and quality
of life was significantly more improved in the integrated CSII+CGM group compared to the
MDI+SMBG group. The number of hypoglycaemic events and hyperglycaemic events
showed no differences between groups.
At 12 months follow-up, results were available from one RCT with 336 adult participants.10
This trial also showed a significant difference in HbA1c change scores in favour of the
integrated CSII+CGM system and a significantly higher number of patients achieving HbA1c
≤7%. Hyperglycaemic AUC was significantly lower in the integrated CSII+CGM group, but
hypoglycaemic AUC showed no significant difference. Results for severe hypoglycaemia
showed no differences between groups; nor did the number of patients with DKA. Quality of
life was significantly more improved in the integrated CSII+CGM group compared to the
MDI+SMBG group. The Hypoglycaemia Fear Survey showed significantly more reductions
in fear in the integrated CSII+CGM group compared to the MDI+SMBG group, for both
hypoglycaemia worries and hypoglycaemia avoidant behaviour.
Integrated CSII+CGM versus CSII+SMBG and MDI+SMBG
Results at three months follow-up:
Proportion of patients with severe hypoglycaemia
Figure 3: Network of studies comparing ‘severe hypoglycaemia’ at three months follow-up in
adults
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Table 15: Included studies for children
Study ID
Veo
CSII+CGM
integrated
Ly 201338
Hirsch 20084
STAR-310
Weintrob 200345
Thrailkill 201146
Doyle 200447



CSII+
SMBG
MDI+
SMBG
Baseline Age,
Mean (SD), Range




19 (12), 4-50
33 (16), 12-17
12 (3), 7-18
12 (1.5), 8-14
12 (3), 8-18
13 (3), 8-21





Baseline
HbA1c (%)
Mean, SD
7.5 (0.8)
8.7 (0.9)
8.3 (0.5)
8 (1)
11.5 (2.4)
8.1 (1.2)
Pump
use
Follow-up
(months)
>6m
>6m
Naive
NR
Naive
Naive
6m
6m
12m
3.5m
6, 12m
3.7m
VEO versus CSII+SMBG
One study compared the MiniMed Veo system with CSII+SMBG at six months follow-up in a mixed population of patients between 4 and 50 years old.
Results were not reported separately for adults and children. However, about 70% of patients were children (<18 years). As explained above, we have
included this study as a study in children.
No results were found for the MiniMed Veo system versus any other treatment at three months or nine months or longer follow-up.
Table 16: Results for the MiniMed Veo system versus CSII+SMBG at six months follow-up in a mixed population (mainly children)
MiniMed Veo system (n=46)
CSII+SMBG (n=49)
Baseline
6m follow-up
Baseline
6m follow-up
6 months follow-up
Difference at 6m
Change in HbA1c
7.6% (95% CI
7.5 (95% CI 7.3,
7.4 (95% CI
7.4 (95% CI
0.07 (95% CI: -0.2,
7.4, 7.9)
7.7)
7.2, 7.6)
7.2, 7.7)
0.3), p=0.55
Number of people with hypoglycaemic
0/41
6/45
NS
events
Rate of hypoglycaemic events (Incidence
rate per 100 patient-months)
HUS
5.9 (95% CI 5.5,
6.4)
9.5 (95% CI 5.2,
17.4)
4.7 (95% CI 4.0,
5.1)
6.4 (95% CI
5.9, 6.8)
HUS=Hypoglycaemia Unawareness Score (Clarke questionnaire), higher is worse; IRR=Incidence rate ratio
34.2 (95% CI
22.0, 53.3)
5.1 (95% CI
4.5, 5.6)
IRR=3.6 (95% CI 1.7,
7.5), p<0.001
-0.2 (95% CI -0.9,
0.5), p=0.58
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Table 18: Results for the integrated CSII+CGM system versus CSII+SMBG at six months
follow-up in children
Integrated CSII+CGM (n=17)
CSII+SMBG (n=23)
Baseline
6m follow-up
Baseline
6m follow-up
6 months follow-up
Difference at 6m
Change in HbA1c
8.82 (1.05)
8.02 (1.11)
8.59 (0.80)
8.21 (0.97)
0.4894 (SE 0.2899),
(%)
p=0.10
Results for the head-to-head comparison of the integrated CSII+CGM system versus
CSII+SMBG at six months follow-up in children showed no significant difference in HbA1c
scores between groups.
Integrated CSII+CGM versus MDI+SMBG
One study compared the integrated CSII+CGM system with MDI+SMBG at 12 months
follow-up in children.10
At 12 months follow-up, results for the head-to-head comparison of the integrated
CSII+CGM system versus MDI+SMBG were available for: change in HbA1c, proportion
achieving HbA1c ≤7%, proportion with severe hypoglycaemia, rate of severe hypoglycaemic
events, hypoglycaemic AUC, hyperglycaemic AUC, DKA and quality of life. These results
are reported in Table 19.
Table 19: Results for the integrated CSII+CGM system versus MDI+SMBG at 12 months
follow-up in children
12 months follow-up
Change in HbA1c (%)
Integrated CSII+CGM
Baseline (n=78)
12m followup
8.3 (0.6)
7.9 (NR)
Proportion achieving HbA1c ≤7%
Number of people with Severe
hypoglycaemic events
Severe hypoglycaemic event rate (per
100 person-year; HbA1c <50 mg.dL)
Hypoglycaemic AUC (Threshold <70
mg/dL)
Hyperglycaemic AUC ( >250 mg/dL)
Patients with DKA
QoL:
MDI+SMBG (n=81)
Baseline
12m follow-up
Difference at 12m
8.3 (0.5)
8.5 (NR)
10/78
4/78
4/78
4/81
-0.5 (95% CI -0.8, 0.2), p<0.001
p=0.15
NS
8.98/78
4.95/81
p=0.35
0.23 (0.41)
0.25 (0.41)
p=0.79
9.2 (8.08)
17.64 (14.62)
p<0.001
1/78
1/81
NS
PedsQL – Psychosocial
78.38 (14.59)
Change: 3.39
78.76 (10.27)
Change: 3.64
NS
PedsQL – Physical
86.99 (12.93)
Change: 2.53
88.37 (11.16)
Change: 1.41
NS
HFS-Worry
28.88 (9.74)
Change: -3.62
26.97 (8.06)
Change: -2.43
NS
HFS-Avoidance
30.60 (5.43) Change: -4.01 29.70 (6.04)
Change: -2.25
NS
DKA = Diabetic ketoacidosis; HFS=Hypoglycaemia Fear Survey (Higher is worse); PedsQL=Pediatric
Quality of Life (Higher is better)
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Table 37: Annual outpatient care related costs
Outpatient costs
Year 1
Year 2+
Average yearly cost (based on 80 years time horizon)
Insulin pump
£1,386.00
£396.00
MDI
£396.00
£396.00
£408.38
£396.00
HbA1c tests costs
Cost and frequency of HbA1c tests were also estimated based on clinical expert opinion. We
assumed that on average this test would be performed three times a year. The cost of the test
will depend on the hospital, lab, etc. where the test would be performed. Based on the average
of three hospital prices we assumed £3.14 as the average price for an HbA1c test.
5.3.2.5 Summary of treatment and other hospital costs
A summary of treatment-related costs for the six technologies considered in this study can be
seen in Table 38.
Table 38: Summary of annual treatment-related costs per technology
Technology
MiniMed Veo system
Integrated CSII+CGM
(Vibe)
CSII+CGM
CSII+SMBG
MDI+CGM
MDI+SMBG
Equipment +
consumables
Blood
glucose tests
Insulin
Outpatient
HbA1c
Total
£4,862.10
£5,298.65
£5,261.29
£2,166.13
£3,288.50
£200.75
£423.40
£423.40
£423.40
£423.40
£423.40
£423.40
£342.74
£342.74
£342.74
£342.74
£416.63
£416.63
£408.38
£408.38
£408.38
£408.38
£396.00
£396.00
tests
£9.42
£9.42
£9.42
£9.42
£9.42
£9.42
£6,046.04
£6,482.59
£6,445.22
£3,350.07
£4,533.94
£1,446.20
5.3.3 Utilities
Health benefits were expressed in terms of life years and quality-adjusted life years (QALYs)
gained. When more than one complication occurs at the time a multiplicative approach is
applied.118 For the PSA utility and disutility values are sampled from a beta distribution1. The
utilities used in the model are summarised in Table 39.
1
Mean and standard deviation are inputs of the IMS CDM which are parameterized into parameters a
and b of the Beta distribution as follows: a = ((mean2)*(1-mean)/(sd2)); b = (mean*(1-mean)/(sd2))((mean2)*(1-mean)/(sd2)).
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PAGE 91:
reference treatment in this case, because the number of studies (n=6) that the weighted
average rate was based on is the highest for integrated CSII+CGM and the Bergenstal et al
trial,37 from which the baseline population characteristics were derived, is one of these six
studies.
In addition, we conducted a scenario analysis in which a higher severe hypoglycaemic
episode rate from Hirsch et al4 is taken as the baseline rate for integrated CSII+CGM, and the
RRs from the indirect comparison in Chapter 5.3.4 are applied for other treatments. Severe
hypoglycaemic episode rates (number of events per 100 patient years) are given in Table 46
for each scenario.
Table 46: Severe hypoglycaemia rates (no of events per 100 pt years) for different scenarios
Intervention
Scenario 1
RR=1
MDI+SMBG
16.32
CSII+SMBG
16.32
CSII+CGM stand-alone
16.32
MiniMed Veo system
16.32
Integrated CSII+CGM (Vibe) 16.32
Scenario 2
RR=0.5
16.32
16.32
16.32
8.16
16.32
Scenario 3
RR=0.25
16.32
16.32
16.32
4.08
16.32
Scenario 4:
RR=0.125
16.32
16.32
16.32
2.04
16.32
Scenario 5:
Hirsch4
38.37
10.20
33
3.96
33
5.4.2.7 Non-zero death probability due to severe hypoglycemia
In the base case, the case fatality rate for severe hypoglycemia was taken as zero. This
assumption is in line with the updated CG153 and systematic review results, since none of the
included studies reported a death due to severe hypoglycemia.
As an extreme scenario, as in CG15, we assumed a case fatality rate of 4.9%, derived from
Ben-Ami et al136, where five patients were reported to die among 102 patients who had druginduced hypoglycemic coma.
5.4.2.8 QALY estimation method
In the base case, a multiplicative approach is applied for the QALY estimation. This
approach, in which the utility values of multiple events are multiplied to derive an overall
utility in case of multiple events/complications, is considered to be appropriate in this
condition, where simultaneous complications develop frequently118. As a scenario analysis,
the minimum approach will be used as an alternative QALY estimation method, where the
minimum of the multiple health state utility values is applied for patients having a history of
multiple events.
5.4.2.9 Different time horizons
In the base case, a lifetime analysis is achieved by selecting 80 years as the model time
horizon. As scenario analyses, a four year time horizon (the average lifetime of an insulin
pump) was selected and the effect of this time horizon on the results was explored.
5.4.2.10 Fear of hypoglycaemia unawareness
In the STAR-3 trial,10 patients using integrated CSII+CGM devices demonstrated an
improvement from baseline values on the “worry” subscale of the Hypoglycemia Fear Survey
98, compared to the MDI group. Later in Kamble et al 2012,67 this improvement was
translated into a utility increment of 0.0329 using the EQ-5D questionnaire index. As a
scenario analysis, we applied this utility increment associated with less fear of hypoglycaemia
throughout the remaining lifetimes of patients using integrated devices (the MiniMed
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Treatment effects
33. Treatment effects are estimated as the mean reduction from the baseline value from our systematic
review. This reduction is assumed to occur up to 12 months. After this, annual progression occurs. In
the base case we followed the CG15 update,3 which chose a type 1 diabetes trial, DCCT (annual
progression of 0.045%) for the base case and no progression in sensitivity analysis.
34. In the absence of data treatment effects of integrated CSII+CGM and non-integrated CSII+CGM
were assumed to be identical.
Disease natural history
35. The probability of death from severe hypoglycaemic event was assumed to be zero for the base
case.3 Other values were explored in separate scenarios.
5.6 Results of cost-effectiveness analyses
5.6.1 Base case results
The base case results from the full incremental analysis reported as cost per QALY gained
(ICER) per technology for type 1 diabetes adult patients are summarised in Table 48.
Table 48: Base case model results (all technologies) probabilistic simulation
MDI+SMBG
CSII+SMBG
QALYs
11.4146
11.9756
Cost
£61,050
£90,436
Incr. QALY
Incr. Cost
0.561
£29,386
ICER
£52,381
Extendedly dominated†
MiniMed Veo system
12.0412
£138,357
by CSII+CGM standalone
CSII+CGM stand12.0604
£146,476
0.0849
£56,039
£660,376
alone
Integrated
CSII+CGM 12.0604
Dominated by
£147,150
(Vibe)
CSII+CGM stand-alone
† An extendedly dominated strategy has an ICER higher than that of the next most effective strategy.
First note that since the same treatment effects were assumed for CSII+CGM stand-alone and
integrated, the latter is dominated (effectiveness is the same as in the stand-alone technology
but the integrated technology is more expensive as can be seen in Table 38). As expected
MDI+SMBG is the cheapest treatment but also the one providing the lowest amount of
QALYs. The ICER of CSII+SMBG compared to MDI+SMBG is £52,381. MiniMed
Paradigm Veo is extendedly dominated by CSII+CGM stand-alone. Essentially this means
that in a full incremental analysis, where all the interventions and comparators are considered,
CSII+CGM is better value than MiniMed Veo. This is because from our systematic review
the decrease on HbA1c with respect to baseline was highest for CSII+CGM stand-alone, and
this relatively small decrease in HbA1c leads to a decrease in the number of complications
that occur over life time to such an extent that it compensates for the higher number of
hypoglycaemic events. In any case, the ICER of CSII+CGM stand-alone compared to
CSII+SMBG is £660,376. Thus, given the common threshold ICER of £30,000, it is clear that
CSII+CGM stand-alone is not cost-effective.
Alternatively, we present in Table 49 the base case ICERs for the two interventions against
every comparator. Integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone.
Note that when the MiniMed Veo system is compared to CSII+CGM stand-alone the ICER
obtained is high (£422,849) but that this comes from both negative incremental QALYs and
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incremental costs, i.e. the ICER is in the south-west quadrant of the cost-effectiveness plane.
In this case, the cost savings outweighs the loss in QALYs and therefore the MiniMed Veo
system is cost-effective compared to CSII+CGM stand-alone. This might not be immediately
apparent when looking at the full incremental results in Table 48 because there MiniMed Veo
is in position of extended dominance. The lowest ICERs are obtained when the interventions
are compared to MDI+SMBG, but these are above £100,000 in the north-east quadrant of the
cost-effectiveness plane. When the interventions are compared to CSII+SMBG the highest
ICERs are obtained (around £700,000 in the north-east quadrant of the cost-effectiveness
plane). Thus, given the common threshold ICER of £30,000 the interventions are not costeffective.
Table 49: Base case model results (intervention versus comparator only) probabilistic
simulation
Intervention
MiniMed Veo system
MiniMed Veo system
MiniMed Veo system
Integrated CSII+CGM (Vibe)
Integrated CSII+CGM (Vibe)
Integrated CSII+CGM (Vibe)
Comparator
MDI+SMBG
CSII+SMBG
CSII+CGM stand-alone
MDI+SMBG
CSII+SMBG
CSII+CGM stand-alone
Incr. QALY
0.6266
0.0656
-0.0192
0.6458
0.0849
0
Incr. Cost
£77,307
£47,921
-£8,119
£86,100
£56,713
£674
ICER
£123,375
£730,501
£422,849
£133,323
£668,789
Undefined
In the deterministic simulation the cost-effectiveness results are very similar except that now
MiniMed Veo is not extendedly dominated by CSII+CGM stand-alone. These are shown in
Table 24. Although overall cost and QALY estimates are higher than in the probabilistic
simulation, the ICERs and the main conclusions from Table 50 are similar to the ones from
Table 48.
Table 50: Base case model results (all technologies) deterministic simulation
MDI+SMBG
CSII+SMBG
MiniMed Veo system
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
QALYs
12.1450
12.7258
12.8087
12.8223
12.8223
Cost
£62,927
£93,433
£143,309
£151,671
£152,372
Incr. QALY
Incr. Cost
ICER
0.5808
0.0829
0.0136
£30,506
£49,876
£8,363
£52,524
£601,641
£614,910
Dominated by
CSII+CGM stand-alone
The base case ICERs for the two interventions against every comparator in the deterministic
simulation are shown in Table 51. These are similar to those in Table 49 and so are the
conclusions.
Table 51: Base case model results (intervention versus comparator only) deterministic
simulation
Intervention
MiniMed Veo system
MiniMed Veo system
MiniMed Veo system
Integrated CSII+CGM (Vibe)
Integrated CSII+CGM (Vibe)
Integrated CSII+CGM (Vibe)
Comparator
MDI+SMBG
CSII+SMBG
CSII+CGM stand-alone
MDI+SMBG
CSII+SMBG
CSII+CGM stand-alone
Incr. QALY
0.6637
0.0829
-0.0136
0.6773
0.0965
0
Incr. Cost
£80,382
£49,876
-£8,363
£89,445
£58,939
£701
ICER
£121,112
£601,639
£614,910
£132,061
£610,772
Undefined
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When we looked at the break-down of the total costs, we observed that treatment costs always
represent the largest proportion of the total costs, independently of the treatment chosen. In
Figure 11, the treatment costs constitute 79% of the total direct costs for the MiniMed
Paradigm Veo system, and integrated and stand-alone CSII+CGM. For CSII+SMBG
treatment costs represent 66% of the total costs and for MDI+SMBG this is 41%. In each
treatment, foot ulcer/amputation/neuropathy cost category is the second largest, and eye
diseases and renal diseases are the third and fourth largest cost categories. MDI+SMBG has
higher complication (CVD, ulcer, eye disease, etc.) incidences, whereas for the other four
treatments these incidences are comparable. Lifetime hypoglycaemia events were reported the
least for the MiniMed Paradigm Veo system (0.622 severe hypoglycaemic events per patient),
and the highest for MDI+SMBG (5.412 severe hypoglycaemic event per patient).
Figure 11: Breakdown of costs per treatment
5.6.2 Results of the probabilistic sensitivity analyses
Statistical uncertainties in the model were investigated in the PSA. Since we compared five
treatments simultaneously, the scatter plot of the PSA outcomes in the cost-effectiveness (CE)
plane was not very informative (Figure 12). Nevertheless, we can observe a clear positive
correlation between costs and QALYs and that the treatments including CGM are similarly
scattered, showing that they are more expensive but also providing more QALYs.
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Figure 12: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
patients
The cost-effectiveness acceptability curves (CEACs) for each treatment are shown in Figure
13. These confirmed that only the treatments including SMBG are those considered costeffective. At ceiling ratio values lower than £52,381 MDI+SMBG was the treatment with the
highest probability of being cost-effective. When that threshold is exceeded then CSII+SMBG
was the treatment with the highest probability of being cost-effective. Note that for all the
three treatments including CGM the cost-effectiveness probability was zero for all the ceiling
ratios considered in the analysis. This is to be expected as the difference in costs between
CGM-treatments and SMBG-treatments was too large to outweigh the additional QALYs
gained by using CGM.
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Figure 13: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes patients
5.6.2.1 MDI non-suitable subgroup
As mentioned in Chapter 2.3 insulin pumps are recommended for people with type 1 diabetes
for whom MDI is not suitable. Therefore, we may question to what extent insulin pumps
(especially modern pumps such as the integrated systems) and MDI are used in comparable
populations. This seems a reasonable question in light of the lack of studies found in our
systematic review comparing these two treatments. When MDI+SMBG is not considered in
the analysis, the ICERs from the full incremental analysis are the same as those reported in
Table 48, but excluding the first row. It appears that CSII+SMBG is the strategy most likely
to be cost-effective, independently of the ceiling ratio value (up to 100,000/QALY), which
can be seen from Figure 14.
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Figure 15: Cost-effectiveness acceptability curves for CGM treatments in type 1 diabetes
patients
5.6.3 Results of scenario analyses
In the scenarios presented below only the ICERs from the full incremental analysis are
discussed. The ICERs for the two interventions against every comparator are shown in
Appendix 8.
5.6.3.1 Baseline population characteristics
In the scenario analysis, where the baseline population characteristics are updated as in the
updated CG15,3 the main results are comparable to the base case results as can be seen in
Table 52.
Table 52: Model results (all technologies), scenario with different baseline population
characteristics
MDI+SMBG
CSII+SMBG
QALYs
9.6117
10.0991
Cost
£65,070
£91,189
MiniMed Veo system
10.1474
£132,149
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
10.164
£139,157
10.164
£139,733
Incr. QALY
Incr. Cost
ICER
0.4874
£26,119
0.0649
£47,967
£53,588
Extendedly
dominated by
CSII+CGM
stand-alone
£738,593
Dominated by
CSII+CGM
stand-alone
MDI+SMBG is the intervention with minimum costs and QALYs gained. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERs of £53,588/QALY and
£738,593/QALY, respectively. Thus, given the common threshold ICER of £30,000 they are
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PAGE 101:
not cost-effective. MiniMed Veo and integrated CSII+CGM are extendedly dominated and
dominated, respectively, by CSII+CGM stand-alone.
5.6.3.2 Number of blood glucose tests per day
All the scenarios listed in Table 44 gave similar results. Compared to the base case, costs
decreased in the scenarios for treatments that require less than four blood glucose tests per
day and increased otherwise. Since all results were similar, we only present in Table 53 the
full incremental cost-effectiveness results of the scenario with two blood glucose tests per day
for CGM-containing treatments and eight blood glucose tests per day for SMBG. These eight
tests per day for SMBG represent the most cost-effective frequency as was shown in the
updated CG15.3
Table 53: Model results (all technologies), scenario with two (CGM) versus eight (SMBG)
blood glucose testing per day
MDI+SMBG
CSII+SMBG
QALYs
11.4146
11.9756
Cost
£68,460
£98,034
MiniMed Veo system
12.0412
£138,357
CSII+CGM stand-alone
12.0604
£146,476
Integrated CSII+CGM
(Vibe)
12.0604
£147,150
Incr. QALY
Incr. Cost
ICER
0.561
£29,574
0.0849
£48,441
£52,717
Extendedly
dominated by
CSII+CGM
stand-alone
£570,844
Dominated by
CSII+CGM
stand-alone
MDI+SMBG is the intervention with minimum costs and gain in QALYs. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERS of £52,717/QALY and
£570,844/QALY, respectively. Therefore, given the common threshold ICER of £30,000 they
are not cost-effective. MiniMed Veo and integrated CSII+CGM are extendedly dominated
and dominated, respectively, by CSII+CGM stand-alone.
5.6.3.3 Amount of insulin per day
In this scenario the costs in MDI+SMBG increased but this had a very small impact on the
cost-effectiveness results since all QALYs and the costs of the other treatments remained
unchanged. Since the main conclusions of the cost-effectiveness analyses were the same in
this scenario as in the base case, we do not present the results in a separate table for this
scenario here but in Appendix 8.
5.6.3.4 HbA1c progression
In this scenario no HbA1c progression after year one was assumed for each treatment. Table
54 summarises the model results.
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Table 54: Model results (all technologies), scenario with no HbA1c progression
MDI+SMBG
CSII+SMBG
QALYs
11.8715
12.4558
Cost
£58,520
£88,663
MiniMed Veo system
12.5228
£137,739
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
12.5398
£146,076
12.5398
£146,767
Incr. QALY
Incr. Cost
ICER
0.5843
£30,143
0.0840
£57,414
£51,615
Extendedly dominated
by CSII+CGM standalone
£683,889
Dominated by
CSII+CGM stand-alone
MDI+SMBG is the intervention with minimum costs and QALYs gained. CSII+SMBG and
CSII+CGM stand-alone are on the efficient frontier, with ICERS of £51,615/QALY and
£683,889/QALY, respectively. Therefore, they are not cost-effective given the common
threshold ICER of £30,000. The MiniMed Veo system and integrated CSII+CGM (Vibe) are
extendedly dominated and dominated, respectively, by CSII+CGM stand-alone.
5.6.3.5 Treatment effects part-I: HbA1c change in the first year
In this scenario analysis we assumed that the baseline HbA1c value is stabilised for one year
and that it does not change in any of the treatments (i.e. 0% change in HbA1c level in the first
year). The model results for this scenario can be seen in Table 55.
Table 55: Cost-effectiveness results when no treatment effect (in terms of HbA1c change) in
the first year is assumed (all technologies)
QALYs
12.0006
Cost
£146,632
Integrated CSII+CGM
(Vibe)
12.0006
£147,304
MDI+SMBG
CSII+SMBG
MiniMed Veo system
12.0016
12.0160
12.0260
£56,928
£90,178
£138,538
CSII+CGM stand-alone
Incr. QALY
Incr. Cost
ICER
Dominated
by
MDI+SMBG
Dominated
by
MDI+SMBG
0.0144
0.0099
£33,250
£48,360
£2,309,028
£4,871,356
The QALY expectations for all treatments are very similar. The minor differences in QALYs
can be explained due to the differences in severe hypoglycaemic episode rates. Note that
although the rate of severe hypoglycaemic events for MDI+SMBG was estimated higher than
the rate for integrated CSII+CGM in Chapter 5.3.4, MDI+SMBG resulted in a slightly higher
gain in QALYs which can be due to randomness. CSII+CGM systems were dominated by
MDI+SMBG. Furthermore, CSII+SMBG and the MiniMed Veo system are on the efficient
frontier but with extremely high ICER values. As can be seen in the resulting CEACs in
Figure 16, MDI+SMBG was the most cost-effective treatment for all the values of the ceiling
ratio considered in the analysis.
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Figure 16: Cost-effectiveness acceptability curves for all treatments when there is no HbA1c
treatment effect
5.6.3.6 Treatment effects part-II: severe hypoglycaemic event rates
When we used different RR (0.125, 0.25, 0.5 and 1) for the severe hypoglycaemic episode
rates for MiniMed Veo system, the results did not deviate significantly from the base case. In
all of the scenarios, MDI+SMBG was the cheapest intervention, MiniMed Veo system was
extendedly dominated by CSII+CGM stand-alone and integrated CSII+CGM was dominated.
Table 56 shows the results for the most extreme scenario which is obtained when RR=0.125.
For this RR, the different rates per 100 patient years can be seen in Table 46.
Table 56: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system severe
hypoglycaemic rate (all technologies)
Hypo MiniMed Veo
system RR=0.125
QALYs
Cost
MDI+SMBG
CSII+SMBG
11.4120
11.9597
£60,812
£91,195
MiniMed Veo system
12.0453
£138,333
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
12.0604
£146,476
12.0604
£147,150
Incr.
