Clinical Study Protocol
CLASS08 – Closed-Loop Assessment Study
“An open-label, randomized, three-way, cross-over study to assess the efficacy of
single-hormone closed-loop strategy, dual-hormone closed-loop strategy and
conventional pump therapy in regulating overnight glucose levels in children with type 1
diabetes in a diabetes camp”
Version 3: July 16th 2014
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Table of Contents
1
Background and Rationale .................................................................................................. 4
2
Hypothesis .......................................................................................................................... 7
3
Trial Objectives ................................................................................................................... 7
4
Study Design ...................................................................................................................... 7
4.1
Trial Design.................................................................................................................. 7
4.2
Study Population .......................................................................................................... 7
4.2.1
Inclusion criteria .................................................................................................... 7
4.2.2
Exclusion criteria ................................................................................................... 8
4.3
5
6
4.3.1
Conventional pump therapy .................................................................................. 8
4.3.2
Single-hormone closed-loop strategy .................................................................... 8
4.3.3
Dual-hormone closed-loop strategy ...................................................................... 9
Study Procedures ............................................................................................................... 9
5.1
Recruitment ................................................................................................................. 9
5.2
Visit Schedule .............................................................................................................. 9
5.2.1
Verbal consent ...................................................................................................... 9
5.2.2
Day 1 – Diabetic camp .........................................................................................10
5.2.3
Intervention Night Procedures ..............................................................................10
5.3
Randomization ............................................................................................................11
5.4
Treatment of Hypoglycemia and Hyperglycemia .........................................................11
Statistical Analysis .............................................................................................................12
6.1
7
Study Interventions ...................................................................................................... 8
Study Endpoints ..........................................................................................................12
6.1.1
Primary endpoint..................................................................................................12
6.1.2
Secondary endpoints ...........................................................................................12
6.2
Sample Size and Power Calculations..........................................................................12
6.3
Level of Significance ...................................................................................................13
6.4
Statistical Tests...........................................................................................................13
Ethical and Legal Consideration.........................................................................................14
7.1
Good Clinical Practice.................................................................................................14
7.2
Delegation of Investigators Duties ...............................................................................14
7.3
Participant Information and Informed Consent: ...........................................................14
7.4
Confidentiality .............................................................................................................15
2
8
7.5
Approval of the Clinical Study Protocol and Amendments ...........................................15
7.6
Record Retention ........................................................................................................16