QALY
Incr. Cost
ICER
0.5477
£30,383
£55,474
Extendedly dominated by
CSII+CGM stand-alone
0.1007
£55,281
£549,080
Dominated by CSII+CGM
stand-alone
5.6.3.7 Non-zero death probability due to severe hypoglycemia
In this scenario we assumed a mortality due to severe hypoglycaemia equal to 4.9%, as
derived from Ben-Ami et al 1999.136 The model results can be seen in Table 57.
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Table 57: Cost-effectiveness results mortality due to severe hypoglycaemia scenario (all
technologies)
MDI+SMBG
CSII+CGM stand-alone
Integrated CSII+CGM
(Vibe)
CSII+SMBG
MiniMed Veo system
QALYs
11.1041
11.7701
11.7701
11.8781
12.0071
Cost
£58,510
£142,215
£142,872
£89,475
£137,801
Incr. QALY
0.774
0.129
Incr. Cost
ICER
£30,965
£8,326
Dominated by CSII+SMBG
Dominated by CSII+SMBG
£40,006
£374,531
In this scenario both integrated and stand-alone CSII+CGM were dominated by CSII+SMBG.
The ICER of CSII+SMBG compared to MDI+SMBG was £40,006 and the ICER of MiniMed
Veo compared to CSII+SMBG was £374,531. Thus, they are not cost-effective given the
common threshold ICER of £30,000. Both CE-plane scatter plot and CEACs are similar to
those in the base case scenario and therefore they are not shown here. When only the CGM
treatments were considered we observed that the probability of being cost-effective for
MiniMed Paradigm Veo was equal to 1 for almost all the values of the ceiling ratio
considered in the analysis. This can be seen in Figure 17.
Figure 17: Cost-effectiveness acceptability curves for CGM treatments only nonzero mortality
due to severe hypoglycaemia scenario
5.6.3.8 QALY estimation method
In this scenario we assumed the minimum approach as an alternative QALY estimation
method, where the minimum of the multiple health state utility values is applied for patients
having a history of multiple events. The results of this scenario can be seen in Table 58.
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Table 58: Cost-effectiveness results minimum QALY estimation method scenario (all
technologies)
MDI+SMBG
CSII+SMBG
MiniMed Veo
system
CSII+CGM
standalone
Integrated
CSII+CGM (Vibe)
QALYs
12.1327
12.5861
12.6408
12.6462
Cost
£61,050
£90,436
£138,357
£146,476
12.6462
£147,150
Incr. QALY
Incr. Cost
ICER
0.4534
0.0546
0.0601
£29,386
£47,920
£56,039
£64,813
£876,987
£932,305
Dominated by CSII+CGM
stand-alone
Results are similar to the base case scenario but here MiniMed Paradigm Veo is not
extendedly dominated by CSII+CGM stand-alone. All the ICERs are larger than £50,000; and
therefore the different treatments are not cost-effective given the common threshold ICER of
£30,000.
5.6.3.9 Different time horizon
In this scenario we assumed a four year time horizon, which corresponds to the average
lifetime of an insulin pump. The results can be seen in Table 59.
Table 59: Four year time horizon scenario (all technologies)
QALYs
2.7718
Cost
£6,706
2.7882
£24,803
Dominated by
CSII+SMBG
Integrated
CSII+CGM (Vibe)
2.7886
£24,939
Dominated by
CSII+SMBG
CSII+SMBG
MiniMed Paradigm
Veo
2.7906
2.7928
£13,365
£23,144
MDI+SMBG
CSII+CGM standalone
Incr. QALY
0.0188
0.0022
Incr. Cost
£6,659
£9,778
ICER
£354,202
£4,461,063
We observed that both stand-alone and integrated CSII+CGM are dominated by
CSII+SMBG. Although MiniMed Paradigm Veo is the treatment with the highest amount of
QALYs gained, its high cost when compared with CSII+SMBG does not outweigh the gain in
QALYs and results in an ICER equal to £4,461,063. Therefore, also in this scenario it is very
unlikely that MiniMed Paradigm Veo is chosen as cost-effective as it is illustrated by the
corresponding CEACs in Figure 18.
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Figure 18: Cost-effectiveness acceptability curves for all treatments four year time horizon
scenario
When only the CGM treatments are considered we observed that MiniMed Paradigm Veo is
clearly the treatment with the highest probability of being cost-effective as shown in Figure
19.
Figure 19: Cost-effectiveness acceptability curves for CGM treatments only; four year time
horizon scenario
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5.6.3.10 Fear of hypoglycaemia unawareness
Table 60 shows the results obtained when the utility increment from Kamble et al 2012 67
(0.0329) was used to represent the reduced fear of hypoglycaemia. We applied this utility
increment throughout the remaining lifetimes of patients using integrated devices (the
MiniMed Paradigm Veo system and integrated CSII+CGM). This benefit is not applied to
non-integrated devices (CSII+CGM stand-alone, CSII+SMBG and MDI+SMBG), as these
non-integrated devices do not give a warning nor activate/stop releasing of insulin
automatically based on low blood glucose levels.
Table 60: Cost-effectiveness results fear of hypoglycaemia scenario (all technologies)
QALYs
Cost
MDI+SMBG
11.4146
£61,050
CSII+SMBG
11.9756
£90,436
Incr. QALY
Incr. Cost
ICER
0.5610
£29,386
£52,381
Extendedly
dominated by
MiniMed Veo
system
CSII+CGM stand-alone
12.0604
£146,476
MiniMed Veo system
12.6224
£138,357
0.6468
£47,920
£74,088
Integrated CSII+CGM
(Vibe)
12.6429
£147,150
0.0205
£8,792
£428,595
The main difference with respect to the base case scenario is that here CSII+CGM stand-alone
is extendedly dominated by MiniMed Paradigm Veo, which has an ICER compared to
CSII+SMBG equal to £74,088. Moreover, integrated CSII+CGM is no longer dominated by
the corresponding stand-alone combination, as the utility increment for the integrated system
led to a larger number of QALYs accumulated compared to the non-intergrated options.
Nevertheless, the ICER of integrated CSII+CGM compared to MiniMed Paradigm Veo is still
very large (£428,595).
The scatter plot of the PSA outcomes in the CE plane is very similar to the one in the base
case scenario and therefore we decided not to show it here. The CEACs for each treatment are
shown in Figure 20. We observed that compared to the base case scenario, the probability of
being cost-effective for CSII+SMBG starts decreasing at approximately £60,000. As the
ceiling ratio increases the probability of being cost-effective for MiniMed Paradigm Veo and
integrated CSII+CGM also increases. At ceiling ratio values larger than (approximately)
£75,000 MiniMed Paradigm Veo was the treatment with the highest probability of being costeffective, followed by integrated CSII+CGM at ceiling ratio values larger than
(approximately) £90,000. Note that for CSII+CGM stand-alone the cost-effectiveness
probability was zero for all the ceiling ratios considered in the analysis.
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Figure 20: Cost-effectiveness acceptability curves for reduced fear of hypoglycaemia scenario
When only the CGM treatments were considered we observed similar CEACs (Figure 21) as
in the base case (Figure 14) but in this scenario the role of integrated and stand-alone
CSII+CGM was interchanged in the CEAC.
Figure 21: Cost-effectiveness acceptability curves for CGM treatments only fear of
hypoglycaemia scenario
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5.6.3.11 Cost of stand-alone insulin pump and continuous glucose monitoring device
In this scenario we assumed that the yearly cost of stand-alone CSII+CGM was estimated as
the average costs of the different stand-alone devices shown in Table 32 and Table 33 but
without the weighting for market share from White et al 2013.114, 115 Therefore, in this
scenario the estimated yearly cost of the stand-alone CSII+CGM was £5,460.19. The results
of this scenario can be seen in Table 61.
Table 61: Cost-effectiveness results cost of stand-alone CSII+CGM without market share
scenario (all technologies)
MDI+SMBG
CSII+SMBG
MiniMed Veo system
Integrated CSII+CGM
(Vibe)
CSII+CGM
stand-alone
QALYs
11.4146
11.9756
Cost
£61,050
£92,272
12.0412
£138,357
12.0604
£147,150
12.0604
£150,063
Incr. QALY
Incr. Cost
ICER
0.5610
£31,222
£55,654
Extendedly dominated by
Integrated CSII+CGM
0.0849
£54,878
£646,692
Dominated by Integrated
CSII+CGM
The main difference with respect to the base case scenario was that as expected stand-alone
CSII+CGM became more expensive than integrated CSII+CGM (Vibe). Since both
technologies are assumed to have the same efficacy, integrated CSII+CGM (Vibe) dominated
stand-alone CSII+CGM. The CEACs for each treatment are shown in Figure 22. These are
very similar to those in the base case scenario. The increase in cost of CSII+CGM stand-alone
had almost no impact on the cost-effectiveness probability since MDI+SMBG and
CSII+SMBG are the only strategies that are considered cost-effective.
Figure 22: Cost-effectiveness acceptability curves cost of stand-alone CSII+CGM without
market share scenario
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PAGE 117:
in the integrated CSII+CGM group, but hypoglycaemic AUC showed no significant difference.
Other outcomes showed no significant differences between groups.
For pregnant women we found only one trial comparing CSII+SMBG with MDI+SMBG which is
not relevant to the decision problem.
Cost-effectiveness
We assessed the cost-effectiveness of the MiniMed Paradigm Veo system and the Vibe and G4
PLATINUM CGM system compared with stand-alone CSII+CGM, CSII+SMBG, MDI+CGM,
and MDI+SMBG for the management of type 1 diabetes in adults.
Besides the literature limitations regarding the population subgroups of interest (i.e. children and
pregnant women) mentioned above, the model employed to conduct the cost-effectiveness
analyses, the IMS CDM, is not suitable to model long-term outcomes for children/adolescent and
pregnant women populations, because the background risk adjustment/ risk factor progression
equations are all based on adult populations.
The comparator MDI+CGM was not included in the cost-effectiveness analyses since no evidence
was found in the systematic review. Moreover, in the absence of data on comparing the clinical
effectiveness of integrated CSII+CGM systems against stand-alone CSII+CGM systems, we
assumed in our analyses that both technologies would be equally effective, which seems to be
plausible. The immediate consequence of this assumption is that stand-alone CSII+CGM systems
dominated the integrated CSII+CGM systems since the stand-alone system was cheaper,
according to our estimated cost, whilst being equally effective.
Overall, the cost-effectiveness results suggested that the technologies using SMBG (either with
CSII or MDI) are more likely to be cost-effective since the higher quality of life provided by the
technologies using CGM did not outweigh the increased costs. This is in line with the findings in
the currently updated T1DM guideline3 where CGM was compared to several SMBG setups and it
was found to be not cost-effective. In particular, the base case results showed that MDI+SMBG
was the cheapest treatment but also the one providing the lowest amount of QALYs. The ICER of
CSII+SMBG compared to MDI+SMBG was £52,381. MiniMed Paradigm Veo was extendedly
dominated by CSII+CGM stand-alone. This was mainly because from our systematic review the
decrease on HbA1c with respect to baseline was highest for integrated CSII+CGM, and this
relatively small decrease in HbA1c leads to a decrease in the number of complications that occur
over life time to such an extent that it compensates for the higher number of severe hypoglycaemic
events. In any case, the ICER of CSII+CGM stand-alone compared to CSII+SMBG was £660,376.
Thus, given the common threshold ICER of £30,000, it is clear that CSII+CGM stand-alone would
not be cost-effective.
We also considered two additional base case analyses. Since insulin pumps are recommended for
people with type 1 diabetes for whom MDI is not suitable, we excluded the MDI-containing
technology from the analysis. We observed that CSII+SMBG was the strategy most likely to be
cost-effective, with a cost-effectiveness probability almost equal to 1 for all the ceiling ratios
considered in the analysis. Afterwards, we also excluded SMBG treatments from the analysis in
order to capture the effect of the LGS function of the MiniMed Paradigm Veo which is expected
to have influence on reducing the number of severe hypoglycaemic events, and thus on the
number of QALYs gained. In this situation the only relevant comparison is MiniMed Veo versus
CSII+CGM stand-alone, since the Vibe and G4 PLATINUM CGM system was dominated by the
stand-alone combination of CSII+CGM. The
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PAGES 284-290:
Appendix 8: Results (full incremental and intervention versus comparator) of
base case and scenario analyses
Table 90: Base case model results (all technologies) probabilistic simulation
Incr.
Incr.
QALYs
Cost
ICER
QALY
Cost
MDI+SMBG
11.4146 £61,050
CSII+SMBG
11.9756 £90,436
MiniMed Veo system
12.0412 £138,357
CSII+CGM stand-alone
12.0604 £146,476
Integrated CSII+CGM
(Vibe)
0.561
£29,386
£52,381
Extendedly
dominated† by
CSII+CGM standalone
0.0849
£56,039
£660,376
Dominated by
CSII+CGM standalone
12.0604 £147,150
† An extendedly dominated strategy has an ICER higher than that of the next most effective strategy
Table 91: Base case model results (intervention versus comparator only) probabilistic
simulation
Incr.
Intervention
Comparator
Incr. Cost
ICER
QALY
MiniMed Veo system
MDI+SMBG
0.6266
£77,307
£123,375
MiniMed Veo system
CSII+SMBG
0.0656
£47,921
£730,501
MiniMed Veo system
CSII+CGM
stand-alone
-0.0192
-£8,119
£422,849
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6458
£86,100
£133,323
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.0849
£56,713
£668,789
Integrated CSII+CGM (Vibe)
CSII+CGM
stand-alone
0
£674
Undefined
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Table 92: Base case model results (all technologies) deterministic simulation
Incr.
QALY
Incr. Cost
ICER
£93,433
0.5808
£30,506
£52,524
12.8087
£143,309
0.0829
£49,876
£601,641
12.8223
£151,671
0.0136
£8,363
£614,910
QALYs
Cost
MDI+SMBG
12.1450
£62,927
CSII+SMBG
12.7258
MiniMed
system
Veo
CSII+CGM
stand-alone
Integrated
CSII+CGM
12.8223
Dominated by
CSII+ CGM
stand-alone
£152,372
(Vibe)
Table 93:
Base case model results (intervention versus comparator only)
deterministic simulation
Intervention
Comparator
MiniMed Veo system
MDI+SMBG
0.6637
£80,382
£121,112
MiniMed Veo system
CSII+SMBG
0.0829
£49,876
£601,639
MiniMed Veo system
CSII+CGM standalone
-0.0136
-£8,363
£614,910
MDI+SMBG
0.6773
£89,445
£132,061
CSII+SMBG
0.0965
£58,939
£610,772
CSII+CGM standalone
0
£701
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Incr. QALY Incr. Cost
ICER
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Table 94: Model results (all technologies), scenario with different baseline population
characteristics
QALYs
Cost
MDI+SMBG
9.6117
£65,070
CSII+SMBG
10.0991 £91,189
MiniMed Veo system
10.1474 £132,149
CSII+CGM stand-alone
10.164 £139,157
Integrated CSII+CGM
(Vibe)
Incr.
QALY
Incr.
Cost
ICER
0.4874
£26,119
£53,588
Extendedly
dominated by
CSII+CGM standalone
0.0649
£47,967
£738,593
Dominated by
CSII+CGM standalone
10.164 £139,733
Table 95: Model results (intervention versus comparator only), scenario with
different baseline population characteristics
Intervention
Comparator
MiniMed Veo system
MDI+SMBG
0.5357
£67,079
£125,217
MiniMed Veo system
CSII+SMBG
0.0483
£40,960
£848,028
MiniMed Veo system
CSII+CGM standalone
-0.0166
-£7,008
£422,148
MDI+SMBG
0.5523
£74,663
£135,186
CSII+SMBG
0.0649
£48,543
£747,971
CSII+CGM standalone
0
£576
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Incr. QALY Incr. Cost
ICER
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Table 96: Model results (all technologies), scenario with two (CGM) versus eight
(SMBG) blood glucose testing per day
QALYs
Cost
MDI+SMBG
11.4146 £68,460
CSII+SMBG
11.9756 £98,034
MiniMed Veo system
Incr.
Cost
ICER
0.561
£29,574
£52,717
Extendedly
dominated by
CSII+CGM standalone
12.0412 £138,357
CSII+CGM stand-alone 12.0604 £146,476
Integrated CSII+CGM
(Vibe)
Incr.
QALY
0.0849
£48,441
£570,844
Dominated by
CSII+CGM standalone
12.0604 £147,150
Table 97: Model results (intervention versus comparator only), scenario with two
(CGM) versus eight (SMBG) blood glucose testing per day
Intervention
Comparator
MiniMed Veo system
MDI+SMBG
0.6266
£69,897
£111,550
MiniMed Veo system
CSII+SMBG
0.0656
£40,323
£614,683
MiniMed Veo system
CSII+CGM standalone
-0.0192
-£8,119
£422,849
MDI+SMBG
0.6458
£78,690
£121,849
CSII+SMBG
0.0849
£49,116
£579,194
CSII+CGM standalone
0
£674
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Incr. QALY Incr. Cost
ICER
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Table 98: Model results (all technologies), scenario with increased amount of daily
insulin for MDI
QALYs
Cost
MDI+SMBG
11.4146
£62,114
CSII+SMBG
11.9756
£90,437
MiniMed Veo system
Incr.
Cost
ICER
0.5610
£28,323
£50,487
Extendedly
dominated by
CSII+CGM standalone
12.0412 £138,358
CSII+CGM stand-alone 12.0604 £146,476
Integrated CSII+CGM
(Vibe)
Incr.
QALY
0.0849
£56,040
£660,376
Dominated by
CSII+CGM standalone
12.0604 £147,150
Table 99: Model results (intervention versus comparator only), scenario with
increased amount of daily insulin for MDI
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6266
£76,244
£121,679
MiniMed Veo system
CSII+SMBG
0.0656
£47,921
£730,501
MiniMed Veo system
CSII+CGM standalone
-0.0192
-£8,119
£422,849
MDI+SMBG
0.6458
£85,036
£131,675
CSII+SMBG
0.0848
£56,713
£668,789
CSII+CGM standalone
0
£674
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 100: Model results (all technologies), scenario with no HbA1c progression
QALYs
Cost
MDI+SMBG
11.8715
£58,520
CSII+SMBG
12.4558
£88,663
MiniMed Veo system
Incr.
Cost
ICER
0.5843
£30,143
£51,615
Extendedly
dominated by
CSII+CGM
stand-alone
12.5228 £137,739
CSII+CGM stand-alone 12.5398 £146,076
Integrated CSII+CGM
(Vibe)
Incr.
QALY
0.0840
£57,414
£683,889
Dominated by
CSII+CGM
stand-alone
12.5398 £146,767
Table 101: Model results (intervention versus comparator only), scenario with no
HbA1c progression
Intervention
Comparator
Incr.
QALY
Incr.
Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6513
£79,219
£121,632
MiniMed Veo system
CSII+SMBG
0.067
£49,076
£732,483
MiniMed Veo system
CSII+CGM standalone
-0.017
-£8,337
£490,424
MDI+SMBG
0.6683
£88,247
£132,047
CSII+SMBG
0.084
£58,104
£691,715
CSII+CGM standalone
0
£690
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 102: Cost-effectiveness results when no treatment effect (in terms of HbA1c
change) in the first year is assumed (all technologies)
Incr.
QALY
QALYs
Cost
CSII+CGM standalone
12.0006
£146,632
Dominated by
MDI+SMBG
Integrated
CSII+CGM (Vibe)
12.0006
£147,304
Dominated by
MDI+SMBG
MDI+SMBG
12.0016
£56,928
CSII+SMBG
12.016
£90,178
0.0144
£33,250
£2,309,028
12.026
£138,538
0.0099
£48,360
£4,871,356
MiniMed
system
Veo
Incr. Cost
ICER
Table 103: Cost-effectiveness results when no treatment effect (in terms of HbA1c
change) in the first year is assumed (intervention versus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.0244
£81,610
£3,344,672
MiniMed Veo system
CSII+SMBG
0.0099
£48,360
£4,871,356
MiniMed Veo system
CSII+CGM standalone
0.0254
-£8,093
-£318,634
MDI+SMBG
-0.0009
£90,376
-£100,417,778
CSII+SMBG
-0.0154
£57,126
-£3,709,460
CSII+CGM standalone
0
£672
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 104: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system
severe hypoglycaemic rate (all technologies)
Hypo MiniMed Veo
QALYs
system RR=0.125
Cost
MDI+SMBG
11.412
£60,812
CSII+SMBG
11.9597
£91,195
MiniMed Veo system
Incr. Cost
ICER
0.5477
£30,383
£55,474
Extendedly
dominated by
CSII+CGM standalone
12.0453 £138,333
CSII+CGM stand-alone 12.0604 £146,476
Integrated CSII+CGM
(Vibe)
Incr.
QALY
0.1007
£55,281
£549,080
Dominated by
CSII+CGM standalone
12.0604 £147,150
Table 105: Cost-effectiveness results RR=0.125 is used for the MiniMed Veo system
severe hypoglycaemic rate (intervention versus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6333
£77,521
£122,408
MiniMed Veo system
CSII+SMBG
0.0856
£47,138
£550,675
MiniMed Veo system
CSII+CGM standalone
-0.0151
-£8,143
£539,295
MDI+SMBG
0.6484
£86,338
£133,155
CSII+SMBG
0.1007
£55,955
£555,659
CSII+CGM standalone
0
£674
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 106: Cost-effectiveness results mortality due to severe hypoglycaemia scenario
(all technologies)
QALYs
Cost
11.1041
£58,510
11.7701
£142,215
Dominated by
CSII+SMBG
Integrated
CSII+CGM (Vibe)
11.7701
£142,872
Dominated by
CSII+SMBG
CSII+SMBG
11.8781
£89,475
0.774
£30,965
£40,006
MiniMed Veo system
12.0071
£137,801
0.129
£8,326
£374,531
MDI+SMBG
CSII+CGM
alone
stand-
Incr. QALY Incr. Cost
ICER
Table 107: Cost-effectiveness results mortality due to severe hypoglycaemia scenario
(intervention versus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.9029
£79,291
£87,818
MiniMed Veo system
CSII+SMBG
0.1290
£48,327
£374,626
MiniMed Veo system
CSII+CGM standalone
0.2369
-£4,413
-£18,622
MDI+SMBG
0.6659
£84,362
£126,689
CSII+SMBG
-0.1079
£53,397
-£494,418
CSII+CGM standalone
0
£ 657
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 108: Cost-effectiveness results minimum QALY estimation method scenario
(all technologies)
Incr.
QALY
Incr. Cost
ICER
£90,436
0.4534
£29,386
£64,813
12.6408
£138,357
0.0546
£47,920
£876,987
12.6462
£146,476
0.0601
£56,039
£932,305
QALYs
Cost
MDI+SMBG
12.1327
£61,050
CSII+SMBG
12.5861
MiniMed Veo
system
CSII+CGM
stand-alone
Integrated
CSII+CGM
(Vibe)
12.6462
Dominated by
CSII+CGM standalone
£147,150
Table 109: Cost-effectiveness results minimum QALY estimation method scenario
(intervention versus comparator only)
Intervention
Comparator
MiniMed Veo system
MDI+SMBG
0.5081
£77,307
£152,149
MiniMed Veo system
CSII+SMBG
0.0547
£47,921
£876,067
MiniMed Veo system
CSII+CGM standalone
-0.0054
-£8,119
£1,503,465
MDI+SMBG
0.5135
£86,100
£167,673
CSII+SMBG
0.0601
£56,713
£943,649
CSII+CGM standalone
0
£674
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Incr. QALY Incr. Cost
ICER
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Table 110: Four year time horizon scenario (all technologies)
Cost
MDI+SMBG
2.7718
£6,706
CSII+CGM
stand-alone
2.7882
£24,803
Dominated by
CSII+SMBG
Integrated
CSII+CGM
(Vibe)
2.7886
£24,939
Dominated by
CSII+SMBG
CSII+SMBG
2.7906
£13,365
0.0188
£6,659
£354,202
2.7928
£23,144
0.0022
£9,778
£4,461,063
MiniMed
system
Veo
Incr. QALY
Incr.
Cost
QALYs
ICER
Table 111: Four year time horizon scenario (intervention versus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.0210
£16,438
£782,762
MiniMed Veo system
CSII+SMBG
0.0022
£9779
£4,445,000
MiniMed Veo system
CSII+CGM standalone
0.0046
-£1659
-£360,652
Integrated CSII+CGM
(Vibe)
MDI+SMBG
0.0168
£18,233
£1,085,298
Integrated CSII+CGM
(Vibe)
CSII+SMBG
-0.0020
£11,574
-£5,787,000
Integrated CSII+CGM
(Vibe)
CSII+CGM standalone
0.0004
£136
£340,000
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Table 112:
technologies)
Cost-effectiveness results fear of hypoglycaemia scenario (all
QALYs
Cost
MDI+SMBG
11.4146
£61,050
CSII+SMBG
11.9756
£90,436
CSII+CGM
alone
stand-
Incr.
QALY
Incr. Cost
ICER
0.5610
£29,386
£52,381
Extendedly
dominated by
MiniMed Veo
system
12.0604
£146,476
MiniMed Veo system 12.6224
£138,357
0.6468
£47,920
£74,088
Integrated
CSII+CGM (Vibe)
£147,150
0.0205
£8,792
£428,595
12.6429
Table 113: Cost-effectiveness results fear of hypoglycaemia scenario (intervention
vsersus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
1.2077
£77,307
£64,012
MiniMed Veo system
CSII+SMBG
0.6468
£47,921
£74,088
MiniMed Veo system
CSII+CGM standalone
0.5619
-£8,119
-£14,448
MDI+SMBG
1.2282
£86,100
£70,103
CSII+SMBG
0.6468
£47,921
£74,089
CSII+CGM standalone
0.5824
£674
£1,157
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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Table 114: Cost-effectiveness results cost of stand-alone CSII+CGM without market
share scenario (all technologies)
QALYs
Cost
MDI+SMBG
11.4146
£61,050
CSII+SMBG
11.9756
£92,272
Incr.
QALY
Incr. Cost
ICER
0.561
£31,222
£55,654
Extendedly
dominated by
Integrated
CSII+CGM
MiniMed Veo system
Integrated
CSII+CGM (Vibe)
CSII+CGM
alone
12.0412
£138,357
12.0604
£147,150
0.0849
£54,878
Dominated by
Integrated
CSII+CGM
stand12.0604
£646,692
£150,063
Table 115: Cost-effectiveness results cost of stand-alone CSII+CGM without market
share scenario (intervention versus comparator only)
Intervention
Comparator
Incr.
QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.6266
£77,307
£123,375
MiniMed Veo system
CSII+SMBG
0.0656
£46,086
£702,530
MiniMed Veo system
CSII+CGM standalone
-0.0192
-£11,705
£609,635
MDI+SMBG
0.6458
£86,100
£133,323
CSII+SMBG
0.0848
£54,878
£647,146
CSII+CGM standalone
0
-£2,913
Undefined
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
Integrated
(Vibe)
CSII+CGM
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in collaboration with:
ADDENDUM TO
Type 1 diabetes: Integrated sensor-augmented pump therapy
systems for managing blood glucose levels (The MiniMed Paradigm
Veo System and the Vibe and G4 PLATINUM CGM system)
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Addendum by the EAG documenting what information would need to be available for a
model to be developed for children and adolescents
As mentioned in Chapter 4 of the DAR, there is a lack and/or poor quality of age specific
effectiveness data for the interventions/comparators in question for children and adolescents,
causing uncertainty regarding the clinical effectiveness of MiniMed Paradigm Veo and
integrated CSII+CGM systems. This lack of effectiveness data also hinders the costeffectiveness analysis of these interventions. In addition, there are currently no health
economic models available in diabetes (to the best of the EAG’s knowledge) that are
designed and validated for a population of children and adolescents. As outlined in section
5.7.2 of the DAR, the model used for the adult population, the IMS CDM, cannot be applied
to children. Below we propose a list with suggested HE model requirements for T1DM
children and adolescents and an overview of the data requirements for such a new HE model.
Suggested requirements for a HE model for children and adolescents in diabetes type I
1. The model should incorporate the long term consequences of hypoglycaemia and
ketoacidosis such as cognitive impairment or cerebral oedema. If there are additional
relevant complications for children, this should be added (note that some of the
complications for adults may not be relevant for children).
2. Since the rate of severe hypoglycaemic/ketoacidosis events as well as the treatment
effect on these rates differs between children and adults, a model with the flexibility
to incorporate age specific effects of treatment on the rates of severe hypoglycaemic
episodes and ketoacidosis is needed.
3. The model would need to be able to reflect the possible differences of costs, utilities
and disease natural history parameters between children/adolescents and adults. This
can be achieved by using different cost/utility and disease natural history input sets
for different age-specific patient groups.
4. Since the treatment benefits (of lowering HbA1c) may be seen later than 1 year in
children, the model should have the flexibility to incorporate treatment related change
in HbA1c level beyond the first 12 months.
5. Some additional disease management categories can be relevant for children/
adolescents such as screening/management of eating disorders and anxiety. Also it is
uncertain whether some of the disease management parameters (like proportion on
ACE-inhibitor treatment) are the same for adults and children. Additional relevant
children/adolescent specific disease management categories should be added and
children/ adolescent specific disease management parameters should be incorporated.
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Data requirements
When a model is developed according to the suggestions above, additional data will be
needed to populate the model.
The most urgent data requirements concern data on effectiveness of the various treatment
options (i.e. MiniMed Paradigm Veo, integrated CSII+CGM systems and their comparators,
see also Chapter 4) and transition probabilities/risk equations for T1DM related
complications. The current IMS CDM includes risk equations that are based on adult
populations that cannot be extrapolated to children. Therefore, it is important to either find
existing longitudinal data to derive children specific risk equations, or to set up new studies to
estimate the children/adolescent specific risk of the various diabetes related complications.
In general, some of the input parameters in a new diabetes model may be estimated/derived
from literature. Where this is not available, databases may be available, for example for
changes in HbA1c over time or for resource use. Otherwise, parameters may be informed by
expert opinion and new studies. If new studies are being set up, the design should vary
according to the type of parameter, for example effectiveness parameters should ideally be
informed by an RCT, whereas utility estimates could be found with a cross-sectional
observational study.
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in collaboration with:
ADDENDUM TO
Type 1 diabetes: Integrated sensor-augmented pump therapy
systems for managing blood glucose levels (The MiniMed Paradigm
Veo System and the Vibe and G4 PLATINUM CGM system)
Addendum by the EAG documenting additional data and analyses
requested by NICE after the first Diagnostics Advisory Committee Meeting
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TABLE OF CONTENTS
TABLE OF TABLES........................................................................................................... 3
TABLE OF FIGURES ......................................................................................................... 5
Details of additional analyses requested by NICE ............................................................ 6
1.
Clinical effectiveness .................................................................................................. 7
1.1 Clinical effectiveness – cross-over studies .................................................................. 7
1.2 Clinical effectiveness – observational studies ........................................................... 11
2.
Cost-effectiveness Analysis ..................................................................................... 18
2.1 Review of the economic evaluation by Roze et al. .................................................... 18
2.2 Formal comparison between Roze et al. UK study (2015) and MiniMed DAR ....... 23
2.3 Focused review of severe hypoglycaemic event parameters ..................................... 31
2.3.1 Methods.............................................................................................................. 31
2.3.2 Results ................................................................................................................ 32
2.4 Additional Cost-Effectiveness Analyses ................................................................... 36
2.4.1 Population 1: Adults with difficulty maintaining target HbA1c (>8.5%) ......... 36
2.4.2 Population 2: Adults experiencing frequent hypoglycaemic events .................. 40
2.4.3 Results of cost effectiveness analyses................................................................ 44
2.4.4 Conclusions ........................................................................................................ 69
2.4.5 Discussion .......................................................................................................... 70
References ........................................................................................................................... 72
Appendix 1 Data extraction tables ............................................................................... 77
Appendix 2 Literature search strategies ..................................................................... 82
Appendix 3 Technical calculations on the treatment effects ..................................... 90
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TABLE OF TABLES
Table 1: Included studies and comparisons .............................................................................. 7
Table 2: Characteristics of included studies ............................................................................. 7
Table 3: Risk of Bias assessment for all included studies ........................................................ 8
Table 4: In/exclusion criteria used in included studies for HbA1c and hypoglycaemic events8
Table 5: Baseline characteristics of study participants ............................................................. 9
Table 6: Results for the integrated CSII+CGM system versus CSII+SMBG at end of study
(n=147)....................................................................................................................................... 9
Table 7: Summary of Roze et al. paper................................................................................... 19
Table 8: Quality assessment of the Roze et al. study, using Drummond 1996....................... 20
Table 9: Main outcomes of Roze et al. study (base case and scenario 7) and DAR (base case
scenario) ................................................................................................................................... 23
Table 10: Differences in general simulation settings (structural uncertainty). ........................ 24
Table 11: Main differences in baseline characteristics. ........................................................... 25
Table 12: Breakdown of incremental complication costs (MiniMed Veo vs. CSII + SMBG).
.................................................................................................................................................. 26
Table 13: Treatment costs. ....................................................................................................... 27
Table 14: Utilities. ................................................................................................................... 27
Table 15: Treatment effects. .................................................................................................... 28
Table 16: Results of the different scenarios. ............................................................................ 30
Table 17: Utility decrements .................................................................................................... 34
Table 18: Mortality .................................................................................................................. 35
Table 19: Baseline cohort characteristics ................................................................................ 37
Table 20: Treatment effects for base case analysis of population 1. ....................................... 38
Table 21: Treatment effects in scenario 1 for population 1. .................................................... 39
Table 22: Treatment effects in scenario 2 of population 1. ..................................................... 39
Table 23: Treatment effects in scenario 3 of population 1. ..................................................... 40
Table 24: Treatment effects in scenario 4 of population 1. ..................................................... 40
Table 25: Baseline cohort characteristics (population 2) ......................................................... 41
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Table 26: Treatment effects for the base case analysis of population 2. ................................. 42
Table 27: Treatment effects in scenario 1 for population 2. .................................................... 43
Table 28: Treatment effects that will be used in scenario 2 for population 2. ......................... 43
Table 29: Base case scenario first population (all technologies) ............................................. 44
Table 30: Base case scenario first population (intervention vs. comparator only) .................. 45
Table 31: Scenario 1 first population (all technologies) .......................................................... 47
Table 32: Scenario 1 first population (intervention vs. comparator only) ............................... 48
Table 33: Scenario 2 first population (all technologies) .......................................................... 50
Table 34: Scenario 2 first population (intervention vs. comparator only) ............................... 51
Table 35: Scenario 3 first population (all technologies) .......................................................... 53
Table 36: Scenario 3 first population (intervention vs. comparator only) ............................... 53
Table 37: Scenario 4 first population (all technologies) .......................................................... 55
Table 38: Scenario 4 first population (intervention vs. comparator only) ............................... 55
Table 39: Base case scenario second population (all technologies) ........................................ 57
Table 40: Base case scenario second population (intervention vs. comparator only) ............. 58
Table 41: Scenario 1 second population (all technologies) ..................................................... 60
Table 42: Scenario 1 second population (intervention vs. comparator only) .......................... 61
Table 43: Scenario 2 second population (all technologies) ..................................................... 62
Table 44: Scenario 2 second population (intervention vs. comparator only) .......................... 63
Table 45: Scenario 3 second population (all technologies) ..................................................... 64
Table 46: Scenario 3 second population (intervention vs. comparator only) .......................... 65
Table 47: Cost-effectiveness results where dominance did not occur for the first population 67
Table 48: Cost-effectiveness results where dominance did not occur for the second population
.................................................................................................................................................. 68
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TABLE OF FIGURES
Figure 1: HbA1c progression Roze et al. UK study. ............................................................... 29
Figure 2: Evidence network when studies with baseline HbA1c<8.5 and studies that include
more than 50% children are excluded ...................................................................................... 37
Figure 3: Evidence network used in the analysis of population 1 ........................................... 38
Figure 4: Evidence network when studies with baseline HbA1c > 8.5 and studies that include
more than 50% children are excluded ...................................................................................... 41
Figure 5: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
adult patients with difficulties in maintaining their target HbA1c level (<8.5%) – base case 46
Figure 6: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – base case .......................... 47
Figure 7: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – scenario 1 ......................... 49
Figure 8: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – scenario 2 ......................... 52
Figure 9: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulties in controlling their HbA1c target level – scenario 3 ........................ 54
Figure 10: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulties in controlling their HbA1c target level – scenario 4 ........................ 56
Figure 11: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
adult patients experiencing frequent hypoglycaemic events ................................................... 59
Figure 12: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events ............................................................ 60
Figure 13: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 1 ........................................ 62
Figure 14: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 2 ........................................ 64
Figure 15: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 3 ........................................ 66
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Details of additional analyses requested by NICE

Population for additional base cases:
o Adults with difficulty maintaining target HbA1c (>8.5%)
o Adults experiencing frequent hypoglycaemic events (Whether the existing
scenario analysis could become the base case for this population).
o Children with difficulty managing HbA1c
o Children experiencing frequent hypoglycaemic events.

Considerations for the clinical effectiveness analysis:
o Observational studies reporting data for the MiniMed Paradigm Veo and Vibe
and G4 PLATINUM CGM (or proxy for consistency) should be included in a
narrative analysis for adults and for children, particularly where they report
results from a relevant population (e.g. Choudhary study for nocturnal
hypoglycaemia). Consideration should also be given to the data from cross
over studies which the clinical experts suggested were relevant to the decision
problem (e.g. the SWITCH study).
o Relevant estimates from the narrative analysis should be used in the economic
modelling where possible

Considerations for the economic analyses:
o Formal comparison of the ICERs reported in the Medtronic AIC manuscript
and those reported in the DAR (and in the additional analyses)
o Scenario analysis where clinical data from the proxy integrated sensoraugmented pump therapy system is applied to the MiniMed Paradigm Veo
o Sensitivity analysis around HbA1c
o Exploration of uncaptured disutility for hypoglycaemic events – the DAC
raised particular concern around the impact of nocturnal hypoglycaemia which
may be picked up by the interventions and prevent downstream hypo
unawareness)
o Exploration of utility associated with good control of diabetes
o Consideration of the impact of duration of sensor use on outcomes.
o Exploration of the trade-off between short and long-term outcomes, it was
suggested that including young adult aged 20-30 years as a subgroup could be
a way of eliciting the difference.

Written response to DAR consultation comments table (as per standard DAR
consultation response process), including commentary on the likely impact (if any) of
the alternative parameter values suggested by stakeholders.
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1.
Clinical effectiveness
1.1
Clinical effectiveness – cross-over studies
We checked the list of excluded studies to find all studies that were excluded on the grounds
of being a cross-over study only, and found three studies that met these criteria:
-
The SWITCH study1-3
Radermecker et al. (2010)4
Hanaire-Broutin et al. (2000)5
The results of these three studies will be discussed below. However, as these are cross-over
studies, the results cannot be compared with parallel studies in a network analysis.
Nevertheless, the results can be used to inform the economic analyses.
One study compared an integrated CSII+CGM system with CSII+SMBG, one study
compared CSII+CGM (stand alone) with CSII+SMBG and one study compared CSII+SMBG
with MDI+SMBG.
SWITCH recruited patients at four adult and four paediatric sites in Europe (Austria,
Denmark, Italy, Luxembourg, Netherland, Slovenia, Spain, and Sweden). The study by
Radermecker was performed in Belgium and France and the study by Hanaire-Broutin et al.
in France. None of these studies included patients from the UK.
Table 1: Included studies and comparisons
Study ID
Veo CSII+CGM
integrated
The SWITCH study1-3
Radermecker et al. (2010)4
Hanaire-Broutin et al. (2000)5
CSII+
CGM
CSII+
SMBG





MDI+
CGM
MDI+
SMBG

All three studies reported data for adults. In addition, the SWITCH trial also reported data for
children (see Table 2).
Table 2: Characteristics of included studies
Study ID
Population
(Age
range)
M (6-64)
A (21-64)
The SWITCH study1-3
C (6-18)
4
A (NR)
Radermecker et al. (2010)
Hanaire-Broutin et al. (2000)5 A (21-65)
Baseline
Age,
Mean (SD)
28 (17)
42 (11)
12 (3.4)
47 (11)
43.5 (10.3)
Baseline
HbA1c (%)
Mean, SD
8.4 (0.7)
8.3 (0.6)
8.5 (0.7)
8.3 (0.4)
8.39 (0.87)
Pump
use
Follow-up
(months)
>6m
2x6m
>12m
NR
2x3m
2x4m
A=Adults, C=Children, M=Mixed, NR=Not reported; m=months.
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Two out of three studies include patients who are pump experienced, while this is not
reported in the third study. Both the SWITCH trial and Radermecker et al. (2010)
included patients with poor control at baseline.
Two out of three trials were rated as high risk of bias. However, the SWITCH trial
was rated as low risk of bias (see Table 3).
Table 3: Risk of Bias assessment for all included studies
Study ID
SWITCH
Radermecker 2010
Hanaire-Broutin
2000
Random
sequence
generatio
n
Low
Unclear
Unclear
Allocatio
n
Concealment
Low
Unclear
Unclear
Particip
ant
blindin
g
High
High
High
Care
staff
blindin
g
High
High
High
Outcome
assessor
blinding
Selective
outcome
reporting
Incomplet
e data
Overal
l
High
High
High
Low
Unclear
Low
Low
High
Low
Low
High
High
The SWITCH trial included two treatment periods of 6 months duration, with a 4month washout phase between the two periods. In the trial by Radermecker et al., two
consecutive 12-week periods were included, without a wash-out period. The trial by
Hanaire-Broutin et al. did not include a wash-out period either; but the authors
reported that “All of the results could be analyzed during the 2 periods of treatment,
because no carry-over effect was observed”. However, it was not clear how this was
assessed.
Overall, the SWITCH trial seems the most reliable study out of these three cross-over
trials, with low risk of bias, and minimal chance of carry-over effects of treatments
between periods.
Table 4 shows the inclusion criteria regarding HbA1c and hypoglycaemic events used
in the included studies.
Table 4: In/exclusion criteria used in included studies for HbA1c and hypoglycaemic events
Study ID
In/exclusion criteria regarding
HbA1c
hypoglycaemia
The SWITCH study1-3
7.5 – 9.5%
Excluded: ≥3 incidents of severe hypoglycaemia in the last 12 months, and a
history of hypoglycaemia unawareness
(i.e. hypoglycemia without symptoms)
4
Radermecker et al. (2010)
NR
NR
5
Hanaire-Broutin et al. (2000)
< 10%
None of the patients had a history of
hypoglycemia unawareness
The results of the SWITCH trial will be discussed below. As the other two cross-over
studies did not include a comparison with the MiniMed Veo system or with an
integrated CSII+CGM system, and because these studies cannot be combined with
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parallel studies in a network analysis, the results of the other two cross-over studies
will not be discussed. Full details of all three trials are reported in Appendix 1.
Integrated CSII+CGM versus CSII+SMBG
One study compared the integrated CSII+CGM system (Mini-Med Paradigm REALTime System with CGM (Guardian REAL-Time Clinical), Medtronic) with
CSII+SMBG (Mini-Med Paradigm REAL-Time System, Medtronic – Sensor-off) in a
mixed population of adults and children (The SWITCH trial). Children and adults
(n=153) on CSII with HbA1c 7.5–9.5% (58.5–80.3 mmol/mol) were randomised to
(CGM) a Sensor On or Sensor Off arm for 6 months. After 4 months’ washout,
participants crossed over to the other arm for 6 months.
The baseline characteristics and results of this study are reported in the tables below.
Table 5: Baseline characteristics of study participants
Sequence OFF/ON
Characteristic
All participants
Adults
Children
Sample size, n
Mean age (years)
Male sex, n (%)
HbA1c (%)
Time since diagnosis
of diabetes (years)
Time since start of
CSII (years)
Sequence ON/OFF
All participants
Adults Children
76
28±17
37 (49)
8.5±0.6
14±10
41
42±11
20 (49)
8.4±0.6
21±8.9
35
12±3.2
17 (49)
8.5±0.6
6.3±3.1
77
28±16
42 (54)
8.3±0.7
16±12
40
42±10
18 (45)
8.1±0.5
24±11
37
12±3.6
24 (65)
8.6±0.7
7.4±4.1
5.1±4.1
6.4±4.8
3.5±2.2
5.0±4.2
6.3±5.3
3.5±1.7
Values are presented as mean±SD, unless stated otherwise. Observed paediatric group (6 to 18 years); observed
adult group (21 to 64 years)
Table 6: Results for the integrated CSII+CGM system versus CSII+SMBG at end of study (n=147)
Integrated CSII+CGM
CSII+SMBG
Difference between groups
Change in HbA1c:
- All patients
8.04%
8.47%
-0.43% (95% CI: -0.32, -0.55)
-0.41% (95% CI: -0.28, -0.53)
- Adults
-0.46% (95% CI: -0.26, -0.66)
- Children
Time spent with a sensor
19 min/day
31 min/day
p = 0.009
glucose level <3.9 mmol/l
Average daily min spent
669±208
774±232
p < 0.001
in euglycaemia (3.9−10.0
mmol/l)
Average daily min >10.0
429 (307–568)
348 (227–487)
p < 0.001
mmol/l; median
(interquartile range)
Average daily AUC <3.9
71 (20–195)
41 (15–113)
p = 0.002
mmol/l per 24 hb; median
(interquartile range)
Average daily AUC >13.9
1362 (548–3,242)
722 (210–2,043)
p = <0.001
mmol/l per 24 hb; median
(interquartile range)
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MAGE (mmol/l)
Overall HRQOL
(PedsQL) – Children
only. Mean (±SE) change
Overall treatment
satisfaction (DTSQ) –
Adults only. Change
versus baseline
At least one adverse event
(95% CI)
Severe hypoglycaemic
events
Diabetic ketoacidosis
events
Integrated CSII+CGM
5.05
CSII+SMBG
4.61
Difference between groups
p = 0.6075
Child: -0.31 ± 0.84; p = 0.712
Parent: -3.92 ± 1.18; p = 0.002
(Not considered clinically
significant)
1.16; p = 0.010 (favours
integrated system)
44.9% (36.4–53.7)
50.4% (41.7–59.1%)
-5.5 %; p = 0.3467
4 (5.70 per 100
patient-years)
2
2 (2.83 per 100
patient-years)
4
p = 0.40
p = 0.47
Summary statistics (mean, SD, median and inter-quartile range) are reported as statistically appropriate;
AUC=Area under the curve; MAGE=Mean amplitude of glycaemic excursions; PedsQL=Pediatric quality of
life inventory; DTSQ=Treatment Satisfaction Questionnaire; CI=Confidence Interval
Mean sensor use was 80% (median 84%) of the required time (mean 81% over the
final 4 weeks). In the paediatric group, mean sensor use was 73% (median 78%) of
the required time (mean 74% over the final 4 weeks); in the adult group mean sensor
use was 86% (median 89%) of the required time (mean 87% over the final 4 weeks).
A total of 72% of participants used the sensor ≥70% of the required time; 24% (37
participants) >90% of the required time. The decrease in HbA1c was smaller in the
group that used the sensor <70% of the required time (mean±SD: −0.24±1.11%
[−2.6±12.1 mmol/mol]; p=0.03) than in the group that used it ≥70% of the required
time (−0.51±0.07% [−5.6±0.76 mmol/mol]; p<0.001). An improvement in glycaemic
control was seen across the range of HbA1c levels and age groups.
Overall, the authors concluded that both in paediatric and adult participants with type
1 diabetes using CSII therapy alone, the addition of CGM resulted in an improvement
in HbA1c with a concomitant decrease in time spent in hypoglycaemia. More frequent
self-adjustments of insulin therapy with SAP may have contributed to these effects.
The removal of CGM resulted in a loss of metabolic benefit.
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Clinical effectiveness – observational studies
1.2
In addition, based on comments from NICE committee members and stakeholders a
number of additional studies reporting data for the MiniMed Paradigm Veo and Vibe
and G4 PLATINUM CGM (or proxy) have been included in a narrative analysis for
adults and for children, particularly where they report results from a relevant
population (e.g. Choudhary study for nocturnal hypoglycaemia). None of these
studies fulfilled the original inclusion criteria for the systematic review for reasons
explained below.
The following studies will be discussed:
-
Choudhary et al. (2011)6
Choudhary et al. (2013)7
The DySF study (2012)8
Nixon & Pickup (2011)9
Battelino et al. (2011)10
Choudhary et al. 2011
Objective: To evaluate a sensor-augmented insulin pump with a low glucose suspend
(LGS) feature that automatically suspends basal insulin delivery for up to 2 hours in
response to sensor-detected hypoglycaemia.
Research Design and Methods: The LGS feature of the Paradigm Veo insulin pump
was tested for 3 weeks in 31 adult patients (10 men) with type 1 diabetes (mean age,
41.9 ± 10.6 years) from six U.K. centres.
During a 2-week run-in, CGM was used with all alerts active, except LGS (LGSOFF). LGS was then activated for 3 weeks (LGS-ON). The response to LGS was
evaluated and hypoglycaemia exposure and mean blood glucose were compared
during LGS-OFF and LGS-ON. Patients were divided into four equal groups
(quartiles) by the duration of hypoglycaemia during the run-in period; this was done
to test the hypothesis that those with the most hypoglycaemia at baseline (without
LGS) would have the greatest benefit with LGS.
Results: Two patients withdrew during run-in due to difficulties using sensors, and
one subject failed to activate the LGS. There were 166 LGS episodes in 25 of 28
(89%) completers (mean 1.9 LGS events/week), of which 76% occurred during
daytime, and 55% were terminated within 10 min. LGS continued for the maximum
2-h in 20 episodes (12%), 75% of which were nocturnal. Of 20 completed 2-h
suspends, 7 (35%) had no patient response throughout. In the remaining 13 (65%),
patients responded to the alarm but elected to continue LGS for 2-h.
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LGS use was associated with significant reduction in the duration of nocturnal
hypoglycaemia (≤ 2.2 mmol/L) in those in the highest quartile of hypoglycaemia
duration at baseline: median 46.2 (36.6–191.4) vs. 1.8 (0.0–45) min/day (P = 0.02;
LGS-OFF vs. LGS-ON) and mean 75.1 ± 54 vs. 10.2 ± 18 min/day (P = 0.02). Mean
sensor glucose was not different with LGS-OFF or LGS-ON (6.4 ± 1.3 vs. 6.6 ± 1.1
mmol/L, P = 0.26). After the 20 complete 2-h LGS episodes, median sensor glucose
was 3.9 (2.4–14.2) mmol/L at the restart of basal insulin and was 8.2 (3.3–17.3)
mmol/L 2-h after restart. Carbohydrate ingestion was not recorded.
Concomitant (within 15 min of LGS) capillary glucose values were available for 43 of
166 episodes (25.9%) of LGS. These were > 5mmol/L in 13 episodes and > 10
mmol/L in 4, although it is not known if any carbohydrate was ingested before testing.
LGS was terminated within 2 min in all four episodes with capillary glucose > 10
mmol/L, with sensor error alerts in two of these.
All subjects reported finding LGS “useful,” and 93% reported feeling more secure at
night, with reduced anxiety, and wanted to continue using it.
Authors’ conclusion: Use of an insulin pump with LGS was associated with reduced
nocturnal hypoglycemia in those at greatest risk and was well accepted by patients.
This study was funded by Medtronic, Inc.
ERG comment:
This study confirms the results from the ASPIRE in-Home trial (Bergenstal 2013),
showing that the MiniMed Veo system can reduce nocturnal hypoglycaemia. Similar
as in the ASPIRE in-Home trial, there is no significant change in HbA1c levels,
although HbA1c is slightly lower in the LGS-OFF state compared to LGS-ON.
However, this is based on a very small study (N=31) without a control group.
Choudhary et al. 2013
Objective: To evaluate the effect of continuous glucose monitoring (CGM) on the
frequency of severe hypoglycaemia (SH) in patients with established hypoglycaemia
unawareness
Research Design: Retrospective audit of 35 patients (no control or comparison group)
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Population: Adult type 1 diabetes patients with ongoing problematic hypoglycaemia
leading to limitation in daily activities and impaired awareness of hypoglycaemia
(IAH) (Gold score1 > 4) despite structured education with or without continuous
subcutaneous insulin infusion (CSII), who then used CGM in addition to CSII or
multiple daily injection (MDI) for at least 12 months.
Intervention: Thirty-five patients were seen in a specialized clinic with expertise in
structured education in flexible insulin therapy and CSII (>700 pump patients across
two sites). Twenty-three patients used the Medtronic Paradigm Veo system; 7 patients
used the Medtronic Paradigm RealTime system, and 3 patients used Dexcom G4
sensors in combination with an Animas Vibe pump. One patient continued receiving
MDIs, and one pump user used the Freestyle Navigator CGM system.
Results: The mean age of the patients was 43.2 ± 12.4 years, the duration of diabetes
was 29.6 ± 13.6 years, 24 patients were female, 33 of 35 patients were receiving
CSIIs prior to starting CGM, and 1 more patient converted to CSII within 2 months of
starting CGM. The median duration of CSII use was 40 months (range 8–352 months)
prior to CGM start.
The median rate (interquartile range [IQR]) of SH was reduced from 4.0 (0.75–7.25)
episodes/patient-year at baseline to 0.0 (0.0–1.25) episodes/patient-year (P < 0.001)
(mean 8.1 ± 13 to 0.6 ± 1.2 episodes/year; P =0.005) after 1 year of CGM. There was
no difference between those patients receiving treatment with or without low glucose
suspend (LGS) in final mean HbA1c level [7.7 ± 0.7% vs. 7.8 ± 1.5%; P = 0.9] or
median SH rate (0.0 [0–0] vs. 0.0 [0–2.0]; P = 0.3), but three patients were transferred
onto LGS pumps after having SH on standard CGM and did not have any further
episodes. HbA1c levels for all patients were reduced from 8.1 ± 1.2% to 7.8 ± 1.0%
(65 ± 10 to 62 ± 10 mmol/mol) at 1 year (P = 0.007).
Nineteen patients (54%) reported subjective improvement in awareness, with 13
reporting no change and 3 reporting a slight worsening in awareness. Paired Gold
scores were available in 19 of 34 subjects, showing no change over the year: 5.0 ± 1.5
vs. 5.0 ± 1.9 at 1 year (P = 0.67).
Authors’ conclusion: In a specialist experienced insulin pump centre, in carefully
selected patients, CGM reduced SH while improving HbA1c but failed to restore
hypoglycaemia awareness.
1 Gold score = a Likert linear analogue scale in which patients are asked to score between 1 and 7,
respectively, if they are always aware or never aware of the onset of hypoglycaemia.
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ERG comment:
This study showed that in patients with ongoing problematic hypoglycaemia, CGM
can lead to reduced severe hypoglycaemia. The intervention in this study was CGM in
addition to optimized medical therapy, which could be either continuous
subcutaneous insulin infusion or multiple daily insulin injections. If the intervention
was CSII+CGM it could be either an integrated system or stand-alone. Therefore, it is
unclear how the results of this study relate to the interventions included in the current
NICE assessment.
The DySF study
Objective: To introduce and compare the Dynamic Stress Factor, DySF, a newly
developed metric that quantifies glycaemic volatility based on patient-specific glucose
transition density profiles with HbA1c and with currently used glucose variability
metrics in predicting severe hypoglycaemia in children with type 1 diabetes.
Research Design: Secondary analysis of publicly archived CGM data from the
Juvenile Diabetes Research Foundation (JDRF) Continuous Glucose Monitoring
Randomized Trial.
Population: Enrolment criteria for the trial were children and adults with type 1
diabetes mellitus (T1DM) for more than 1 year (aged 8 to 85 yrs), use of either an
insulin pump or at least three daily insulin injections, and HbA1c < 10.0%. This
analysis used CGM data and HbA1c levels collected at baseline from 441 T1DM
patients with complete demographic and CGM data. Of the 441 patients analyzed,
32.4% were aged 8-14 yrs, 30.8% were aged 15-24 yrs and, 36.7% were ≥ 25 yrs.
DySF instrument: DySF is the daily weighted number of large monotonic glucose
transitions that occur in less than one hour. DySF is derived from transition density
profiles, with the exception of employing equally-spaced bin thresholds for DySF
analysis. First, raw CGM data were partitioned into 40 mg/dL bins and exact
transition points were established. Second, the magnitude of every continuous
monotonic change in glucose bin levels was sorted into the number of thresholds
crossed (e.g. 2, 4, −3, −5). Negative numbers indicate monotonic decreases and
positive numbers indicate monotonic increases in glucose levels. Third, transitions
were separated into the time interval necessary to complete each change (i.e. < 1 h,
between 1-2 h, 2-3 h, etc.). Finally, the frequency of each monotonic threshold
crossing per day was plotted against the time interval needed to cross the indicated
number of thresholds.
Results: DySF was found to be a predictor of severe HE in children (p = 0.018) with
the likelihood of a child, aged 8-14 yrs, experiencing severe hypoglycaemia
increasing by up to 20% with decreasing values of up to 60% of DySF. Patients of
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any age who had one or multiple severe hypoglycaemic episodes had on average a
lower DySF when compared to those with no HE. Additionally, when considering
mean glucose levels, DySF/mean was a preliminary predictor of severe HE in patients
with HbA1c ≤ 6.5% (p = 0.062).
Authors’ conclusion: DySF is a dynamic, quantitative, measure of daily glucose
“volatility” that separates patients, within the same strata of HbA1c, into visually
distinct patient profiles. DySF can be used as a preliminary predictor of clinically
severe hypoglycemia in children and “well-controlled” patients with HbA1c ≤ 6.5%.
ERG comment:
It would be extremely useful to have a measure of glucose volatility as a predictor of
severe hypoglycaemia in T1DM patients. However, as none of the included studies
have used such a measure, or any measures that assess glucose variability or time
spend in hyperglycaemic or hypoglycaemic states, this cannot be used within the
current assessment.
Nixon & Pickup (2011)
Objective: To test the hypothesis that suboptimal glycaemic control during continuous
subcutaneous insulin infusion (CSII) is related to fear of hypoglycaemia.
Research Design and Methods: A survey of non-pregnant type 1 diabetes patients
attending an Insulin Pump Clinic in London with at least 6 months’ duration of CSII.
In 104 eligible patients, fear of hypoglycaemia was assessed by questionnaire; 75
responded. A fear of hypoglycaemia score was calculated for each patient using a
minimal modification of the “Worry” subcategory of the Hypoglycaemia Fear Survey
(HFS) questionnaire.
Results: The median duration of CSII was 5 years (range, 1–29 years). Poor
glycaemic control (HbA1c ≥ 8.5%; mean±SD, 9.1±1.0%) was present in 27%, and
this group had more men than a good-control group with HbA1c < 7.0% (43% vs.
11%). Substantial fear of hypoglycaemia (score >50%) occurred in 27% of patients,
but fear of hypoglycaemia was not correlated with HbA1c. The only significant
correlates of fear of hypoglycaemia were accumulated episodes of severe
hypoglycaemia (r=0.48, P<0.001) and rate of hypoglycaemia on CSII (r=0.48,
P<0.001). The HbA1c on CSII was correlated with multiple daily injection (MDI)
HbA1c (r=0.66, P<0.001) and the change in HbA1c (r=0.63, P<0.001).
Authors’ conclusion: Fear of hypoglycaemia is not correlated with, and is unlikely to
be a major determinant of HbA1c on CSII. Other factors (such as HbA1c on MDI and
adherence to insulin pump procedures) are likely to be more important. Nevertheless,
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substantial fear of hypoglycaemia is present in many CSII-treated people and may
adversely affect quality of life and psychological well-being.
ERG comment:
The relationship between fear of hypoglycaemia and glycaemic control is complex
and still needs further research. However, this study found that HbA1c on CSII is not
correlated with fear of hypoglycaemia, and fear is therefore unlikely to be a major
determinant of HbA1c on CSII.
Battelino et al. 2011
Objective: To assess the impact of continuous glucose monitoring on hypoglycaemia
in people with type 1 diabetes.
Research Design and Methods: In this randomized, controlled, multicenter study, 120
children and adults on intensive therapy for type 1 diabetes and a screening level of
glycated haemoglobin A1c. (HbA1c) <7.5% were randomly assigned to a control
group performing conventional home monitoring with a blood glucose meter and
wearing a masked continuous glucose monitor every second week for five days or to a
group with real-time continuous glucose monitoring.
The primary outcome was the time spent in hypoglycaemia (interstitial glucose
concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to
treat for all randomized patients.
Results: The time per day spent in hypoglycaemia was significantly shorter in the
continuous monitoring group than in the control group (mean ± SD: 0.48 ± 0.57 and
0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26 to 0.76; P = 0.03).
HbA1c at 26 weeks was lower in the continuous monitoring group than in the control
group (difference -0.27%; 95% CI -0.47 to -0.07; P = 0.008). Time spent in 70 to 180
mg/dL normoglycaemia was significantly longer in the continuous glucose
monitoring group compared with the control group (mean hours per day, 17.6 vs.
16.0, P = 0.009).
Time spent in hypoglycemia below 63 mg/dL was reduced in the continuous
monitoring group by 41% (mean 0.48 vs. 0.81 h/day) in pump users and by 59% (0.49
vs. 1.20) in patients on MDI. This end point was reduced by 48% (0.34 vs. 0.65) in
paediatric patients (10-17 years of age) and by 54% (0.59 vs. 1.27) in adults (18-65
years of age). In the post hoc per protocol analysis, where only patients that wore the
sensor for >20 days (corresponding to one third of the required time in the control
group) were included (44 of 53 paediatric and 53 of 63 adult patients), the primary
outcome was reduced by 64% (P < 0.001) and 50% (P = 0.02) in paediatric and adult
patients, respectively.
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Conclusions: Continuous glucose monitoring was associated with reduced time spent
in hypoglycaemia and a concomitant decrease in HbA1c in children and adults with
type 1 diabetes.
ERG comment:
The study was excluded from the main review because both groups (CGM vs SM)
included a mixture of patients using pump and multiple daily injections (MDI). The
study does show a significant reduction in the time per day spent in hypoglycaemia
for CGM when compared to SMBG and a reduction in HbA1c favouring CGM in
patients with relatively low HbA1c (<7.5%) at baseline. Effects were more
pronounced in patients on MDI, in adults and in patients with better adherence. It is
unclear whether the effect on hypoglycaemia was significant in pump users.
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2.
Cost-effectiveness Analysis
2.1
Review of the economic evaluation by Roze et al.
In this section we discuss the draft paper describing the study by Roze et al.11
evaluating************************************************************
******************* versus CSII + SMBG in
UK.*****************************************************************
*********************************************************************
*********************************************************************
********************************************************************1
2
Treatment effects considered were reduction in HbA1c baseline level and the number
(rate per 100 patient-years) of severe hypoglycaemic events. The study showed that
SAP was cost-effective compared to CSII + SMBG. The cost-effectiveness analysis
was performed with the IMS CDM. The main characteristics of this study are
summarised in Table 7.
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Table 7: Summary of Roze et al. paper
Study, Year,
Country
Summary of model
Intervention/
comparator
Patient population
(average age in years;
HbA1c at baseline)
Roze11
2014
UK
 CORE Diabetes Model
(Markov model for
diabetes, includes a large
number of complications)
 Perspective: ******
 Time horizon: life time
 Discount rate:
*********************
******
 Effectiveness data from
meta-analysis ** and
*********************
*********************
*****
SAP vs
CSII+SMBG
Adult inadequately
controlled type 1
diabetes patients and
experiencing frequent
hypoglycaemic events at
the same time.
.
QALYs
(intervention,
comparator)
Costs
(currency)
(intervention,
comparator)
ICER
**** QALYs
gained
Extra costs
******* over
life time
ICER *******
per QALY
gained
( per QALY
gained)
Sensitivity
analyses
 Sensitivity
analysis on key
drivers
confirmed
robustness of
results under a
wide range of
assumptions
 Age 27
 HbA1c 10%
 Reduced fear of severe
hypoglycaemic events in
SAP group accounted for
in QALY
 Sensitivity analysis
conducted
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Quality assessment
A quality appraisal was carried out using the Drummond checklist.15 A summary of the
results is provided in Table 8.
Table 8: Quality assessment of the Roze et al. study, using Drummond 1996
Roze et al. 201411
Criteria
Study design
1. Was the research question stated?
**********************************
***************************
2. Was the economic importance of the research question stated?
Yes
3. Was/were the viewpoint(s) of the analysis clearly stated and
justified?
Yes
4. Was a rationale reported for the choice of the alternative
programmes or interventions compared?
Yes
5. Were the alternatives being compared clearly described?
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
*************
6. Was the form of economic evaluation stated?
Yes
7. Was the choice of form of economic evaluation justified in
relation to the questions addressed?
Yes
Data collection
8. Was/were the source(s) of effectiveness estimates used stated?
9. Were details of the design and results of the effectiveness
study given (if based on a single study)?
Yes
***********************
10. Were details of the methods of synthesis or meta-analysis of
estimates given (if based on an overview of a number of
effectiveness studies)?
NA
11. Were the primary outcome measure(s) for the economic
evaluation clearly stated?
Yes
12. Were the methods used to value health states and other
benefits stated?
**********************************
************
13. Were the details of the subjects from whom valuations were
obtained given?
*****************************
14. Were productivity changes (if included) reported separately?
NA
15. Was the relevance of productivity changes to the study
question discussed?
NA
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Roze et al. 201411
Criteria
16. Were quantities of resources reported separately from their
unit cost?
No
17. Were the methods for the estimation of quantities and unit
costs described?
No
18. Were currency and price data recorded?
Yes
19. Were details of price adjustments for inflation or currency
conversion given?
**********************************
**********************************
****
20. Were details of any model used given?
Yes
21. Was there a justification for the choice of model used and the
key parameters on which it was based?
Yes
Analysis and interpretation of results
22. Was the time horizon of cost and benefits stated?
Yes
23. Was the discount rate stated?
Yes
24. Was the choice of rate justified?
**********************************
************************
25. Was an explanation given if cost or benefits were not
discounted?
NA
26. Were the details of statistical test(s) and confidence intervals
given for stochastic data?
NA
27. Was the approach to sensitivity analysis described?
*********************************
28. Was the choice of variables for sensitivity analysis justified?
Yes
29. Were the ranges over which the parameters were varied
stated?
Yes
30. Were relevant alternatives compared? (That is, were
appropriate comparisons made when conducting the incremental
analysis?)
Yes
31. Was an incremental analysis reported?
Yes
32. Were major outcomes presented in a disaggregated as well as
aggregated form?
Yes
33. Was the answer to the study question given?
Yes
34. Did conclusions follow from the data reported?
Yes
35. Were conclusions accompanied by the appropriate caveats?
21
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
CONFIDENTIAL UNTIL PUBLISHED
Roze et al. 201411
Criteria
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
**********************************
***********
36. Were generalisability issues addressed?
No
Study design
The Roze study11 is a modelling study that clearly states the approach to economic
evaluation. The intervention is stated as SAP,
***************************************************************************
*****************. Outcomes are presented as costs per QALY gained.
Data
***************************************************************************
****************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
********************. The study assumed a cohort of patients with a baseline HbA1c of
10%,***********************************************************************
***************************************************************************
***************************************************************************
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***************************************************************************
***************************************************************************
**************************************************
2.2
Formal comparison between Roze et al. UK study (2015) and MiniMed DAR
In this section we will compare the DAR16 results for Minimed Veo vs CSII+SMBG with
those of the Roze et al. study.11 The analysis in Roze et al.11 was also performed with the IMS
CORE diabetes model. As their simulation settings were available for review, a detailed
comparison with those in the DAR16 was possible. Hence, this comparison is more detailed
than would have been possible based on the paper alone.
Roze et al.11
present*********************************************************************
************************
********************************************************************* Table
9 summarizes the main results from Roze et al.11 and the DAR.16
Table 9: Main outcomes of Roze et al. study (base case and scenario 7) and DAR (base case
scenario)
Δ Costs
Δ QALY
ICER
case
*******
****
*******
11
*******
****
*******
£47,921
0.066
£730,501
Study
11
Roze
et
al.
base
(*************************
Roze
et
al.
************************************)
DAR base case scenario
16
In the remainder of this section, we will compare ***************************** Roze
et al.11 with the DAR16 settings. There are many differences between Roze et al.11 and the
DAR16 settings. Below these are summarized.
Differences in general simulation settings (structural uncertainty)
Besides the model input parameters (see DAR16 Section 5.3), which will be detailed below in
the coming sections, there are other general settings that can be adjusted before running a
simulation in the IMS CORE model. This can be seen as a source of structural uncertainty
23
CONFIDENTIAL UNTIL PUBLISHED
(i.e. like having two different versions of the IMS CORE model). Several differences
between the Roze et al. UK study11 and the DAR16 were found. These are shown in Table 10.
Table 10: Differences in general simulation settings (structural uncertainty).
MiniMed DAR
16
Roze et al. UK study
11
Alternative regression methods
MI
Framingham
*****************
Stroke
Framingham
*****************
Multiplicative
********
BMI adjustment for QALY
Yes
**
2nd order with sampling
Yes
**
80 years
********
Specific simulation settings
QALE estimation method
Time horizon
We ran a simulation where the DAR16 base case was modified according to the Roze et al.11
settings in Table 10. The ICER of MiniMed Veo vs. CSII + SMBG was then £1,079,824, an
increase of almost 50% with respect to the DAR16 base case ICER.
***************************************************************************
*
**************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
*****************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
****************************************************************************
***************************************************************************
***************************************************************************
********************************************
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***************************************************************************
***************************************************************************
****************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
**********
***************************************************************************
***************************************************************************
**************************
Differences in model input parameters (parameter uncertainty)
a.
Differences in Cohort Baseline Characteristics
Differences in cohort baseline characteristics are shown in Table 11. When the baseline
patient characteristics in the DAR base case were replaced by those in Roze et al. 11 the ICER
of MiniMed Veo vs. CSII + SMBG was £592,769.
For most parameters differences were relatively small. In general, more recent publications
have
been
used
in
the
DAR16
than
for
the
Roze
study11.
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
**Table 11: Main differences in baseline characteristics.
MiniMed DAR16
Parameter
Mean
SD
Start age (years)
41.6
12.8
Duration of Diabetes (years)
27.1
12.5
Proportion Male
0.38
NA
HbA1c (%-points)
7.26
0.71
0
NA
Proportion
background
diabetic retinopathy
Source
Bergenstal et al.17
Bergenstal et al.17
Assumption
25
Roze et al. UK study11
****
**
******
27
****
**
****
*****
**
*********
*********
*********
*********
****
10
***
*
**
*********
*
CONFIDENTIAL UNTIL PUBLISHED
b.
Differences in management costs
Although there are several differences in management costs items between the DAR16 and
Roze et al.11 studies, the total incremental management costs of MiniMed Veo vs.
CSII+SMBG are £3 in the DAR and *** in Roze et al. Therefore, management costs do not
drive the difference in ICER between the two studies. When the management costs in the
DAR base case were replaced by those in Roze et al. the ICER of MiniMed Veo vs. CSII +
SMBG was £729,437.
c.
Differences in complication costs
There are many differences in costs of complications between the DAR16 and the Roze et al.11
study.
***************************************************************************
***********************************************************************
***************************************************************. In general,
the DAR used the same data sources as the updated CG1518, i.e. mostly clinical guidelines
previously
published
by
NICE,
whereas
Roze
et
al.11
***************************************************************************
*******.
Unlike with management costs, the total incremental complication costs of MiniMed Veo vs.
CSII+SMBG are very different. These incremental costs per type of complication are
summarized in Table 12. Note that in the DAR settings, MiniMed Veo is cost saving
compared to CSII+SMBG for all complications (except for keto/lactic acidosis where the
difference in costs is zero). ****************************************************.
***************************************************************************
************************************************** in complication costs by using
CSII+CGM instead of CSII+SMBG, compared to £870 in the DAR16. As can be seen in
Table
12,
***************************************************************************
***************************************************************************
********
***************************************************************************
***************************************************************************
**************.
Table 12: Breakdown of incremental complication costs (MiniMed Veo vs. CSII + SMBG).
Type of complication
MiniMed DAR
16
Roze et al. UK study
CVD
-£30
****
Renal
-£143
******
26
11
CONFIDENTIAL UNTIL PUBLISHED
Type of complication
MiniMed DAR
16
Roze et al. UK study
Ulcer/Amputation/Neuropathy
-£369
******
Eye
-£101
****
Hypoglycaemia
-£225
******
Keto/Lactic acidosis
£0
**
Anti depression treatment
-£2
**
11
Despite these significant differences in complication costs mentioned above, when the
complication costs in the DAR base case were replaced by those in Roze et al. the ICER of
MiniMed Veo vs. CSII + SMBG was £729,366.
d.
Differences in annual treatment costs
Although treatment costs were not exactly the same in the DAR16 and Roze et al. 11 UK
study,
***************************************************************************
***************************************************************************
********************************************************************
Table 13: Treatment costs.
MiniMed DAR
Parameter
16
Roze et al. UK study
11
Veo
CSII+SMBG
Difference
SAP
CSII
Difference
Year 1 Costs
£6046
£3350
£2696
*****
****
*****
Year 2+ Costs
£6046
£3350
£2696
*****
****
*****
e.
Utilities
Main
differences
in
utilities
are
those
related
to
*************************************************** as can be seen in Table 14.
***************************************************************************
***************************************************************************
***************************************************************************
***************************************************************************
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**************************************************************************
Table 14: Utilities.
MiniMed DAR
Parameter
Mean
Type 1 diabetes with no
complication
Severe
event
Fear of
event
hypoglycaemic
0.814
-0.012
0.01
0.00
Roze et al. UK study
Source
Mean
Clarke et al. 200219
*****
Currie et al. 200621
******
0
0.00
Included in the
disutility for severe
hypoglycaemic event
0.6059
0.00
Goldney et al. 200422
hypoglycaemic
Depression non-treated
SD
16
11
SD
Source
*****
************
*************
************
************
********
*
************
************
************
**
******
*
************
************
************
************
************
*********
*****
*****
************
************
Two additional scenarios regarding utilities were explored. When the utilities in the DAR
base
case
were
replaced
by
those
in
Roze
et
al.
***************************************************************************
***************************************************************************
*****
f.
Differences in treatment effects
Differences in treatment effects are very large (see Table 15). In the DAR treatment effects
were based on the EAG systematic review whereas in Roze the change in HbA1c with
respect to the baseline level is based on *************** and the rate of major
hypoglycaemic events is based on ***********
Table 15: Treatment effects.
MiniMed DAR
Parameter
MiniMed Veo
28
16
CSII+
SMBG
Roze et al. UK study
11
2015
SAP +
LGS
CSII +
SMBG
CONFIDENTIAL UNTIL PUBLISHED
MiniMed DAR
Parameter
Mean (SD) change in baseline HbA1c%
Mean (SD) major hypo rate (per 100 pt years)
16
Roze et al. UK study
11
2015
MiniMed Veo
CSII+
SMBG
SAP +
LGS
CSII +
SMBG
-0.02 (0.04)
0.05 (0.12)
*********
*
**********
1.9584 (0)
5.0215 (0)
*****
********
Note that the population in ***************************************************
and is therefore at increased risk of experiencing hypoglycaemic events but in Roze et al. the
***************************************************************************
**********************************************.
In Figure 1 the HbA1c progression for the Roze et al. base case study is shown. The lowest
HbA1c level reached *******************************
**************************** This confirms that these are patients who have difficulty
controlling their HbA1c level. However,
*********************************************************** which were found
in patients with low HbA1c level and thus at risk of experiencing hypoglycaemia.
*************************************************
When treatment effects in the DAR base case were replaced by those in Roze et al. the ICER
of MiniMed Veo vs. CSII + SMBG was £58,015, thus 92% reduction with respect to the base
case ICER in the DAR. In order to determine whether this reduction in ICER is due to the
change in HbA1c or the rate of severe hypoglycaemia two additional scenarios were run.
When only HbA1c reduction in the DAR base case was replaced by the one in Roze et al. the
ICER of MiniMed Veo vs. CSII + SMBG was £63,600. And when only the rate for major
hypoglycaemic events in the DAR base case was replaced by the one in Roze et al. the ICER
of MiniMed Veo vs. CSII + SMBG was £446,640. Seeing these results we can conclude that
most of the benefits are due to the reduction in HbA1c with respect to the baseline level.
g.
Disease management parameters
There are also several differences in disease management parameters between the DAR16 and
the Roze et al. UK study11 ************************. When the disease management
parameters in the DAR base case were replaced by those in Roze et al. the ICER of MiniMed
Veo vs. CSII + SMBG was £579,220. If besides the disease management parameters the
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CONFIDENTIAL UNTIL PUBLISHED
management costs in the DAR base case were replaced by those in Roze et al. the ICER of
MiniMed Veo vs. CSII + SMBG was £579,229.
h.
Natural disease history parameters
Natural disease history parameters are shown in Table 88 in the DAR and these are part of
the
clinical
database
in
the
IMS
CORE
model.
***************************************************************************
***************************************************************************
*******
***************************************************************************
***************************************************************************
***************************************************************************
When the clinical database in the DAR base case was replaced by the one in Roze et al. the
ICER of MiniMed Veo vs. CSII + SMBG was £596,130.
Summary of the comparison
All results are summarized in Table 16. Overall, only one set of the various modules used in
the IMS CORE model by Roze et al.11 would increase the DAR16 ICER: all other modules
lead to a decrease. The most striking decreases are due to the treatment effect estimates used
in the Roze et al. UK study11, which heavily affects the gain in QALYs. This gain in QALYs
is mostly due to the reduction in HbA1c level.
Note also that even in the scenario where the treatment effects from Roze are used in the
DAR settings there is still a large difference in QALYs gained between the Roze study
(**************************************************************************
**************, as shown in Table 9) and the DAR (0.78, as shown in Table 16). The main
driver of this difference is the change in HbA1c baseline level as we will explain now. The
gains in QALYs are dependent among other parameters on the change in HbA1c baseline
level.
***************************************************************************
*******. These equations use baseline HbA1c, baseline age and sensor usage in days per
week for CGM (if applicable) to predict the change in HbA1c baseline level.
***************************************************************************
***************************************************************************
***************************************************************************
************************************************. In Table 16 the QALYs gained
in the DAR setting are also obtained using the treatment effects from Roze. That means that
for the severe hypo rates there is no difference between the two studies, but since the change
in HbA1c is a function of the baseline HbA1c and age, the difference in HbA1c baseline level
between MiniMed Veo and CSII+SMBG is not the same in the DAR and in the Roze study.
In the DAR the baseline HbA1c is 7.26% and baseline age is 41.6. Then, according to the
Pickup equations, and assuming that the sensor is worn 7 days per week, the difference in
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CONFIDENTIAL UNTIL PUBLISHED
HbA1c baseline level between MiniMed Veo and CSII+SMBG is -0.557 (in favour of
MiniMed Veo). Therefore, using the same approach as in Roze the reduction in HbA1c in the
DAR scenario is approximately *********. This will cause most of the remaining difference
in QALYs between the two studies.11, 16
Table 16: Results of the different scenarios.
Scenario
Δ Costs
Δ QALY
ICER
DAR base case
£47,921
0.066
£730,501
Roze et al. general settings (structural
uncertainty)
£46,648
0.043
£1,079,824
All baseline factors for cohort from Roze
£46,295
0.078
£592,769
Management costs from Roze
£47,924
0.066
£729,437
Complication costs from Roze
£47,919
0.066
£729,366
Utilities (without fear of hypo) from Roze
£47,921
0.075
£637,246
Utilities (with fear of hypo) from Roze
£47,921
0.078
£614,370
Treatment effects from Roze
£45,275
0.780
£58,015
- Treatment effects: HbA1c reduction from
Roze and DAR hypo rates
£46,886
0.737
£63,600
- Treatment effects: DAR HbA1c reduction
and hypo rates from Roze
£46,317
0.104
£446,640
Management module from Roze
£45,643
0.079
£579,220
Clinical database from Roze
£48,048
0.081
£596,130
It is important to emphasize that according to our clinical experts there is an inter-relationship
between frequency of hypoglycaemic events and HbA1c control. Patients having difficulty
maintaining optimal Hba1c are unlikely to be greatly troubled by hypoglycaemic events and
those with recurrent hypoglycaemic events on insulin pumps will probably have good HbA1c
control. Although possible, our clinical experts have confirmed that very few patients with
both recurrent hypoglycaemic events and poor Hba1c control are observed in daily practice.
*****************************************************
Since for the vast majority of patients one problem predominates, it was suggested that it
would be most appropriate to study separately the two populations below:
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CONFIDENTIAL UNTIL PUBLISHED


Patients having difficulty maintaining optimal HbA1c level, but not greatly troubled
by hypoglycaemia; and
Patients with recurrent hypoglycaemic events on insulin pumps, who have good
HbA1c control.
These two populations will be central in the next sections of this addendum.
2.3
Focused review of severe hypoglycaemic event parameters
2.3.1 Methods
The purpose of this review was to inform the estimates of utility decrement and additional
mortality associated with severe hypoglycaemic events for use in the cost-effectiveness
model. In order to keep the review focused to the most useful estimates, the search was
limited to the last 5 years. In order to fit with the NICE Reference Case, the inclusion criteria
for utilities included EQ-5D, TTO or SG.23 However, in order not to exclude any potentially
useful estimates, for both utilities and mortality, a pragmatic approach was taken with regards
to population. This meant a preference for the UK and Type I diabetes, but, depending on
availability and quality (e.g. study size), consideration was also given to Type II diabetes.
Targeted literature searches were conducted to identify studies with hypoglycaemia mortality
and utilities data. The literature searches were limited by date range to 2010-2015, and
geographically to the United Kingdom. The search strategies combined relevant search terms
comprising indexed keywords (e.g. Medical Subject Headings, MeSH and EMTREE) and
free text terms appearing in the titles and/or abstracts of database records. The utilities facet
of search terms was based on the NICE Decision Support Unit utilities technical support
document.24
The following databases were searched for studies with hypoglycaemia mortality data:
•
MEDLINE (Ovid): 1946-2015/May week 1
•
MEDLINE In-Process Citations and Daily Update (Ovid): up to May 11 2015
•
PubMed (NLM): up to 12/05/2015
•
EMBASE (Ovid): 1974-2015/week 19
The following databases and resources were searched for hypoglycaemia utilities:
•
MEDLINE (Ovid): 1946-2015/May week 1
•
MEDLINE In-Process Citations and Daily Update (Ovid): up to May 08 2015
•
PubMed (NLM): up to 12/05/2015
•
EMBASE (Ovid): 1974-2015/week 19
•
Cost-Effectiveness Analysis (CEA) Registry (www.cearegistry.org): up to 12/05/15
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•
ScHARRHUD (www.scharrhud.org): up to 12/05/2015
•
RePEc: Research Papers in Economics (www.repec.org): up to 12/05/2015
As a number of databases were searched, there was some degree of duplication. In order to
manage this issue, the titles and abstracts of bibliographic records were downloaded and
imported into EndNote reference management software and duplicate records removed.
The full search strategies are presented in Appendix 1.
2.3.2 Results
The utilities search found 251 references, which from title and abstract screening, produced 5
includes from 3 studies (two references were conference abstracts for the same study by
Evans et al. 2013).25-29 Table 17 shows a summary of the estimates from these 3 studies plus
those
used
in
the
Roze
et
al.
model30
****************************************************** Note that Roze et al. 2014
cites
***************************************************************************
************************************************ Note also that 2 of the 3 studies
found by the search were based on the same original multinational TTO study. Evans et al.
contained estimates from more than one country, including the UK whereas Harris contained
only the Canadian estimates and the purpose of the Lauridsen et al. paper was to publish
estimates of a model to estimate the effect of multiple hypoglycaemic events on the utility
decrement, showing a diminishing effect. Adler et al. 2014 was the most recent publication
and has been included for completeness although it was only available as a conference
abstract and calculation of a decrement was not possible. Also for completeness, the values
for minor events have been presented, although they are not used in the CEA model.
***************************************************************************
***************************************************************************
***************************************************************************
*** This study was an observational study, which followed up Type I diabetes patients for 12
months after the introduction of SAP therapy. This HFS change was then converted to a EQ5D increment using the Currie et al. study.21 However, it is clear from the framing of the
Currie et al. study that the effect of fear is already incorporated in the effect of number of
hypoglycaemic events in that patients are asked for an EQ-5D value at the moment of the
survey and not during the event itself and so this value corresponds to the value given a
history of hypoglycaemia and any associated fear of recurrence.
33
CONFIDENTIAL UNTIL PUBLISHED
Table 17: Utility decrements
Source
Type I or Type II or Country
general population
EQ-5D or
TTO
Severe hypo
Minor hypo
Fear of hypos
Currie et al. 200621
Mixed, n=1305
UK
EQ-5D
0.047
0.014
=HFS*EQ-5D
decrement per HFS
Beaudet et al. 201420 Mixed
UK
EQ-5D
0.047
0.004
Review-value comes
from Currie (only UK
study in the review)
Nørgaard K et al.
Mixed
2013 [The
INTERPRET
Study ]32+Curie et al.
2006
UK
EQ-5D
Harris S et al. Can J
Diabetes . (2014)
General population,
1696 (of 8286 in 5
countries)
Canada
Evans et al. 201328
0.0552
increment
Comments
From Currie et al.
2006
=HFS*EQ-5D
decrement per HFS
TTO
0.045
General population, UK
n=1675 (of 8286 in 5
countries)
TTO
Day: 0.062 [0.054 to 0.071] Day: 0.005 (0.004,0.007)
Adler et al. 201429
Mixed, n=348
UK
TTO
Lauridsen et al.
201425
General population,
n=8286
5 countries TTO
including
UK
Night: 0.066 [0.057 to 0.076] Night: 0.008 [0.060 to 0.010]
‘Severe, frequent
hypoglycemia occurring day
and night, leading to anxiety,
and to modifying behavior
frequently’: 0.401
Disutility per
hypoglycaemic event
per year
‘Non-severe, daytime, no
more than once per year,
rarely causing worry, and
rarely modifying behavior:
0.843
Abstract
Day: Decrement =
0.0141.annual rate0.03393
Regression equations
with diminishing
marginal decrement
shape
Night: Decrement=
0.0221.annual rate0.3277
HFS=Hypoglycemia Fear Survey
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The mortality search found 143 references and screening produced 4 includes, which are summarised in Table 18.33-36
Table 18: Mortality
Source
Country Population
Design
Khunti et al. 201533
UK
Retrospective NA
cohort
Type I
Follow- Mortality
up
risk
NA
HR vs. no hypo
OR vs. no hypo Data source
History of CVD:
1.95 (1.14,3.35)
No CVD: 2.05
(1.69,2.49)
Nirantharakumar et al. UK
201235
Mixed,
Retrospective In
Severe: 15% NA
hospitalised cohort
hospital
Mild to
for any
moderate:
reason
10%
Severe: 2.05
(1.24,3.38)
Mild to
moderate: 1.62
(1.16,2.27)
Clinical Practice
Research Database and
Hospital Episode
Statistics, n=3260
Hypos were both
Severe and Nonsevere
University Hospital
Birmingham routinely
collected data, n=6374
Mild to moderate:
2.3-3.9 mmol/l
Rajendran et al.
201534
UK
Mixed,
Retrospective 30 day 10.6%
presenting to cohort
90 day 16.7%
ED for hypo
1 year 28%
i.e. all
Severe
NA
NA
Ipswich Hospital, n=165
Tan and Flanagan
201336
UK
Mixed
NR
NR
Derriford Hospital,
Plymouth, n=138
Retrospective In
24.3%
cohort
hospital
(vs. 5.4%
with no
hypo)
NA=not applicable, NA=not applicable, ED=emergency department
35
Comments
Severe: <=2.2 mmol/l
CONFIDENTIAL UNTIL PUBLISHED
Based on the studies in Tables 17 and 18 we derived the following estimates to be used in the
health economic analyses (section 2.4).
For severe hypoglycaemic events, a UK based utility decrement of -0.064 from Evans et al.
(2013)28 is used. This utility decrement is TTO specific, and is the average of nocturnal and
daytime hypoglycaemic event decrements. Health state descriptions include the possible fear
of hypoglycaemic events as well.
For the mortality due to severe hypoglycaemia, Nirantharakumar et al.35 is used, since it is the
study with the largest sample and it includes OR estimates. Although in this study only the
in-hospital mortality is reported, a patient with a life-threatening severe hypoglycaemic attack
is generally hospitalized.37
2.4
Additional Cost-Effectiveness Analyses
In this section, a number of new cost-effectiveness analyses are conducted.
Two populations are considered in the analyses:


Adults with difficulty maintaining target HbA1c (>8.5%)
Adults experiencing frequent hypoglycaemic events.
As discussed in the first addendum, the children population will not be analysed due to lack
of data and the modelling limitations of IMS CDM for children population.
In keeping with clinical expert views, it is assumed in the base case that patients having
difficulty maintaining HbA1c target do not experience frequent hypoglycaemic events and
patients who experience frequent hypoglycaemic events have reached their Hba1c target. In
different scenario analyses for each population, this association between HbA1c control and
hypoglycaemia is relaxed.
2.4.1 Population 1: Adults with difficulty maintaining target HbA1c (>8.5%)
Model input parameter updates with respect to the DAR base case
Baseline cohort input parameters were updated according to CG15 (Table 68 in the DAR16).
The key characteristics of the cohort are given in Table 19 below:
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Table 19: Baseline cohort characteristics
Input Variable
Mean
SD/SE
Source/Comment
Start Age
42.98
19.14
DCCT38
Duration of Diabetes
16.92
13.31
National Diabetes Audit39
HbA1c
8.6%
4.0
National Diabetes Audit39
Together with the baseline characteristics, for severe hypoglycaemic events, from our
focused literature review, a UK based utility decrement of -0.064 from Evans et al. (2013)28
is used. This utility decrement is the average of nocturnal and daytime hypoglycaemic event
decrements and in the model applied for each event and scaled to a yearly cycle.
In addition to this disutility, a mortality rate due to severe hypoglycaemia of 0.01596,
obtained from the focused literature review, is also included. This value is based on the
assumption that mortality takes place only in the hospital admissions and uses the in hospital
mortality rate due to severe hypoglycaemic events from Nirantharakumar et al. 201235 and
the hospitalization rate from CG15.37
Finally, treatment effects were also updated for this population. It was assumed that for all
the interventions and comparators, the incidence rate of severe hypoglycaemic events is zero.
For changes in Hba1c baseline level we excluded the studies with average baseline HbA1c
smaller than 8.5% and the studies in which the majority of patients are less than 18 years old
from the evidence network in main DAR report 16. The remaining evidence network directly
linked to one of the interventions (Veo or Integrated CSII+CGM) is given in Figure 2 as
follows:
Figure 2: Evidence network when studies with baseline HbA1c<8.5 and studies that include
more than 50% children are excluded
Integrated
CSII+CGM
Veo
CSII+CGM
Real Trend
Eurythmics
Peyrot 2009
Lee 2007
CSII+SMBG
MDI+SMBG
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As there is no evidence indicating a difference in clinical effectiveness between MiniMed
Veo, CSII+CGM stand-alone and Integrated CSII+CGM for this population, it is assumed
that the treatment effects in terms of HbA1c change for these three interventions are
equivalent (and an umbrella name of CSII+CGM+ is used for convenience). It was observed
that Pickup meta-analysis study13 (comparing CGM vs SMBG) combines the patient level
data of 6 different clinical trials including the RealTrend study40 and it is possible to generate
baseline HbA1c, age and sensor usage frequency dependent treatment effect. Also, it was
decided to exclude Peyrot and Rubin 200941 and Lee 200742 studies since they are very small
(n=27 and n=16).
Thus, the new evidence network used to estimate the 1st year HbA1c change treatment effects
is given in Figure 3 as below:
Figure 3: Evidence network used in the analysis of population 1
Veo
CSII+CGM
Integrated
CSII+CGM
Pickup 2011
Eurythmics
+
CSII+CGM
CSII+SMBG
MDI+SMBG
For MDI+SMBG and CSII+CGM+ systems (Veo, CSII+CGM stand-alone and Integrated
CSII+CGM), HbA1c changes are taken from the Eurythmics trial43 (-0.13 for MDI+SMBG
and -1.23 for CSII+CGM+, respectively). Then the treatment effect difference between CGM
and SMBG is applied from the meta regression in Pickup et al 2011,13 which is +0.73, with a
baseline HbA1c value of 8.6, age of 43 and 7 days per week sensor usage assumption. With
this treatment effect difference, the HbA1c treatment effect for CSII+SMBG is -1.23 + 0.73 =
-0.50. Treatment effects for population 1 are summarized in Table 20.
Table 20: Treatment effects for base case analysis of population 1.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -1.23
(0.158)
0
Integrated
CSII+CGM
-1.23
(0.158)
0
CSII+CGM
-1.23
(0.158)
0
CSII+SMBG
-0.50
(0.169)
0
MDI +SMBG
-0.13
(0.093)
0
*Calculations to derive the uncertainty around treatment effects are given in Appendix 2.
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Scenario Analyses for Population 1
For this population with difficulty maintaining target HbA1c (<8.5%), four scenario analyses
are conducted to explore the impact of different treatment effect assumptions on total costs
and total QALYs. These scenarios are listed below.
Population 1 - Scenario 1: Overall HbA1c treatment effect difference from Pickup 2011
In this scenario the overall HbA1c treatment effect difference between CGM and SMBG
from Pickup 201113 is applied (+0.3) independently of baseline characteristics. Note that this
implies that only the HbA1c reduction for CSII+SMBG changes with respect to the base case
(+0.73 treatment effect difference between CGM and SMBG is assumed in the base case).
Treatment effects assumed for this scenario can be seen in Table 21.
Table 21: Treatment effects in scenario 1 for population 1.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -1.23
(0.158)
0
Integrated
CSII+CGM
-1.23
(0.158)
0
CSII+CGM
-1.23
(0.158)
0
CSII+SMBG
-0.93
(0.169)
0
MDI +SMBG
-0.13
(0.093)
0
*Calculations to derive the uncertainty around treatment effects are given in Appendix 2.
Population 1 – Scenario 2: Nonzero severe hypoglycaemia incidence rates from
reference studies
In this scenario, HbA1c reduction was assumed to be identical to the base case analysis.
However, we assumed here that patients are still experiencing severe hypoglycaemia. Severe
hypoglycaemia incidence rates/ incidence rate ratios are taken from the reference studies
(Eurythmics43 and Pickup 201113). Similarly to what was done for the HbA1c reduction, we
assumed the same for hypoglycaemia rate for MiniMed Veo, integrated CSII+CGM and
CSII+CGM stand-alone. This was estimated from the Eurythmics trial43 and it was equal to
20 severe hypoglycaemia events per 100 patient years. The severe hypoglycaemia incidence
rate for MDI+SMBG (also derived from Eurythmics trial 43) was equal to 6.45 events per 100
patient years. For CSII+SMBG, an incidence rate ratio of 1.4 (favouring SMBG) from Pickup
201113 is used to calculate the severe hypoglycaemia incidence rate, which results in
20/1.4=14.786. The treatment effects used in scenario 2 for this population are shown in
Table 22.
Table 22: Treatment effects in scenario 2 of population 1.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -1.23
(0.158)
20
Integrated
CSII+CGM
-1.23
(0.158)
20
CSII+CGM
-1.23
(0.158)
20
CSII+SMBG
-0.50
(0.169)
14.28
MDI +SMBG
-0.13
(0.093)
6.45
*Calculations to derive the uncertainty around treatment effects are given in Appendix 2.
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Population 1 – Scenario 3: Nonzero severe hypoglycaemia incidence rates from
reference studies, severe hypoglycaemia prevention effect of Veo is applied
In this scenario, all the treatment effects are identical to those from scenario 2, except for the
MiniMed Veo where we assumed a similar decrease of severe hypoglycaemia events as it
was observed in the ASPIRE trial.17 Therefore, an approximate incidence rate ratio for
severe hypoglycaemia from ASPIRE trial17 (~0.13) is applied to the incidence rate of
Integrated CSII+CGM (20) calculate the incidence rate pertaining to MiniMed Veo. The
updated treatment effects that will be used in scenario 3 can be seen in Table 23.
Table 23: Treatment effects in scenario 3 of population 1.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -1.23
(0.158)
2.5971
Integrated
CSII+CGM
-1.23
(0.158)
20
CSII+CGM
-1.23
(0.158)
20
CSII+SMBG
-0.50
(0.169)
14.28
MDI +SMBG
-0.13
(0.093)
6.45
*Calculations to derive the uncertainty around treatment effects are given in Appendix 2.
Population 1-Scenario4: 70% sensor usage
In this scenario, 70% sensor usage is assumed instead of 100% in the base case while
calculating the reduction in HbA1c baseline level using the regression equations from Pickup
201113. Reduced sensor usage decreases the HbA1c treatment effect difference between
CGM and SMBG to 0.4136. This results in the treatment effects shown in Table 24.
Table 24: Treatment effects in scenario 4 of population 1.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -1.23
(0.158)
0
Integrated
CSII+CGM
-1.23
(0.158)
0
CSII+CGM
-1.23
(0.158)
0
CSII+SMBG
-0.816
(0.169)
0
MDI +SMBG
-0.13
(0.093)
0
*Calculations to derive the uncertainty around treatment effects are given in Appendix 2.
2.4.2 Population 2: Adults experiencing frequent hypoglycaemic events
In this section, the health economic analysis for the second population (adults experiencing
frequent hypoglycaemic events) will be described.
Model input parameter updates with respect to the DAR base case
For this population, the original cohort input parameters used in the base case analysis of the
MiniMed DAR report are assumed.16 These cohort input parameters are from the baseline
characteristics of the ASPIRE trial,17 reflecting a patient population with well-controlled
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HbA1c level, but experiencing frequent hypoglycaemic events. The key characteristics of the
cohort are given in Table 25 below:
Table 25: Baseline cohort characteristics (population 2)
Input Variable
Mean
SD/SE
Source/Comment
Start Age
41.6
12.8
ASPIRE17
Duration of Diabetes
27
12.5
ASPIRE17
HbA1c
7.26%
0.71
ASPIRE17
The same utility decrement and mortality rate for severe hypoglycaemia as with the 1st
population was used. In the base case, it was assumed that patients have reached their target
HbA1c level and that this will remain well-controlled. Therefore it is assumed that the first
year HbA1c change of each intervention is 0% for this population.
Since most of the studies do not have an inclusion criteria in terms of an upper HbA1c limit,
it is assumed that studies with average baseline HbA1c less than 8.5 will reflect a patient
population with well-controlled HbA1c level. Hence, when the studies with average baseline
HbA1c higher than 8.5% and the studies in which the majority of patients are less than 18
years old are excluded from the evidence network in main DAR report 16, the remaining
evidence network directly linked to one of the interventions (Veo or Integrated CSII+CGM)
is given in Figure 4 as follows:
Figure 4: Evidence network when studies with baseline HbA1c > 8.5 and studies that include
more than 50% children are excluded
Veo
ASPIRE
Hirsch 2008
SWITCH
Battelino 2011
Integrated
CSII+CGM
CSII+CGM
STAR 3
CSII+SMBG
MDI+SMBG
It is assumed that the treatment effects in terms of hypoglycaemic incidence rates for
Integrated CSII+CGM and CSII+CGM interventions are the same.
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Among the studies in Figure 4, all the studies but Hirsch 200844 have an exclusion criteria
based on severe hypoglycaemic event history (e.g. in SWITCH, patients who has more than 3
severe hypoglycaemic events in the last 12 months were excluded). Because of the absence
of such an exclusion criterion, the base severe hypoglycaemia event incidence rate for
Integrated CSII+CGM is taken from Hirsch 200844, and in order to derive the severe
hypoglycaemia rates of the other interventions, incidence rate ratios from other studies in
Figure 4 were applied to the base incidence rate for integrated CSII+CGM.
The base severe hypoglycaemia incidence rate of integrated CSII+CGM is assumed to be
identical to that of CSII+CGM stand-alone, and equal to 33.33 per 100 patient years, derived
from Hirsch trial.44 Severe hypoglycaemia incidence rates for Veo, MDI+SMBG and
CSII+SMBG are calculated by applying the incidence rate ratios from ASPIRE17, STAR-345
and pooled estimate from Hirsch et al 2008,44 SWITCH1 and Battelino 2011,10 respectively.
Hence, the treatment effects used in the base case for this population are shown in Table 26
below:
Table 26: Treatment effects for the base case analysis of population 2.
HbA1c mean
effect (SE)
Hypo rate*
VEO
treatment 0
(0)
4.33
Integrated
CSII+CGM
0
(0)
33.33
CSII+CGM
0
(0)
33.33
CSII+SMBG
0
(0)
22.67
MDI +SMBG
0
(0)
38.36
*Calculations to derive the intervention specific hypoglycaemia event frequencies are further
discussed in Appendix 2.
Scenario Analyses for Population 2
For this population who experience severe hypoglycaemic events frequently, three additional
scenario analyses were conducted to explore the impact of different treatment effect
assumptions on total costs and total QALYs. These scenarios are listed below.
Population 2 – Scenario 1: Nonzero treatment effects in terms of HbA1c, identical Veo
and Integrated CSII+CGM HbA1c treatment effects
In this scenario, a nonzero HbA1c change with respect to the baseline level is assumed for
each intervention. It is further assumed that this change is identical for the MiniMed Veo,
CSII+CGM stand-alone and Integrated CSII+CGM. The HbA1c effect size for Veo,
Integrated CSII+CGM and CSII+CGM were derived from the ASPIRE study17, and a pooled
estimate of the HbA1c treatment effect of Veo and Integrated CSII+CGM arms (-0.02133)
was applied to all three. For MDI+SMBG, the HbA1c treatment effect difference from
STAR-3 study45 (-0.4+1=0.6) was applied on top of the calculated HbA1c treatment effect of
Integrated CSII+CGM. In a similar fashion, for CSII+SMBG, the pooled estimate of HbA1c
treatment effect difference was calculated from SWITCH,1 Battelino 201110 and Hirsch44
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studies and applied on top of the calculated HbA1c treatment effect of Integrated CSII+CGM.
Final treatment effects that were used in this scenario are given in Table 27.
Table 27: Treatment effects in scenario 1 for population 2.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment -0.021
(0.027)
4.33
Integrated
CSII+CGM
-0.021
(0.027)
33.33
CSII+CGM
-0.021
(0.027)
33.33
CSII+SMBG
0.322
(0.062)
33.33
MDI +SMBG
0.579
(0.087)
38.36
*Calculations to derive the mean treatment effects and the uncertainty around them are given in
Appendix 2.
Population 2 – Scenario 2: Differentiated Veo and Integrated CSII+CGM HbA1c
treatment effects.
In this scenario, instead of using identical change in HbA1c baseline level for MiniMed Veo
and Integrated CSII+CGM, we applied HbA1c change observed in the ASPIRE trial.17 Thus,
0 for Veo and -0.04 for integrated CSII+CGM. All other treatment effects are assumed to be
the same as the previous scenario. These are summarized in Table 28.
Table 28: Treatment effects that will be used in scenario 2 for population 2.
HbA1c mean
effect (SE*)
Hypo rate
VEO
treatment 0
(0.04)
4.33
Integrated
CSII+CGM
-0.04
(0.04)
33.33
CSII+CGM
-0.04
(0.04)
33.33
CSII+SMBG
0.322
(0.062)
33.33
MDI +SMBG
0.579
(0.087)
38.36
*Calculations to derive the mean treatment effects and the uncertainty around them are given in
Appendix 2.
Population 2 – Scenario 3: Fear of hypo unawareness benefit applied to integrated
systems.
In the STAR-3 trial45 patients using integrated CSII+CGM devices demonstrated an
improvement from baseline values on the “worry” subscale of the Hypoglycemia Fear Survey
98, compared to the MDI group. Later in Kamble et al 201246 this improvement was
translated into a utility increment of 0.0329 by using an effect on the EQ-5D questionnaire
index as estimated by Currie et al.21 As a scenario analysis, we applied this utility increment
associated with less fear of hypoglycaemia throughout the remaining lifetimes of patients
using integrated devices (the MiniMed Paradigm Veo system and integrated CSII+CGM).
This benefit is not applied to non-integrated devices (CSII+CGM stand-alone, CSII+SMBG
and MDI+SMBG), as these non-integrated devices do not give a warning nor activate/stop
releasing of insulin automatically based on low blood glucose levels. Other treatment effects
remain the same as the base case in this population.
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2.4.3 Results of cost effectiveness analyses
Population 1 –Base case
The base case results from the full incremental analysis reported as cost per QALY gained
(ICER) per technology for type 1 diabetes adult patients with difficulty maintaining their
target HbA1c (>8.5%), are summarized in Table 29.
Table 29: Base case scenario first population (all technologies)
QALYs Cost
Incr. QALY Incr. Cost ICER
MDI+SMBG
10.243
£ 60,880
Extendedly
dominated† by
MiniMed Veo
CSII+SMBG
10.531
£ 89,488
MiniMed Veo system
11.062
£ 131,586
CSII+CGM stand-alone
11.062
£ 138,089
Dominated by
MiniMed Veo
Integrated CSII+CGM (Vibe)
11.062
£ 138,698
Dominated by
MiniMed Veo
0.819
£ 70,707
£ 86,334
† An extendedly dominated strategy has an ICER higher than that of the next most effective strategy
First note that as the same treatment effects were assumed for CSII+CGM standalone and
integrated, the latter is dominated since effectiveness is the same as in the standalone
technology but the integrated technology is more expensive. MDI+SMBG is the cheapest
treatment but also the one providing the lowest amount of QALYs. CSII+SMBG is
extendedly dominated by MiniMed Veo. Essentially this means that Veo is better value than
CSII+SMBG. ICER of MiniMed Veo is £86,334. Given the common threshold ICER of
£30,000, MiniMed Veo is not cost-effective.
Alternatively, we present in Table 30 the base case ICERs for the two interventions against
every comparator. Integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone and
Veo dominates CSII+CGM stand-alone. Note that when the MiniMed Veo system is
compared to CSII+SMBG the ICER obtained is (£79,281) lower than the ICER when Veo is
compared to MDI+SMBG (£86,334).
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Table 30: Base case scenario first population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.819
£70,707
£ 86,334
MiniMed Veo system
CSII+SMBG
0.531
£42,098
£79,281
MiniMed Veo system
CSII+CGM stand-alone
0
-£ 6,503
Undefined
(Veo
dominates)
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.819
£77,818
£95,017
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.531
£49,210
£92,674
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
£ 609
Undefined
(Vibe is
dominated)
Statistical uncertainties in the model were investigated in the PSA. Since we compared five
treatments simultaneously, the scatter plot of the PSA outcomes in the cost-effectiveness
(CE) plane was not very informative (Figure 5). Nevertheless, we can observe a clear positive
correlation between costs and QALYs and that the treatments including CGM (Veo,
CSII+CGM and Integrated CSII+CGM) are almost identically scattered. These interventions
are more expensive but also providing more QALYs.
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Figure 5: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
adult patients with difficulties in maintaining their target HbA1c level (<8.5%) – base case
The cost-effectiveness acceptability curves (CEACs) for each treatment are shown in Figure
6. In this figure, it can be seen that at ceiling ratio values lower than £75,000 MDI+SMBG
was the treatment with the highest probability of being cost-effective. When that threshold is
exceeded then Veo was the treatment with the highest probability of being cost-effective.
Note that, albeit having a maximum probability value of 10%, probability of CSII+SMBG
being cost effective is nonzero for ceiling ratio values after £35,000.
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Figure 6: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – base case
Population 1 – Scenario 1: Overall HbA1c treatment effect difference from Pickup 2011
In this scenario, the overall HbA1c treatment effect difference of 0.3 from the Pickup study13
is applied instead of the one based on baseline characteristics (HbA1c, age and sensor use
frequency) used for the base case. This makes the difference in QALYs between
CSII+SMBG and CGM-including interventions smaller. This reduced difference in QALYs
can be seen in Table 31 below.
Table 31: Scenario 1 first population (all technologies)
QALYs
Cost
Incr. QALY Incr. Cost
Intervention
ICER
MDI+SMBG
10.243
£
60,880
CSII+SMBG
10.846
£
88,389
0.603
£
27,509
£ 45,632
MiniMed Veo system
11.062
£
131,586
0.216
£
43,198
£ 199,862
CSII+CGM stand-alone
11.062
£
138,089
Dominated by
MiniMed Veo
Integrated CSII+CGM (Vibe)
11.062
£
138,698
Dominated by
MiniMed Veo
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Similar to the base case, MDI+SMBG is the intervention with minimum QALYs and costs.
Increased HbA1c treatment effect of CSII+SMBG increased QALYs pertaining to
CSII+SMBG compared to the base case. Therefore, both CSII+SMBG and MiniMed Veo are
on the efficient frontier, with ICERs of £45,632 and £199,862, respectively.
The ICERs for the two interventions against every comparator are shown in Table 32.
Table 32: Scenario 1 first population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
MiniMed Veo system
MDI+SMBG
0.819
£
70,707
£
86,334
MiniMed Veo system
CSII+SMBG
0.216
£
43,198
£
199,862
MiniMed Veo system
CSII+CGM stand-alone
0
-£
6,503
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.819
£
77,818
£
95,017
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.216
£
50,309
£
232,764
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
Incr. Cost
£
609
ICER
Undefined
(Veo
dominates)
Undefined
(Vibe is
dominated)
The MiniMed Veo system dominates CSII+CGM stand-alone (cost saving with same
QALYs). The ICERs for MiniMed Veo compared to MDI+SMBG is the same as the base
case but the ICER for Veo compared to CSII+SMBG is more than doubled (approximately
£200,000 in the north-east quadrant of the cost-effectiveness plane). This can be explained by
the fact that the HbA1c treatment effect of CSII+SMBG has increased substantially and
makes the difference between the treatment effects of Veo and CSII+SMBG smaller
compared to the base case, whereas the yearly treatment costs between two interventions
remain unchanged.
Integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone. When Vibe is
compared to MDI+SMBG and CSII+SMBG the ICERs are high (approximately £95,017 and
£232,764 in the north-east quadrant of the cost-effectiveness plane, respectively). Thus, given
the common threshold ICER of £30,000 the interventions are not cost-effective.
Regarding PSA results the scatter plot of the PSA outcomes in the CE-plane was very similar
to the one obtained in the base case and therefore it is not shown here. Howeverm CEACs are
different compared to the base case as shown in Figure 7. In this scenario, MDI+SMBG is the
most cost effective scenario until a ceiling ratio of £35,000, and afterwards CSII+SMBG
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becomes the most cost-effective intervention. MiniMed Veo never becomes the most costeffective intervention for the ceiling ratios analyzed, but the probability that Veo becomes
cost-effective is non-zero for ceiling ratios larger than £70,000.
Figure 7: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – scenario 1
Population 1 – Scenario 2: Nonzero severe hypoglycaemia incidence rates from
reference studies
In this scenario, non-zero severe hypoglycemia incidence rates from the reference studies in
Figure 3 were incorporated into the analysis. Change in HbA1c baseline level is assumed
identical to the base case. The main results are given in Table 33.
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Table 33: Scenario 2 first population (all technologies)
MDI+SMBG
QALYs
10.157
£
Cost
61,129
Incr. QALY
Incr. Cost
ICER
Extendedly
dominated by
MiniMed Veo
CSII+SMBG
10.349
£
89,686
MiniMed Veo system
10.7937
£
131,440
CSII+CGM stand-alone
10.7937
£
137,880
Dominated by
MiniMed Veo
Integrated CSII+CGM (Vibe)
10.7937
£
138,483
Dominated by
MiniMed Veo
0.636
£
70,311
£
110,498
Additional inclusion of hypoglycaemic events decreased QALYs for all interventions. Both
integrated and stand-alone CSII+CGM were still dominated by MiniMed Veo, and
CSII+SMBG is extendedly dominated by Veo. Therefore, the only practical difference was in
the ICER for the MiniMed Veo compared to MDI+SMBG. This is higher compared to the
base case (£110,498 per QALY gained) The increase is caused by the more frequent
hypoglycaemic events under MiniMed Veo compared to the MDI+SMBG .
In Table 34 the ICERs for the two interventions against every comparator are shown.
MiniMed Veo system still dominates CSII+CGM stand-alone. The ICERs for MiniMed Veo
compared to CSII+SMBG (£93,933) is lower than the ICER compared to MDI+SMBG, but
higher than in the base case. Increase in the ICER compared to the base case can be explained
by the effects of more frequent severe hypoglycaemic events for MiniMed Veo. Integrated
CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone. When Vibe is compared to
MDI+SMBG and CSII+SMBG the ICERs are higher than the ICERs of MiniMed Veo
(£121,566 and £311,542 in the north-east quadrant of the cost-effectiveness plane,
respectively). Thus, given the common threshold ICER of £30,000 the interventions are not
cost-effective.
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Table 34: Scenario 2 first population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
MiniMed Veo system
MDI+SMBG
0.636
MiniMed Veo system
CSII+SMBG
MiniMed Veo system
CSII+CGM stand-alone
0
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.636
Integrated CSII+CGM (Vibe)
CSII+SMBG
Incr. Cost
ICER
£
70,311
£
41,754
-£
7,043
£
77,354
£ 121,566
£
138,483
£ 311,542
£
603
Undefined
(Vibe is
dominated)
0.445
£ 110,498
£ 93,933
Undefined
(Veo
dominates)
0.445
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
The scatter plot of the PSA outcomes in the CE-plane was very similar to the ones obtained
in the previous scenarios and therefore it is not shown here.
As it can be observed in Figure 8, CEACs in this scenario are also very similar to the ones
obtained in the base case for this population. The main difference with respect to the base
case is that the ceiling ratio when MiniMed Veo starts to become most coset effective
intervention is higher compared to the base case and around £90,000. This is expected due to
the increase of the ICER due to the relatively high number of hypoglycaemic events a Veo
patient is experiencing.
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Figure 8: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulty in maintaining their HbA1c target level – scenario 2
Population 1 – Scenario 3: Nonzero severe hypoglycaemia incidence rates from
reference studies; severe hypoglycaemia prevention effect of Veo is applied
In this scenario similar treatment effects are assumed, except for the MiniMed Veo. The
severe hypoglycaemia prevention effect of MiniMed Veo observed in the ASPIRE trial 17 is
reflected in the hypoglycaemia incidence rate of MiniMed Veo. In this scenario, MiniMed
Veo patients experience relatively less hypoglycaemic events compared to the other
interventions. Results are shown in Table 35.
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Table 35: Scenario 3 first population (all technologies)
QALYs Cost
Incr. QALY Incr. Cost ICER
MDI+SMBG
10.1574
CSII+SMBG
10.3492
CSII+CGM stand-alone
10.7937
£
61,129
Extendedly
dominated by
MiniMed Veo
£ 89,686
£
Dominated by
MiniMed Veo
137,880
Integrated CSII+CGM (Vibe)
10.7937
£ 138,483
MiniMed Veo system
11.0238
£ 131,528
MiniMed Veo
systemDominated
by MiniMed Veo
0.8664
£ 70,399
£ 81,255
The results are very similar to the base case, however it can be seen that the ICER of
MiniMed compared to the MDI+SMBG is slightly lower than the ICER in the base case,
because of the effect of relatively fewer hypoglycemic events for MiniMed Veo patients.
The ICERs for the two interventions against every comparator are shown in Table 36.
MiniMed Veo system also dominates CSII+CGM stand-alone (the ICER obtained was in the
south-east quadrant of the cost-effectiveness plane). The ICERs for MiniMed Veo compared
to MDI+SMBG and CSII+SMBG were £81,255 and £62,025 in the north-east quadrant of the
CE-plane, respectively. Integrated CSII+CGM (Vibe) is dominated by CSII+CGM standalone. ICERs compared to MDI+SMBG and CSII+SMBG the ICERs are above £100,000 in
the north-east quadrant of the cost-effectiveness plane, respectively. Thus, given the common
threshold ICER of £30,000 the integrated CSII+CGM is not cost-effective.
Table 36: Scenario 3 first population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.8664
£ 70,398.75
£ 81,255.30
MiniMed Veo system
CSII+SMBG
0.6746
£ 41,841
£
MiniMed Veo system
CSII+CGM standalone
0.23
-£
6,353
Undefined (Veo
dominates)
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.636
£
77,354
£ 121,566
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.445
£
138,483
£ 311,542
Integrated CSII+CGM (Vibe)
CSII+CGM standalone
0
£
603
53
62,025
Undefined (Vibe
is dominated)
CONFIDENTIAL UNTIL PUBLISHED
Also in this scenario the scatter plot of the PSA outcomes in the CE-plane was similar to the
ones obtained in the previous scenarios and therefore it is not shown here. The CEACs are
shown in Figure 9. We could observe that in this case first MDI+SMBG and then MiniMed
Veo had the highest probability of being the most cost-effective. When the ceiling ratio was
larger than £70,000 the most cost-effective treatments was the MiniMed Veo system.
Figure 9: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulties in controlling their HbA1c target level – scenario 3
Population 1 – Scenario 4: 70% sensor usage
In this scenario, the treatment effects differences between CSII+SMBG and integrated
CSII+CGM are calculated from Pickup study13 under the assumption of 70% sensor use.
Similar to the first scenario, this makes the difference in QALYs between CSII+SMBG and
CGM-including interventions smaller. This reduced difference in QALYs can be seen in
Table 37 below.
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Table 37: Scenario 4 first population (all technologies)
Cost
£ 60,880
Incr. QALY Incr. Cost
ICER
MDI+SMBG
QALYs
10.2431
CSII+SMBG
10.7693
£ 88,726
0.5263
£ 27,846
£ 52,911
MiniMed Veo system
11.062
£ 131,586
0.293
£ 42,860
£ 146,429
CSII+CGM stand-alone
11.062
£ 138,089
Dominated
by
MiniMed Veo
Integrated CSII+CGM (Vibe) 11.062
£ 138,698
Dominated
by
MiniMed Veo
MDI+SMBG is the intervention with minimum QALYs and costs. Increased HbA1c
treatment effect of CSII+SMBG increased QALYs pertaining to CSII+SMBG compared to
the base case. Therefore, both CSII+SMBG and MiniMed Veo are on the efficient frontier,
with ICERs of £52,911 and £146,429, respectively.
The ICERs for the two interventions against every comparator are shown in Table 38.
Table 38: Scenario 4 first population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.819
£ 70,707
£
86,334
MiniMed Veo system
CSII+SMBG
0.293
£ 42,860
£
146,429
MiniMed Veo system
CSII+CGM standalone
0
-£ 6,503
Integrated CSII+CGM
(Vibe)
MDI+SMBG
0.819
£ 77,818
£
95,017
Integrated CSII+CGM
(Vibe)
CSII+SMBG
0.293
£ 49,972
£
170,724
Integrated CSII+CGM
(Vibe)
CSII+CGM standalone
0
£ 09
Undefined (Veo
dominates)
Undefined (Vibe is
dominated)
MiniMed Veo dominates CSII+CGM stand-alone (cost saving with same QALYs). The
ICERs for MiniMed Veo compared to MDI+SMBG is the same as the base case but ICER for
Veo compared to CSII+SMBG is higher (approximately £146,000 in the north-east quadrant
of the cost-effectiveness plane). This can be explained by the fact that the HbA1c treatment
55
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effect of CSII+SMBG has increased substantially and make the difference between the
treatment effects of Veo and CSII+SMBG smaller compared to the base case, whereas the
yearly treatment costs between two interventions remain unchanged.
Integrated CSII+CGM (Vibe) is dominated by CSII+CGM stand-alone. When Vibe is
compared to MDI+SMBG and CSII+SMBG the ICERs are high (approximately £95,017 and
£170,724 in the north-east quadrant of the cost-effectiveness plane, respectively). Thus, given
the common threshold ICER of £30,000 the interventions are not cost-effective.
Regarding PSA results the scatter plot of the PSA outcomes in the CE-plane was very similar
to the one obtained in the base case and therefore it is not shown here. In this scenario,
CEACs resemble the CEACs in scenario 1 as shown in Figure 10. In this scenario,
MDI+SMBG is the most cost effective strategy for ceiling ratios lower than £45,000, and
afterwards CSII+SMBG becomes the most cost-effective intervention. MiniMed Veo is never
the most cost-effective intervention for the ceiling ratios analysed, but the probability that
Veo is cost-effective is non-zero for ceiling ratios larger than £55,000 and continuously
increasing (therefore, it is expected that for large enough values of the ceiling ratio MiniMed
Veo becomes the most cost-effective strategy).
Figure 10: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients with difficulties in controlling their HbA1c target level – scenario 4
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Population 2 –Base case
The base case results for the full incremental analysis for type 1 diabetes adult patients
experiencing frequent hypoglycaemic events are summarized in Table 39.
Table 39: Base case scenario second population (all technologies)
QALYs
Cost
Incr. QALY
Incr. Cost
ICER
MDI+SMBG
11.5222
£56,672
Integrated CSII+CGM (Vibe)
11.5800
£145,898
CSII+CGM stand-alone
11.5800
£145,236
CSII+SMBG
11.7020
£90,180
0.1797
£33,508
£186,423
MiniMed Veo system
11.9563
£138,331
0.2543
£48,151
£189,326
Dominated by
CSII+CGM
stand-alone
Dominated by
CSII+SMBG
MDI+SMBG was the cheapest treatment but also the one providing the lowest amount of
QALYs. Since the same treatment effects were assumed for CSII+CGM stand-alone and
integrated, the latter is dominated because the integrated technology is more expensive.
CSII+CGM stand-alone provided less QALYs and was more expensive than CSII+SMBG,
therefore CSII+CGM stand-alone is also dominated. The ICER of CSII+SMBG compared to
MDI+SMBG was £186,423. Finally, the ICER of MiniMed Paradigm Veo compared to
CSII+SMBG was £189,326. Thus, given the common threshold ICER of £30,000, it is clear
that CSII+SMBG and MiniMed Paradigm Veo are not cost-effective.
We present in Table 40 the base case ICERs for the two interventions against every
comparator. When the MiniMed Veo system was compared to CSII+CGM stand-alone the
ICER obtained was in the south-east quadrant of the cost-effectiveness plane (positive
incremental QALYs and negative incremental costs). In this case, the MiniMed Veo system
dominates CSII+CGM stand-alone. The ICERs obtained when MiniMed Veo is compared to
MDI+SMBG and CSII+SMBG are very similar (approximately £190,000 in the north-east
quadrant of the cost-effectiveness plane). Integrated CSII+CGM (Vibe) is dominated by both
CSII+SMBG and CSII+CGM stand-alone. When Vibe is compared to MDI+SMBG the
ICER is above £1,500,000 in the north-east quadrant of the cost-effectiveness plane. Thus,
given the common threshold ICER of £30,000 the interventions are not cost-effective.
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Table 40: Base case scenario second population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.4341
£81,658
£188,124
MiniMed Veo system
CSII+SMBG
0.2543
£48,151
£189,326
MiniMed Veo system
CSII+CGM stand-alone
0.3761
-£6905
CSII+CGM
stand-alone is
dominated
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.0580
£89,226
£1,538,493
Integrated CSII+CGM (Vibe)
CSII+SMBG
-0.1217
£55,718
Integrated
CSII+CGM is
dominated
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
£662
Undefined
(Vibe is
dominated)
PSA results for the five treatments considered are presented in two ways: a scatter plot of the
PSA outcomes in the cost-effectiveness plane (Figure 11) and cost-effectiveness acceptability
curves (Figure 12).
In the scatter plot of the PSA outcomes in the CE-plane, although it was not very informative,
we could observe a positive correlation between costs and QALYs and also that the
treatments including CGM were similarly scattered (they are more expensive but also provide
more QALYs).
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Figure 11: Cost-effectiveness plane with PSA outcomes for all treatments in type 1 diabetes
adult patients experiencing frequent hypoglycaemic events
The CEACs for each treatment (Figure 12) showed that only the treatments including SMBG
are those considered cost-effective. For the values of the ceiling ratio shown in Figure 12,
MDI+SMBG is always the treatment with the highest probability of being cost-effective.
When the threshold exceeds £186,423 (not shown in Figure 12 but known from Table 39)
then CSII+SMBG is the treatment with the highest probability of being cost-effective. For the
three treatments including CGM the cost-effectiveness probability was zero for all the ceiling
ratios considered in the analysis. This is to be expected since both CSII+CGM integrated and
stand-alone are dominated, and for the MiniMed Veo the difference in costs compared to
SMBG-treatments was too large to outweigh the additional gain in QALYs.
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Figure 12: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events
Population 2 - Scenario 1: Nonzero treatment effects in terms of HbA1c, identical Veo
and Integrated CSII+CGM HbA1c treatment effects
In this scenario a nonzero HbA1c reduction was assumed for all treatments. Furthermore, it
was assumed that such reduction was equal for the three treatments including CGM as shown
in Table 27. The main results can be seen in Table 41.
Table 41: Scenario 1 second population (all technologies)
QALYs
Cost
MDI+SMBG
11.0050
£60,211
CSII+SMBG
11.4118
£91,693
Integrated CSII+CGM (Vibe)
11.5899
£145,620
Dominated by
CSII+CGM
stand-alone
CSII+CGM stand-alone
11.5899
£144,958
Dominated by
MiniMed Veo
MiniMed Veo system
11.9795
£138,267
60
Incr. QALY
Incr. Cost
ICER
0.4068
£31,481
£77,386
0.5677
£46,574
£82,040
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Both integrated and stand-alone CGM provided more QALYs than CSII+SMBG but they
were dominated by MiniMed Veo. Thus, MDI+SMBG was the intervention with minimum
costs and QALYs gained, with CSII+SMBG and MiniMed Veo on the efficient frontier, with
ICERs of £77,386 and £82,040 per QALY gained, respectively. Thus, given the common
threshold ICER of £30,000 they are not cost-effective.
The ICERs for the two interventions against every comparator are shown in Table 42.
MiniMed Veo system dominates CSII+CGM stand-alone (the ICER obtained was in the
south-east quadrant of the cost-effectiveness plane). The ICERs for MiniMed Veo compared
to MDI+SMBG and CSII+SMBG are very similar (approximately £80,000 in the north-east
quadrant of the cost-effectiveness plane). Integrated CSII+CGM (Vibe) is dominated by
CSII+CGM stand-alone. When Vibe is compared to MDI+SMBG and CSII+SMBG the
ICERs are high (approximately £150,000 and £300,000 in the north-east quadrant of the costeffectiveness plane, respectively). Thus, given the common threshold ICER of £30,000 the
interventions are not cost-effective.
Table 42: Scenario 1 second population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.9745
£78,056
£80,098
MiniMed Veo system
CSII+SMBG
0.5677
£46,575
£82,040
MiniMed Veo system
CSII+CGM stand-alone
0.3896
-£6,690
-£17,171
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.5849
£85,409
£146,027
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.1781
£53,927
£302,829
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
£662
Undefined (Vibe is
dominated)
Regarding PSA results the scatter plot of the PSA outcomes in the CE-plane was very similar
to the one obtained in the base case and therefore it is not shown here. The CEACs on the
contrary depict a more interesting situation as shown in Figure 13. Especially when the
ceiling ratio is close to £80,000 the MiniMed Veo system, MDI+SMBG and CSII+SMBG
have approximately the same probability of being cost-effective. As the threshold increases,
MiniMed Veo is the treatment with the highest probability of being cost-effective.
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Figure 13: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 1
Population 2 - Scenario 2: Differentiated Veo and Integrated CSII+CGM HbA1c
treatment effects.
The only difference with respect to the previous scenario is that a different nonzero HbA1c
reduction was assumed for both integrated and stand-alone CSII+CGM, whereas for the
MiniMed Veo no reduction in HbA1c was considered (see Table 28). The main results are
shown in Table 43.
Table 43: Scenario 2 second population (all technologies)
QALYs
Cost
MDI+SMBG
11.0050
£60,211
CSII+SMBG
11.4118
£91,693
Integrated CSII+CGM (Vibe)
11.6059
£145,599
Dominated by
CSII+CGM standalone
CSII+CGM stand-alone
11.6059
£144,936
Dominated by
MiniMed Veo
MiniMed Veo system
11.9590
£138,337
62
Incr. QALY
Incr. Cost
ICER
0.4068
£31,481
£77,386
0.5472
£46,645
£85,237
CONFIDENTIAL UNTIL PUBLISHED
Although both integrated and stand-alone CSII+CGM provided different costs and QALYs
than in the previous scenario, these were still dominated by MiniMed Veo. Therefore, the
only practical difference was in the ICER for the MiniMed Veo compared to CSII+SMBG
which was slightly higher now (£85,237 per QALY gained) but nevertheless higher than the
common threshold ICER of £30,000. Thus, the MiniMed Veo is not cost-effective.
In Table 44 the ICERs for the two interventions against every comparator are shown.
MiniMed Veo system still dominates CSII+CGM stand-alone (the ICER obtained was in the
south-east quadrant of the cost-effectiveness plane). The ICERs for MiniMed Veo compared
to MDI+SMBG and CSII+SMBG are similar and approximately £80,000 in the north-east
quadrant of the CE-plane. Integrated CSII+CGM (Vibe) is dominated by CSII+CGM standalone. When Vibe is compared to MDI+SMBG and CSII+SMBG the ICERs are high
(approximately £140,000 and £275,000 in the north-east quadrant of the cost-effectiveness
plane, respectively). Thus, given the common threshold ICER of £30,000 the interventions
are not cost-effective.
Table 44: Scenario 2 second population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
0.9540
£78,126
£81,890
MiniMed Veo system
CSII+SMBG
0.5472
£46,645
£85,237
MiniMed Veo system
CSII+CGM stand-alone
0.3531
-£6,599
-£18,689
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6009
£85,387
£142,091
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.1941
£53,906
£277,684
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0
£663
Undefined (Vibe
is dominated)
The scatter plot of the PSA outcomes in the CE-plane was very similar to the ones obtained
in the previous scenarios and therefore it is not shown here. The CEACs are also very similar
to the ones obtained in Scenario 1 for this population and it is shown in Figure 14. The main
difference with respect to the previous scenario is that when the ceiling ratio is close to
£80,000 the most cost-effective treatments is CSII+SMBG followed by MDI+SMBG and the
MiniMed Veo system (whereas in the previous scenario they were approximately equally
cost-effective). As the threshold increases, then MiniMed Veo is also here the treatment with
the highest probability of being cost-effective.
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Figure 14: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 2
Population 2 – Scenario 3: Fear of hypo unawareness benefit applied to integrated systems.
In this scenario we applied a utility increment of 0.0329 from Kamble et al 2012 46 associated
with less fear of hypoglycaemia throughout the remaining lifetimes of patients using
integrated devices, thus for the MiniMed Paradigm Veo system and integrated CSII+CGM
only. Treatment effects as defined per HbA1c reduction and rate of experiencing major
hypoglycaemic events remain the same as in the base case for this population. Results are
shown in Table 45.
Table 45: Scenario 3 second population (all technologies)
QALYs
Cost
MDI+SMBG
11.5222
£56,672
CSII+CGM stand-alone
11.5802
£145,236
Dominated by
CSII+SMBG
CSII+SMBG
11.7020
£90,180
Extendedly
dominated by
MiniMed Veo
Integrated CSII+CGM (Vibe)
12.1508
£145,898
Dominated by
MiniMed Veo
MiniMed Veo system
12.5342
£138,331
64
Incr. QALY
1.0120
Incr. Cost
£81,658
ICER
£80,692
CONFIDENTIAL UNTIL PUBLISHED
In this case integrated and stand-alone CSII+CGM were dominated and CSII+SMBG was
extendedly dominated. Therefore, the only relevant comparison was MiniMed Veo against
MDI+SMBG with an ICER equal £80,692 per QALY gained. Thus, given the common
threshold ICER of £30,000 MiniMed Veo is not cost-effective.
The ICERs for the two interventions against every comparator are shown in Table 46.
MiniMed Veo system also dominates CSII+CGM stand-alone (the ICER obtained was in the
south-east quadrant of the cost-effectiveness plane). The ICERs for MiniMed Veo compared
to MDI+SMBG and CSII+SMBG were £80,692 and £57,857 in the north-east quadrant of the
CE-plane, respectively. Integrated CSII+CGM (Vibe) is not dominated in this scenario.
When Vibe is compared to CSII+CGM stand-alone the ICER is £1161 and therefore the
integrated system is cost-effective. Compared to MDI+SMBG and CSII+SMBG the ICERs
are above £100,000 in the north-east quadrant of the cost-effectiveness plane, respectively.
Thus, given the common threshold ICER of £30,000 the integrated CSII+CGM is not costeffective.
Table 46: Scenario 3 second population (intervention vs. comparator only)
Intervention
Comparator
Incr. QALY
Incr. Cost
ICER
MiniMed Veo system
MDI+SMBG
1.0120
£81,658
£80,692
MiniMed Veo system
CSII+SMBG
0.8322
£48,151
£57,857
MiniMed Veo system
CSII+CGM stand-alone
0.3834
-£7,568
-£19,737
Integrated CSII+CGM (Vibe)
MDI+SMBG
0.6286
£89,226
£141,953
Integrated CSII+CGM (Vibe)
CSII+SMBG
0.4488
£55,718
£124,144
Integrated CSII+CGM (Vibe)
CSII+CGM stand-alone
0.5706
£662
£1,161
Also in this scenario the scatter plot of the PSA outcomes in the CE-plane were similar to the
ones obtained in the previous scenarios and therefore it is not shown here. The CEACs are
shown in Figure 15. We could observe that in this case only MDI+SMBG and MiniMed Veo
had large probability of being cost-effective. When the ceiling ratio was larger than £80,000
the most cost-effective treatments was the MiniMed Veo system.
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Figure 15: Cost-effectiveness acceptability curves for all treatments in type 1 diabetes adult
patients experiencing frequent hypoglycaemic events – scenario 3
Cost-effectiveness results summary
All cost-effectiveness results where dominance did not occur are summarized in Table 47 for
the first population and in Table 48 for the second population.
In general the only relevant comparators are MDI+SMBG and CSII+SMBG. The only
exception to this is observed in scenario 3 (fear of hypo unawareness benefit applied to
integrated systems) for the second population (Table 48) where CSII+CGM stand-alone is
not dominated by integrated CSII+CGM (Vibe) but the comparison results in a very low
ICER (£1,161).
For the first population the lowest ICER (£62,025) is obtained in scenario 3 (nonzero severe
hypoglycaemia incidence rates from reference studies; severe hypoglycaemia prevention
effect of Veo is applied) for the comparison MiniMed Veo vs. CSII+SMBG. The highest
ICER (£311,542) is obtained in scenario 2 (nonzero severe hypoglycaemia incidence rates
from reference studies) for the comparison integrated CSII+CGM (Vibe) vs. CSII+SMBG.
Thus, for this population given the common threshold ICER of £30,000, MiniMed Veo and
integrated CSII+CGM (Vibe) are not cost-effective compared to MDI+SMBG or
CSII+SMBG.
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Table 47: Cost-effectiveness results where dominance did not occur for the first population
Population 1
Scenario
Intervention
Comparator
Incr.
QALY
Incr.
Cost
ICER
MDI+SMBG
0.819
£70,707
£86,334
CSII+SMBG
0.531
£42,098
£79,281
MDI+SMBG
0.819
£77,818
£95,017
CSII+SMBG
0.531
£49,210
£92,674
MiniMed Veo system
Base case
Integrated CSII+CGM
(Vibe)
MDI+SMBG
Same as in base case
MiniMed Veo system
Scenario 1 Overall
HbA1c treatment
effect difference
from Pickup 2011
CSII+SMBG
Integrated CSII+CGM
(Vibe)
0.216
MDI+SMBG
£43,198
£199,862
Same as in base case
CSII+SMBG
0.216
£50,309
£232,764
MDI+SMBG
0.636
£70,311
£110,498
CSII+SMBG
0.445
£41,754
£93,933
MDI+SMBG
0.636
£77,354
£121,566
CSII+SMBG
0.445
£138,483
£311,542
MDI+SMBG
0.8664
£70,399
£81,255
CSII+SMBG
0.6746
£41,841
£62,025
MiniMed Veo system
Scenario 2 Nonzero
severe
hypoglycaemia
incidence rates
Scenario 3 Nonzero
severe
hypoglycaemia
incidence rates plus
severe
hypoglycaemia
prevention effect of
Veo
Integrated CSII+CGM
(Vibe)
MiniMed Veo system
Integrated CSII+CGM
(Vibe)
MDI+SMBG
Same as in scenario 2
CSII+SMBG
Same as in scenario 2
MDI+SMBG
Same as in base case
MiniMed Veo system
CSII+SMBG
Scenario 4
70% sensor usage
Integrated CSII+CGM
(Vibe)
0.293
MDI+SMBG
CSII+SMBG
67
£42,860
£146,429
Same as in base case
0.293
£ 49,972
£170,724
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With the exception of the comparison integrated CSII+CGM (Vibe) vs. CSII+CGM standalone in scenario 3 (fear of hypo unawareness benefit applied to integrated systems) where
the integrated system is cost-effective (ICER = £1,161/QALY), for the second population the
lowest ICER (£57,857) is also obtained in scenario 3 for the comparison MiniMed Veo vs.
CSII+SMBG. The highest ICER (£1,538,493) is obtained in the base case scenario for the
comparison integrated CSII+CGM (Vibe) vs. MDI+SMBG. Thus, for this population given
the common threshold ICER of £30,000, MiniMed Veo and integrated CSII+CGM (Vibe) are
not cost-effective compared to MDI+SMBG or CSII+SMBG.
Table 48: Cost-effectiveness results where dominance did not occur for the second population
Population 2
Scenario
Intervention
Comparator
Incr.
QALY
Incr.
Cost
ICER
MDI+SMBG
0.4341
£81,658
£188,124
CSII+SMBG
0.2543
£48,151
£189,326
MDI+SMBG
0.0580
£89,226
£1,538,493
MDI+SMBG
0.9745
£78,056
£80,098
CSII+SMBG
0.5677
£46,575
£82,040
MDI+SMBG
0.5849
£85,409
£146,027
CSII+SMBG
0.1781
£53,927
£302,829
MDI+SMBG
0.9540
£78,126
£81,890
CSII+SMBG
0.5472
£46,645
£85,237
MDI+SMBG
0.6009
£85,387
£142,091
CSII+SMBG
0.1941
£53,906
£277,684
MDI+SMBG
1.0120
£81,658
£80,692
CSII+SMBG
0.8322
£48,151
£57,857
MDI+SMBG
0.6286
£89,226
£141,953
CSII+SMBG
0.4488
£55,718
£124,144
CSII+CGM stand-alone
0.5706
£662
£1,161
MiniMed Veo system
Base case
Integrated CSII+CGM (Vibe)
Scenario 1
Nonzero
treatment
effects HbA1c,
identical Veo
and Integrated
CSII+CGM
HbA1c
treatment
effects
Scenario 2
Differentiated
Veo and
Integrated
CSII+CGM
HbA1c
treatment
effects.
MiniMed Veo system
Integrated CSII+CGM (Vibe)
MiniMed Veo system
Integrated CSII+CGM (Vibe)
MiniMed Veo system
Scenario 3
Fear of hypo
unawareness
benefit applied
to integrated
systems.
Integrated CSII+CGM (Vibe)
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2.4.4 Conclusions
We assessed the cost-effectiveness of the MiniMed Paradigm Veo system and the Vibe and
G4 PLATINUM CGM system compared with stand-alone CSII+CGM, CSII+SMBG,
MDI+CGM, and MDI+SMBG for the management of type 1 diabetes in adults.
Besides the literature limitations regarding the other population subgroups of interest (i.e.
children and pregnant women), the model employed to conduct the cost-effectiveness
analyses, the IMS CDM, is not suitable to model long-term outcomes for children/adolescent
and pregnant women populations, because the background risk adjustment/ risk factor
progression equations are all based on adult populations.
The comparator MDI+CGM was not included in the cost-effectiveness analyses since no
evidence was found in the systematic review. Moreover, in the absence of data comparing the
clinical effectiveness of integrated CSII+CGM systems against stand-alone CSII+CGM
systems, we assumed in our analyses that both technologies would be equally effective,
which seems to be plausible. The immediate consequence of this assumption is that standalone CSII+CGM systems dominated the integrated CSII+CGM systems since the standalone system was cheaper, according to our estimated cost, whilst being equally effective.
We focused on two populations, first a patient population who had difficulty in maintaining
their HbA1c levels and a second population experiencing frequent severe hypoglycaemic
events. Based on the characteristics of the disease, it is further assumed that in the base case
analysis, the first population does not suffer from severe hypoglycaemia and second
population has a well-controlled HbA1c.
In the first population, the base-case cost-effectiveness results suggested that the
MDI+SMBG technology is the cheapest option, and the option that provides the lowest
number of QALYs. MiniMed Veo compared to MDI+SMBG has an ICER of £86,334.
CSII+SMBG was extendedly dominated and Integrated CSII+CGM and CSII+CGM stand
alone were dominated by MiniMed Veo. When MiniMed Veo is compared to CSII+SMBG,
the ICER is around £ 86,334 and when integrated CSII+CGM is compared to the SMBG
including devices, the ICER is around £90,000. Given the common threshold ICER of
£30,000, MiniMed Veo and Integrated CSII+CGM would not be cost-effective.
The results of the four scenario analyses can differ substantially from the base case results.
Especially in the scenarios where the effectiveness of CSII+SMBG is estimated based on the
70% sensor usage assumption and when overall HbA1c treatment effect difference is used
instead of baseline specific HbA1c treatment difference from Pickup. In these scenarios,
CSII+SMBG has an ICER of around £50,000 and the ICER of MiniMed Veo when compared
to CSII+SMBG increases substantially, to £150,000 and £200,000, respectively .
The scenario that was most favourable to MiniMed Veo was the one that incorporated severe
hypoglycaemic event incidence rates and the severe hypoglycaemia reducing effect of
MiniMed Veo. In that scenario the ICER of MiniMed Veo compared to CSII+SMBG was
around £62,000 (the lowest found in all analyses). However, given the common threshold
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ICER of £30,000, MiniMed Veo would still not be considered cost-effective. The Vibe and
G4 PLATINUM CGM system were always dominated by MiniMed Veo.
In the second population (adults experiencing frequent hypoglycaemic events), MDI+SMBG
technology is also the cheapest option, and the one providing the minimum QALYs. In the
base case scenario no change in HbA1c baseline level was assumed for all the treatments.
Both integrated and stand-alone CSII+CGM are dominated. The ICER of CSII+SMBG
compared to MDI+SMBG was £186,423; and the ICER of MiniMed Paradigm Veo
compared to CSII+SMBG was £189,326. Thus, given the common threshold ICER of
£30,000, CSII+SMBG and MiniMed Paradigm Veo are not cost-effective.
In two of the additional scenarios a nonzero change in HbA1c baseline level was assumed.
This resulted in an ICER of MiniMed Veo compared to CSII+SMBG of approximately
£80,000. Integrated and stand-alone CSII+CGM were still dominated. In the last scenario
explored, the change in HbA1c baseline level is restored to zero but an utility increment
associated with less fear of hypoglycaemia throughout the remaining lifetimes of patients
using integrated devices, thus for the MiniMed Paradigm Veo system and integrated
CSII+CGM only. In this case the only relevant comparison was MiniMed Veo against
MDI+SMBG with an ICER equal £80,692 per QALY gained. All other technologies were
dominated. However, given the common threshold ICER of £30,000 MiniMed Veo is not
cost-effective.
2.4.5 Discussion
Many of the strengths and weaknesses discussed in the DAR are also relevant in the analyses
presented in this addendum. It was observed in this addendum that the UK study by Roze et
al. uses different values for many of the input parameters. In many cases, our input values
that were taken from CG1537 were more recent or UK specific and often used or estimated in
earlier
clinical
guidelines.
***************************************************************************
************************************************
***************************************************************************
***************************************************************************
**************************
An important issue in this study is the interaction between HbA1c and the hypoglycaemic
event rate. For example, if a population has high HbA1c and has a low hypoglycaemic event
rate, it is possible that lowering the HbA1c may cause the hypoglycaemic event rate to go up.
However, the IMS CORE model does not allow for the hypoglycaemic event rate to change
according to HbA1c changes. Also it does not allow for the option to increase the rate of
severe hypoglycaemic rates due to the unawareness caused by earlier severe hypoglycaemic
attacks.
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As mentioned in Section 3, it is clear from the Currie et al. study 21 that the effect of fear is
already incorporated in the EQ-5D value. Therefore, it should be emphasized that the
scenario explored in population 2 (adults who experience severe hypoglycaemic events
frequently) where an additional utility increment of 0.0329 associated with less fear of
hypoglycaemia is applied for the MiniMed Paradigm Veo system and integrated CSII+CGM
only, represents an extreme case. The results of this scenario (integrated and stand-alone
CSII+CGM were dominated, CSII+SMBG was extendedly dominated and the ICER for
MiniMed Veo against MDI+SMBG was approximately £80,000) should be then interpreted
with caution.
Effects of different baseline ages (43 vs. 25) are also explored in this study, while keeping the
baseline HbA1c (7.26) and HbA1c treatment effects (same as the MiniMed DAR) constant.
The ICER comparing MiniMed Veo and CSII+SMBG in these two settings were very similar
(results not reported). Thus, it is unlikely that MiniMed Veo is more cost-effective in an age
defined subgroup of the adult patients. Of course, given the relationship between treatment
effect and age estimated by Pickup et al., it cannot be ruled out that, if there is a sub-group of
patients with both high HbA1c and high severe hypoglycaemic event rate and who are young,
Minimed Veo might be cost effective.
Overall, it has been emphasised by clinical experts, patients and parents of patients that fear
of hypoglycaemic events is an important feature of living with type 1 diabetes. This is mostly
related to the fact that a hypoglycaemic event has the potential to lead to death almost
immediately whereas the consequences of not-well controlled blood glucose may be just as
severe but will occur most likely not until later in life. However, a non-fatal hypoglycaemic
event will only have short term effects on costs and quality of life whereas prolonged
uncontrolled blood glucose will have long lasting impact on both costs and quality of life. It
is exactly this balance between short and long term consequences of health interventions that
is best investigated using health economic modelling.
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References
[1] Battelino T, Conget I, Olsen B, Schutz-Fuhrmann I, Hommel E, Hoogma R, et al. The use
and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump
therapy: a randomised controlled trial. Diabetologia 2012;55(12):3155-62.
[2] Conget I, Battelino T, Gimenez M, Gough H, Castaneda J, Bolinder J, et al. The SWITCH
study (sensing with insulin pump therapy to control HbA(1c)): design and methods of a
randomized controlled crossover trial on sensor-augmented insulin pump efficacy in type 1
diabetes suboptimally controlled with pump therapy. Diabetes Technol Ther 2011;13(1):4954.
[3] Hommel E, Olsen B, Battelino T, Conget I, Schutz-Fuhrmann I, Hoogma R, et al. Impact
of continuous glucose monitoring on quality of life, treatment satisfaction, and use of medical
care resources: analyses from the SWITCH study. Acta Diabetol 2014;51(5):845-51.
[4] Radermecker RP, Saint Remy A, Scheen AJ, Bringer J, Renard E. Continuous glucose
monitoring reduces both hypoglycaemia and HbA1c in hypoglycaemia-prone type 1 diabetic
patients treated with a portable pump. Diabetes Metab 2010;36(5):409-13.
[5] Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous
subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in
type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for
the Development of Pump Therapy in Diabetes. Diabetes Care 2000;23(9):1232-5.
[6] Choudhary P, Shin J, Wang Y, Evans ML, Hammond PJ, Kerr D, et al. Insulin pump
therapy with automated insulin suspension in response to hypoglycemia: reduction in
nocturnal hypoglycemia in those at greatest risk. Diabetes Care 2011;34(9):2023-5.
[7] Choudhary P, Ramasamy S, Green L, Gallen G, Pender S, Brackenridge A, et al. Realtime continuous glucose monitoring significantly reduces severe hypoglycemia in
hypoglycemia-unaware patients with type 1 diabetes. Diabetes Care 2013;36(12):4160-4162.
[8] Rawlings R, Yuan L, Shi H, Brehm W, Pop-Busui R, Nelson P. Dynamic Stress Factor
(DySF): a significant predictor of severe hypoglycemic events in children with type 1
diabetes. J Diabetes Metab 2012;3:17.
[9] Nixon R, Pickup JC. Fear of hypoglycemia in type 1 diabetes managed by continuous
subcutaneous insulin infusion: is it associated with poor glycemic control? Diabetes Technol
Ther 2011;13(2):93-8.
72
CONFIDENTIAL UNTIL PUBLISHED
[10] Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J. Effect of
continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care
2011;34(4):795-800.
[11] Roze S, Smith-Palmer J, Valentine WJ, Cook M, Jethwa M, de Portu S, et al. Long-term
health economic benefits of sensor-augmented pump therapy versus continuous subcutaneous
insulin infusion alone in type 1 diabetes: a UK perspective [unpublished]. 2015.
[12] Roze C. Cost effectiveness study SAP vs. CSII in UK [online]. E-mail to Isaac Corro
Ramos ([email protected]) 2015 May 5 [cited 2015 Jun 1].
[13] Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real
time continuous glucose monitoring compared with self monitoring of blood glucose: metaanalysis of randomised controlled trials using individual patient data. BMJ 2011;343:d3805.
[14] Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW. Effect of sensoraugmented insulin pump therapy and automated insulin suspension vs standard insulin pump
therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA
2013;310(12):1240-7.
[15] Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic
submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ
1996;313(7052):275-83.
[16] Riemsma R, Corro Ramos I, Birnie R, Büyükkaramikli N, Armstrong N, Ryder S, et al.
Type 1 diabetes: Integrated sensor-augmented pump therapy systems for managing blood
glucose levels (The MiniMed Paradigm Veo System and the Vibe and G4 PLATINUM CGM
system), a systematic review and economic evaluation. York: Kleijnen Systematic Reviews
Ltd, 2015
[17] Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et al.
Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med
2013;369(3):224-32.
[18] National Institute for Health and Care Excellence. Type 1 diabetes: diagnosis and
management of type 1 diabetes in children, young people and adults. NICE clinical guideline
15 [Internet]. London: National Institute for Health and Care Excellence, 2004 [accessed
31.7.14] Available from: http://www.nice.org.uk/Guidance/CG15
[19] Clarke P, Gray A, Holman R. Estimating utility values for health states of type 2 diabetic
patients using the EQ-5D (UKPDS 62). Med Decis Making 2002;22(4):340-9.
73
CONFIDENTIAL UNTIL PUBLISHED
[20] Beaudet A, Clegg J, Thuresson PO, Lloyd A, McEwan P. Review of utility values for
economic modeling in type 2 diabetes. Value Health 2014;17(4):462-70.
[21] Currie CJ, Morgan CL, Poole CD, Sharplin P, Lammert M, McEwan P. Multivariate
models of health-related utility and the fear of hypoglycaemia in people with diabetes. Curr
Med Res Opin 2006;22(8):1523-34.
[22] Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of
life: a population study. Diabetes Care 2004;27(5):1066-70.
[23] National Institute for Health and Care Excellence. Guide to the methods of technology
appraisal 2013 [Internet]. London: National Institute for Health and Care Excellence, 2013
[accessed 8.7.14]. 93p. Available from: http://publications.nice.org.uk/pmg9
[24] Papaioannou D, Brazier JE, Paisley S. Figure 4: Common free-text terms for electronic
database searching for HSUVs. In: NICE DSU Technical Support Document 9: the
identification, review and synthesis of health state utility values from the literature [Internet],
2011 [accessed 5.5.15]. Available from: http://www.nicedsu.org.uk
[25] Lauridsen JT, Lonborg J, Gundgaard J, Jensen HH. Diminishing marginal disutility of
hypoglycaemic events. Paper presented at ISPOR 16th Annual European Congress; 2-6 Nov
2013; Dublin: Ireland. Value Health 2013;16(7):A445.
[26] Gundgaard J, Harris SB, Evans M, Khunti K, Mamdani M, Galbo-Jorgensen CB, et al.
Health-related quality of life associated with daytime and nocturnal hypoglycaemic events: a
time trade-off survey. Paper presented at 48th Annual Meeting of the European Association
for the Study of Diabetes, EASD; 1-5 Oct 2012; Berlin: Germany. Diabetologia
2012;55:S101.
[27] Evans M, Khunti K, Mamdani M, Harris S, Galbo-Jorgensen C, Gundgaard J, et al.
Health-related quality of life associated with daytime and nocturnal hypoglycemic events: a
time trade-off survey. Paper presented at 72nd Scientific Sessions of the American Diabetes
Association; 8-12 Jun 2012; Philadelphia: USA. Diabetes 2012;61:A36.
[28] Evans M, Khunti K, Mamdani M, Galbo-Jorgensen CB, Gundgaard J, Bogelund M, et
al. Health-related quality of life associated with daytime and nocturnal hypoglycaemic
events: a time trade-off survey in five countries. Health Qual Life Outcomes 2013;11:90.
[29] Adler A, Jofre-Bonet M, Wilkinson G, Martin A, McGuire A. Quantifying the loss of
health-related quality of life from hypoglycemia. Paper presented at 74th Scientific Sessions
74
CONFIDENTIAL UNTIL PUBLISHED
of the American Diabetes Association; 13-17 Jun 2014; San Francisco: USA. Diabetes
2014;63:A564.
[30] Roze S, Cook M, Jethwa M, de Portu S. Projection of long term health-economic
benefits of sensor augmented pump (SAP) versus pump therapy alone (CSII) in type 1
diabetes, a UK perspective. Paper presented at ISPOR 17th Annual European Congress; 8-12
Nov 2014; Amsterdam: The Netherlands. Value Health 2014;17(7):A348.
[31] Harris S, Mamdani M, Galbo-Jørgensen CB, Bøgelund M, Gundgaard J, Groleau D. The
effect of hypoglycemia on health-related quality of life: Canadian results from a multinational
time trade-off survey. Can J Diabetes 2014;38(1):45-52.
[32] Norgaard K, Scaramuzza A, Bratina N, Lalic NM, Jarosz-Chobot P, Kocsis G, et al.
Routine sensor-augmented pump therapy in type 1 diabetes: the INTERPRET study. Diabetes
Technol Ther 2013;15(4):273-80.
[33] Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. Hypoglycemia and
risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1
and type 2 diabetes: a cohort study. Diabetes Care 2015;38(2):316-22.
[34] Rajendran R, Hodgkinson D, Rayman G. Patients with diabetes requiring emergency
department care for hypoglycaemia: characteristics and long-term outcomes determined from
multiple data sources. Postgrad Med J 2015;91(1072):65-71.
[35] Nirantharakumar K, Marshall T, Kennedy A, Narendran P, Hemming K, Coleman JJ.
Hypoglycaemia is associated with increased length of stay and mortality in people with
diabetes who are hospitalized. Diabet Med 2012;29(12):e445-8.
[36] Tan HK, Flanagan D. The impact of hypoglycaemia on patients admitted to hospital with
medical emergencies. Diabet Med 2013;30(5):574-80.
[37] National Institute for Health and Care Excellence. Type 1 Diabetes (update). [Internet].
London: National Institute for Health and Care Excellence, 2015 [accessed 15.1.15].
Available from: http://www.nice.org.uk/guidance/indevelopment/gid-cgwaver122/documents
[38] The absence of a glycemic threshold for the development of long-term complications:
the perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45(10):128998.
[39] Health and Social Care Information Centre. National Diabetes Audit 2011–2012. Report
1: care processes and treatment targets. Findings about the quality of care for people with
75
CONFIDENTIAL UNTIL PUBLISHED
diabetes in England and Wales. Report for the audit period 2011-2012. [Internet]. London:
Health and Social Care Information Centre, 2013 [accessed 15.1.15] Available from:
https://catalogue.ic.nhs.uk/publications/clinical/diabetes/nati-diab-audi-11-12/nati-diab-audi11-12-care-proc-rep.pdf
[40] Raccah D, Sulmont V, Reznik Y, Guerci B, Renard E, Hanaire H, et al. Incremental
value of continuous glucose monitoring when starting pump therapy in patients with poorly
controlled type 1 diabetes: the RealTrend study. Diabetes Care 2009;32(12):2245-50.
[41] Peyrot M, Rubin RR. Patient-reported outcomes for an integrated real-time continuous
glucose monitoring/insulin pump system. Diabetes Technol Ther 2009;11(1):57-62.
[42] Lee SW, Sweeney T, Clausen D, Kolbach C, Hassen A, Firek A, et al. Combined insulin
pump therapy with real-time continuous glucose monitoring significantly improves glycemic
control compared to multiple daily injection therapy in pump naïve patients with type 1
diabetes; single center pilot study experience. J Diabetes Sci Technol 2007;1(3):400-4.
[43] Hermanides J, Nørgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, et al.
Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled type 1 diabetes;
a randomized controlled trial. Diabet Med 2011;28(10):1158-67.
[44] Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J, et al. Sensoraugmented insulin pump therapy: results of the first randomized treat-to-target study.
Diabetes Technol Ther 2008;10(5):377-83.
[45] Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, et al.
Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.[Erratum appears
in N Engl J Med. 2010 Sep 9;363(11):1092]. N Engl J Med 2010;363(4):311-20.
[46] Kamble S, Schulman KA, Reed SD. Cost-effectiveness of sensor-augmented pump
therapy in adults with type 1 diabetes in the United States. Value Health 2012;15(5):632-8.
76
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Appendix 1 Data extraction tables
Study Characteristics
Follow-up
(mths)
Study name
Countries
Inclusion
Intervention
2.76
Radermecker
Belgium
Age: Adults
HbA1c: NR
CSII Experience: >1 year CSII
treatment
No. of Hypoglycaemic events:
NR
Age: Adults
HbA1c: <10%
CSII Experience: NR
No. of Hypoglycaemic events:
NR
 CSII + CGM Non-integrated: Guardian
Age: 6-70
HbA1c: 7.5-9.5%
CSII Experience: >6 months
prior CSII treatment
No. of Hypoglycaemic events:
≥3 incidents of severe
hypoglycaemia in the last 12
months excluded
 CSII + CGM Integrated: Sensor ON:
4
6
Hanaire-Broutin
SWITCH
France
Europe
No. analysed
for efficacy per
arm
9
RT®, Medtronic, Northridge, CA, USA
 CSII + SMBG: NR
9
 CSII + SMBG: MiniMed 506 or 507;
NR
Minimed, Sylmar, CA, and HTron D or
V; Disetronic, Burgdorf, Switzerland
 MDI + SMBG: NR
Guardian REAL-Time CGM and
Medtronic MiniMed Paradigm REALTime System
 CSII + SMBG: Sensor OFF: Guardian
REAL-Time CGM and Medtronic
MiniMed Paradigm REAL-Time
System
NR
153
153
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Baseline Characteristics
Follow-up
(mths)
Study name
2.76 Radermecker
4 Hanaire-Broutin
6 SWITCH
Intervention
CSII + CGM Non-integrated:
Guardian RT®, Medtronic,
Northridge, CA, USA
CSII + SMBG: NR
CSII + SMBG: MiniMed 506
or 507; Minimed, Sylmar, CA,
and HTron D or V; Disetronic,
Burgdorf, Switzerland
MDI + SMBG: NR
CSII + CGM Integrated:
Sensor ON: Guardian REALTime CGM and Medtronic
MiniMed Paradigm REALTime System
CSII + SMBG: Sensor OFF:
Guardian REAL-Time CGM
and Medtronic MiniMed
Paradigm REAL-Time System
Total N
Age in yrs
Gender (N(%))
Duration
Diabetes
(yrs)
26 (16.0)
BMI
Weight
(kg)
HbA1c
(%)
NR (NR)
NR (NR)
8.2 (0.4)
9 47.1 (11.0)
Male: NR (NR)
Female: NR (NR)
9 47.1 (11.0)
Male: NR (NR)
Female: NR (NR)
Male: 21 (51.2)
Female: 20 (48.8)
26 (16.0)
NR (NR)
NR (NR)
8.2 (0.4)
20 (11.3)
24 (2.4)
68.2
(10.0)
8.39 (0.9)
Male: 21 (51.2)
Female: 20 (48.8)
Male: 42 (54.0)
Female: 35 (46.0)
20 (11.3)
24 (2.4)
8.39 (0.9)
16 (12.0)
23 (5.0)
68.2
(10.0)
65 (23.0)
Male: 37 (49.0)
Female: 39 (51.0)
14 (10.0)
24 (4.5)
66 (21.0)
8.5 (0.6)
NR 43.5 (10.3)
NR 43.5 (10.3)
153 28 (16.0)
153 28 (17.0)
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Change from baseline in HbA1c
Follow-up
(mths)
Study ID
Intervention
2.76
Radermecker
4
6
Hanaire-Broutin
SWITCH
Number
analysed
Change from baseline in HbA1c
(%)
CSII + CGM Non-integrated: Guardian RT®,
Medtronic, Northridge, CA, USA
9
Baseline: 7.9 (0.7)
Follow-up: 8 (0.8)
Change from baseline: -0.09 (0.5)
CSII + SMBG: NR
9
Baseline: 8.3 (0.5)
Follow-up: 7.7 (0.6)
Change from baseline: 0.53 (0.66)
CSII + SMBG: MiniMed 506 or 507;
Minimed, Sylmar, CA, and HTron D or V;
Disetronic, Burgdorf, Switzerland
40
Baseline: 8.39 (0.87)
Follow-up: 7.89 (0.77)
Change from baseline: NR (NR)
MDI + SMBG: NR
40
Baseline: 8.39 (0.87)
Follow-up: 8.24 (0.77)
Change from baseline: NR (NR)
CSII + CGM Integrated: Sensor ON:
Guardian REAL-Time CGM and Medtronic
MiniMed Paradigm REAL-Time System
153
Baseline: NR (NR)
Follow-up: 8.04 (NR)
Change from baseline: NR (NR)
CSII + SMBG: Sensor OFF: Guardian REALTime CGM and Medtronic MiniMed
Paradigm REAL-Time System
153
Baseline: NR (NR)
Follow-up: 8.47 (NR)
Change from baseline: NR (NR)
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Hypoglycaemia
Population
Severity
Adults
NR
Severe
Mixed
Severe
Followup
(mths)
2.76
4
6
Study ID
Intervention
Radermecker
CSII + CGM Non-integrated: Guardian
RT®, Medtronic, Northridge, CA, USA
HanaireBroutin
SWITCH
No. of people with
Hypoglycaemia
(No. with event/ No. Analysed
(%))
6/9 (66.70)
No. of Hypoglycaemic
events (No. of
events/No. of people
Analysed)
NR
CSII + SMBG: NR
CSII + SMBG: MiniMed 506 or 507;
Minimed, Sylmar, CA, and HTron D or
V; Disetronic, Burgdorf, Switzerland
1/9 (11.10)
2/40 (5.00)
NR
3/NR
MDI + SMBG: NR
CSII + CGM Integrated: Sensor ON:
Guardian REAL-Time CGM and
Medtronic MiniMed Paradigm REALTime System
1/40 (2.50)
NR
1/NR
4/NR
NR
2/NR
CSII + SMBG: Sensor OFF: Guardian
REAL-Time CGM and Medtronic
MiniMed Paradigm REAL-Time
System
80
CONFIDENTIAL UNTIL PUBLISHED
Hypoglycaemia event rate
Population
Severity
Follow-up
(mths)
Event rate
definition
Study ID
Intervention
Hypoglycaemia
event rate
Hyperglycaemia
event rate
Total N
Adults
NR
2.76
Hypoglycaemic
events - events
per 14 patient
days
Hypoglycaemic
events - events
per 14 patient
days
Radermecker
CSII + CGM Non-integrated:
Guardian RT®, Medtronic,
Northridge, CA, USA
CSII + SMBG: NR
CSII + SMBG: MiniMed 506 or
507; Minimed, Sylmar, CA, and
HTron D or V; Disetronic,
Burgdorf, Switzerland
MDI + SMBG: NR
7.6 (6.8)
NR
9
11.1 (4.5)
3.9 (4.2)
NR
NR
9
40
4.3 (3.9)
NR
40
4
Hanaire-Broutin
81
CONFIDENTIAL UNTIL PUBLISHED
Appendix 2 Literature search strategies
Hypoglycaemia mortality searches
Medline (Ovid): 1946-2015/May week 1
Searched: 12.5.15
1 Diabetes Mellitus, Type 1/ (62982)
2 Diabetic Ketoacidosis/ (5199)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (70434)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (20572)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (30382)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (13269)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(9386)
8 or/1-7 (102907)
9 exp Hypoglycemia/ (22359)
10 hypoglyc?em$.ti,ab,ot. (38671)
11
((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or
fallen or falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or
a1c or h?emoglob$ or glycoh?emoglob$)).ti,ab,ot,hw. (37347)
12 or/9-11 (78614)
13 exp Death/ (119503)
14 exp Mortality/ (292978)
15 (dead or death or mortalit$ or dead-in-bed).ti,ab,ot. (863358)
16 or/13-15 (1097098)
17 exp Great Britain/ (307788)
18 (britain or united kingdom or uk or england or scotland or ireland or wales or english or
scottish or irish or welsh).ti,ab,in. (1089639)
19 17 or 18 (1269442)
20 8 and 12 and 16 and 19 (103)
21 exp Animals/ not (exp Animals/ and Humans/) (4037496)
22 (editorial or letter).pt. (1201653)
23 20 not (21 or 22) (102)
24 limit 23 to yr="2010 -Current" (34)
Medline In-Process & Other Non-Indexed Citations (Ovid); Medline Daily Update
(Ovid): May 11 2015
Searched: 12.5.15
1 Diabetes Mellitus, Type 1/ (12)
2 Diabetic Ketoacidosis/ (1)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (3200)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (1345)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (780)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (1153)
82
CONFIDENTIAL UNTIL PUBLISHED
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(516)
8 or/1-7 (5202)
9 exp Hypoglycemia/ (2)
10 hypoglyc?em$.ti,ab,ot. (3266)
11
((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or
fallen or falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or
a1c or h?emoglob$ or glycoh?emoglob$)).ti,ab,ot,hw. (3420)
12 or/9-11 (6201)
13 exp Death/ (36)
14 exp Mortality/ (108)
15 (dead or death or mortalit$ or dead-in-bed).ti,ab,ot. (78306)
16 or/13-15 (78389)
17 exp Great Britain/ (54)
18 (britain or united kingdom or uk or england or scotland or ireland or wales or english or
scottish or irish or welsh).ti,ab,in. (134781)
19 17 or 18 (134807)
20 8 and 12 and 16 and 19 (13)
21 exp Animals/ not (exp Animals/ and Humans/) (638)
22 (editorial or letter).pt. (54904)
23 20 not (21 or 22) (13)
24 limit 23 to yr="2010 -Current" (11)
PubMed (NLM): up to 12.5.15
Searched: 12.5.15
#5
#4
#3
#2
#1
Search (#1 and #2 and #3 and #4)
34
Search pubstatusaheadofprint OR publisher[sb]
473068
Search (dead[tiab] or death[tiab] or mortalit*[tiab] or "dead-in-bed"[tiab]) 944980
Search Hypoglyc*[tiab
43143
Search Diab*[tiab] 445165
Embase (Ovid): 1974-2015/week 19
Searched: 12.5.15
1 insulin dependent diabetes mellitus/ (83035)
2 exp diabetic ketoacidosis/ (8285)
3 (diabet$ adj3 (typ$ 1 or typ$ i or type1 or typei or typ$ one)).ti,ab,ot,hw. (53343)
4
(diabet$ adj3 (britt$ or juvenil$ or pediatric or paediatric or early or keto$ or labil$ or
acidos$ or autoimmun$ or auto immun$ or sudden onset)).ti,ab,ot,hw. (31065)
5 ((insulin$ adj2 depend$) or insulindepend$).ti,ab,ot,hw. (233244)
6 (dm1 or dm 1 or dmt1 or dm t1 or t1dm or t1 dm or t1d or iddm).ti,ab,ot,hw. (21856)
7
(ketoacidosis or acidoketosis or keto acidosis or ketoacidemia or ketosis).ti,ab,ot,hw.
(15027)
8 or/1-7 (267586)
9 exp hypoglycemia/ (58617)
10 hypoglyc?em$.ti,ab,ot. (59431)
83
CONFIDENTIAL UNTIL PUBLISHED
11
((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or
fallen or falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or
a1c or h?emoglob$ or glycoh?emoglob$)).ti,ab,ot,hw. (51809)
12 or/9-11 (124451)
13 exp death/ (508409)
14 exp mortality/ (719285)
15 (dead or death or mortalit$ or dead-in-bed).ti,ab,ot. (1247328)
16 or/13-15 (1709758)
17 animal/ or animal experiment/ (3487608)
18
(rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or
pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow
or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5912066)
19 or/17-18 (5912066)
20 exp human/ or human experiment/ (15884730)
21 19 not (19 and 20) (4690046)
22 (editorial or letter or note).pt. (1960794)
23 (8 and 12 and 16) not (13 or 14) (935)
24 United Kingdom/ (348902)
25 exp British citizen/ (94)
26 (britain or united kingdom or uk or england or scotland or ireland or wales or english or
scottish or irish or welsh).ti,ab,in. (2339597)
27 or/24-26 (2495278)
28 23 and 27 (173)
29 limit 28 to yr="2010 -Current" (82)
Hypoglycaemia utilites searches
Medline (Ovid): 1946-2015/May week 1
Searched: 11.5.15
1 exp Hypoglycemia/ (22359)
2 hypoglyc?em$.ti,ab,ot. (38671)
3 ((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen or
falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or h?emoglob$
or glycoh?emoglob$)).ti,ab,ot,hw. (37347)
4 or/1-3 (78614)
5 quality-adjusted life years/ or quality of life/ (131595)
6 (sf36 or sf 36 or sf-36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform
thirtysix or shortform thirty six or short form thirty six or short form thirtysix or short form thirty
six).ti,ab,ot. (15950)
7 (sf6 or sf 6 or sf-6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or short form
six).ti,ab,ot. (1023)
8 (sf12 or sf 12 or sf-12 or short form 12 or shortform 12 or sf twelve or sftwelve or shortform
twelve or short form twelve).ti,ab,ot. (2798)
9 (sf6D or sf 6D or sf-6D or short form 6D or shortform 6D or sf six D or sfsixD or shortform six D
or short form six D).ti,ab,ot. (450)
10 (sf20 or sf 20 or sf-20 or short form 20 or shortform 20 or sf twenty or sftwenty or shortform
twenty or short form twenty).ti,ab,ot. (336)
11 (sf8 or sf 8 or sf-8 or short form 8 or shortform 8 or sf eight or sfeight or shortform eight or short
form eight).ti,ab,ot. (259)
84
CONFIDENTIAL UNTIL PUBLISHED
12 "health related quality of life".ti,ab,ot. (21985)
13 (Quality adjusted life or Quality-adjusted-life).ti,ab,ot. (6349)
14 "assessment of quality of life".ti,ab,ot. (1162)
15 (euroqol or euro qol or eq5d or eq 5d).ti,ab,ot. (4175)
16 (hql or hrql or hqol or h qol or hrqol or hr qol).ti,ab,ot. (10341)
17 (hye or hyes).ti,ab,ot. (53)
18 health$ year$ equivalent$.ti,ab,ot. (38)
19 (hui or hui1 or hui2 or hui3 or hui4 or hui-4 or hui-1 or hui-2 or hui-3).ti,ab,ot. (891)
20 (quality time or qwb or quality of well being or "quality of wellbeing" or "index of wellbeing" or
"index of well being").ti,ab,ot,hw. (612)
21 (Disability adjusted life or Disability-adjusted life or health adjusted life or health-adjusted life
or "years of healthy life" or healthy years equivalent or "years of potential life lost" or "years of health
life lost").ti,ab,ot. (1762)
22 (QALY$ or DALY$ or HALY$ or YHL or HYES or YPLL or YHLL or qald$ or qale$ or
qtime$ or AQoL$).ti,ab,ot. (7093)
23 (timetradeoff or time tradeoff or time trade-off or time trade off or TTO or Standard gamble$ or
"willingness to pay").ti,ab,ot. (3834)
24 15d.ti,ab,ot. (1158)
25 (HSUV$ or health state$ value$ or health state$ preference$ or HSPV$).ti,ab,ot. (236)
26 (utilit$ adj3 ("quality of life" or valu$ or scor$ or measur$ or health or life or estimat$ or elicit$
or disease$)).ti,ab,ot. (6840)
27 (utilities or disutili$).ti,ab,ot. (4064)
28 or/5-27 (155888)
29 animals/ not (animals/ and humans/) (3943260)
30 28 not 29 (154290)
31 letter.pt. (845717)
32 editorial.pt. (356006)
33 historical article.pt. (315957)
34 or/31-33 (1502284)
35 30 not 34 (147222)
36 4 and 35 (891)
37 exp Great Britain/ (307788)
38 (britain or united kingdom or uk or england or scotland or ireland or wales or english or scottish
or irish or welsh).ti,ab,in. (1089639)
39 37 or 38 (1269442)
40 36 and 39 (150)
41 limit 40 to yr="2010 -Current" (73)
42 15 or 23 (7686)
43 4 and 42 and 39 (22)
44 limit 43 to yr="2010 -Current" (13) [EQ-5D/TTO specific]
45 41 not 44 (60) [non-EQ-5D/TTO specific]
Utilities filter:
HRQoL free-text terms based on: Figure 4: Common free-text terms for electronic database searching
for HSUVs in Papaioannou D, Brazier JE, Paisley S. NICE DSU Technical Support Document 9: the
identification, review and synthesis of health state utility values from the literature (Internet), 2011
(accessed: 18.8.11) Available from: http://www.nicedsu.org.uk
Medline In-Process & Other Non-Indexed Citations (Ovid); Medline Daily Update
(Ovid): May 08 2015
Searched: 11.5.15
1
exp Hypoglycemia/ (1)
85
CONFIDENTIAL UNTIL PUBLISHED
2 hypoglyc?em$.ti,ab,ot. (3256)
3 ((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen
or falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or
h?emoglob$ or glycoh?emoglob$)).ti,ab,ot,hw. (3397)
4 or/1-3 (6167)
5 quality-adjusted life years/ or quality of life/ (64)
6 (sf36 or sf 36 or sf-36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or
shortform thirtysix or shortform thirty six or short form thirty six or short form thirtysix or
short form thirty six).ti,ab,ot. (1654)
7
(sf6 or sf 6 or sf-6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or
short form six).ti,ab,ot. (438)
8
(sf12 or sf 12 or sf-12 or short form 12 or shortform 12 or sf twelve or sftwelve or
shortform twelve or short form twelve).ti,ab,ot. (416)
9
(sf6D or sf 6D or sf-6D or short form 6D or shortform 6D or sf six D or sfsixD or
shortform six D or short form six D).ti,ab,ot. (47)
10
(sf20 or sf 20 or sf-20 or short form 20 or shortform 20 or sf twenty or sftwenty or
shortform twenty or short form twenty).ti,ab,ot. (13)
11
(sf8 or sf 8 or sf-8 or short form 8 or shortform 8 or sf eight or sfeight or shortform
eight or short form eight).ti,ab,ot. (40)
12 "health related quality of life".ti,ab,ot. (2989)
13 (Quality adjusted life or Quality-adjusted-life).ti,ab,ot. (864)
14 "assessment of quality of life".ti,ab,ot. (117)
15 (euroqol or euro qol or eq5d or eq 5d).ti,ab,ot. (683)
16 (hql or hrql or hqol or h qol or hrqol or hr qol).ti,ab,ot. (1343)
17 (hye or hyes).ti,ab,ot. (2)
18 health$ year$ equivalent$.ti,ab,ot. (1)
19 (hui or hui1 or hui2 or hui3 or hui4 or hui-4 or hui-1 or hui-2 or hui-3).ti,ab,ot. (108)
20
(quality time or qwb or quality of well being or "quality of wellbeing" or "index of
wellbeing" or "index of well being").ti,ab,ot,hw. (43)
21
(Disability adjusted life or Disability-adjusted life or health adjusted life or healthadjusted life or "years of healthy life" or healthy years equivalent or "years of potential life
lost" or "years of health life lost").ti,ab,ot. (311)
22 (QALY$ or DALY$ or HALY$ or YHL or HYES or YPLL or YHLL or qald$ or qale$
or qtime$ or AQoL$).ti,ab,ot. (998)
23
(timetradeoff or time tradeoff or time trade-off or time trade off or TTO or Standard
gamble$ or "willingness to pay").ti,ab,ot. (477)
24 15d.ti,ab,ot. (116)
25 (HSUV$ or health state$ value$ or health state$ preference$ or HSPV$).ti,ab,ot. (21)
26 (utilit$ adj3 ("quality of life" or valu$ or scor$ or measur$ or health or life or estimat$
or elicit$ or disease$)).ti,ab,ot. (789)
27 (utilities or disutili$).ti,ab,ot. (533)
28 or/5-27 (7821)
29 animals/ not (animals/ and humans/) (410)
30 28 not 29 (7820)
31 letter.pt. (32849)
32 editorial.pt. (21576)
33 historical article.pt. (43)
34 or/31-33 (54463)
35 30 not 34 (7784)
86
CONFIDENTIAL UNTIL PUBLISHED
36 4 and 35 (62)
37 exp Great Britain/ (24)
38 (britain or united kingdom or uk or england or scotland or ireland or wales or english or
scottish or irish or welsh).ti,ab,in. (134120)
39 37 or 38 (134127)
40 36 and 39 (13)
41 limit 40 to yr="2010 -Current" (12)
42 15 or 23 (1126)
43 4 and 42 and 39 (3)
44 limit 43 to yr="2010 -Current" (3) [EQ-5D/TTO specific]
45 41 not 44 (9) [non-EQ-5D/TTO specific]
Utilities filter:
HRQoL free-text terms based on: Figure 4: Common free-text terms for electronic database
searching for HSUVs in Papaioannou D, Brazier JE, Paisley S. NICE DSU Technical Support
Document 9: the identification, review and synthesis of health state utility values from the
literature (Internet), 2011 (accessed: 18.8.11) Available from: http://www.nicedsu.org.uk
PubMed (NLM): up to 12.5.15
Searched: 12.5.15
#6
Search (#1 and #4 and #5) 6
#5
Search ((pubstatusaheadofprint OR publisher[sb])) 472952
#4
Search (#2 or #3)
135921
#3
Search utility[tiab] or utilities[tiab] or disutili*[tiab] 131629
#2
Search "euro qual"[tiab] or "euro qol"[tiab] or eq-5d[tiab] or eq5d[tiab] or "eq
5d"[tiab] or euroqual[tiab] or euroqol[tiab] or tto[tiab] or timetradeoff[tiab] or "time
tradeoff"[tiab] or "time trade off"[tiab] or "standard gamble"[tiab] 6341
#1
Search Hypoglyc*[tiab]
43135
Embase (OvidSP): 1974-2015/week 19
Searched: 11.5.15
1 exp hypoglycemia/ (58617)
2 hypoglyc?em$.ti,ab,ot. (59431)
3 ((low or lower or deficien$ or insufficien$ or reduce$ or reduction$ or fluctuat$ or fallen
or falling or threshold or safe) adj3 (glucose$ or sugar$ or hba1c or hb a1 or hba1 or a1c or
h?emoglob$ or glycoh?emoglob$)).ti,ab,ot,hw. (51809)
4 or/1-3 (124451)
5 quality adjusted life year/ or quality of life index/ (15636)
6 Short Form 12/ or Short Form 20/ or Short Form 36/ or Short Form 8/ (15771)
7
"International Classification of Functioning, Disability and Health"/ or "ferrans and
powers quality of life index"/ or "gastrointestinal quality of life index"/ (1765)
8 (sf36 or sf 36 or sf-36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or
shortform thirtysix or shortform thirty six or short form thirty six or short form thirtysix or
short form thirty six).ti,ab,ot. (25836)
9
(sf6 or sf 6 or sf-6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or
short form six).ti,ab,ot. (1602)
87
CONFIDENTIAL UNTIL PUBLISHED
10
(sf12 or sf 12 or sf-12 or short form 12 or shortform 12 or sf twelve or sftwelve or
shortform twelve or short form twelve).ti,ab,ot. (4967)
11
(sf6D or sf 6D or sf-6D or short form 6D or shortform 6D or sf six D or sfsixD or
shortform six D or short form six D).ti,ab,ot. (829)
12
(sf20 or sf 20 or sf-20 or short form 20 or shortform 20 or sf twenty or sftwenty or
shortform twenty or short form twenty).ti,ab,ot. (351)
13
(sf8 or sf 8 or sf-8 or short form 8 or shortform 8 or sf eight or sfeight or shortform
eight or short form eight).ti,ab,ot. (486)
14 "health related quality of life".ti,ab,ot. (33495)
15 (Quality adjusted life or Quality-adjusted-life).ti,ab,ot. (9994)
16 "assessment of quality of life".ti,ab,ot. (1875)
17 (euroqol or euro qol or eq5d or eq 5d).ti,ab,ot. (8459)
18 (hql or hrql or hqol or h qol or hrqol or hr qol).ti,ab,ot. (17330)
19 (hye or hyes).ti,ab,ot. (98)
20 health$ year$ equivalent$.ti,ab,ot. (39)
21 (hui or hui1 or hui2 or hui3 or hui4 or hui-4 or hui-1 or hui-2 or hui-3).ti,ab,ot. (2270)
22
(quality time or qwb or "quality of well being" or "quality of wellbeing" or "index of
wellbeing" or index of well being).ti,ab,ot,hw. (832)
23
(Disability adjusted life or Disability-adjusted life or health adjusted life or healthadjusted life or "years of healthy life" or healthy years equivalent or "years of potential life
lost" or "years of health life lost").ti,ab,ot. (2393)
24 (QALY$ or DALY$ or HALY$ or YHL or HYES or YPLL or YHLL or qald$ or qale$
or qtime$ or AQoL$).ti,ab,ot. (12804)
25
(timetradeoff or time tradeoff or time trade-off or time trade off or TTO or Standard
gamble$ or "willingness to pay").ti,ab,ot. (6053)
26 15d.ti,ab,ot. (1770)
27 (HSUV$ or health state$ value$ or health state$ preference$ or HSPV$).ti,ab,ot. (332)
28 (utilit$ adj3 ("quality of life" or valu$ or scor$ or measur$ or health or life or estimat$
or elicit$ or disease$)).ti,ab,ot. (11137)
29 (utilities or disutili$).ti,ab,ot. (7041)
30 or/5-29 (105832)
31 animal/ or animal experiment/ (3487608)
32
(rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or
pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow
or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5912066)
33 or/31-32 (5912066)
34 exp human/ or human experiment/ (15884730)
35 33 not (33 and 34) (4690046)
36 30 not 35 (103981)
37 letter.pt. (885889)
38 editorial.pt. (476505)
39 note.pt. (598400)
40 or/37-39 (1960794)
41 36 not 40 (100752)
42 4 and 41 (896)
43 United Kingdom/ (348902)
44 (britain or united kingdom or uk or england or scotland or ireland or wales or english or
scottish or irish or welsh).ti,ab,in. (2339597)
45 or/43-44 (2495266)
88
CONFIDENTIAL UNTIL PUBLISHED
46
47
48
49
50
51
42 and 45 (279)
limit 46 to yr="2010 -Current" (216)
17 or 25 (13914)
4 and 45 and 48 (80)
limit 49 to yr="2010 -Current" (71) [EQ-5D/TTO specific]
47 not 50 (145) [non-EQ-5D/TTO specific]
Utilities filter:
HRQoL free-text terms based on: Figure 4: Common free-text terms for electronic database
searching for HSUVs in Papaioannou D, Brazier JE, Paisley S. NICE DSU Technical Support
Document 9: the identification, review and synthesis of health state utility values from the
literature (Internet), 2011 (accessed: 18.8.11) Available from: http://www.nicedsu.org.uk
CEA Registry (Internet): up to 12/05/2015
www.cearegistry.org
Searched 12.5.15
hypoglycemia
10 records retrieved
ScHARRHUD (Internet): up to 12/05/2015
www.scharrhud.org.
Searched 12.5.15
hypoglyc*
9 records retrieved
RePEc (Internet): 12/05/2015
http://repec.org/
Searched 12.5.15
IDEAS search interface
(hypoglycemia | hypoglycaemia | hypoglycaemia | hypoglycaemic) + (utility | utilities |
disutility | disutilities | "euro qual" | "euro qol" | eq-5d | eq5d | "eq 5d" | euroqual | euroqol | tto
| timetradeoff | "time tradeoff" | "time trade off" | "standard gamble")
Key:
|
+
" "
OR
AND
phrase search
89
CONFIDENTIAL UNTIL PUBLISHED
Appendix 3 Technical calculations on the treatment effects
Population 1: Base case
Standard error (SE) of the HbA1c change of CSII+CGM+ (Veo, Integrated CSII+CGM and
CSII+CGM) is calculated from the Eurythmics trial43, and the standard deviation (SD) of the
HbA1c change and the number of patients receiving sensor augmented pumps (n) are used:
SE(CSII+CGM+ ) = SD/√n = 1.01/√41 = 0.158
Similarly, standard error (SE) of the HbA1c change of MDI+SMBG is also calculated from
the Eurythmics trial 43, and the standard deviation (SD) of the HbA1c change and the number
of patients receiving MDI+SMBG (n) are used:
SE(MDI+SMBG) = SD/√n = 0.56/√36 = 0.093
Treatment effect of CSII+SMBG is found by adding the HbA1c treatment effect diff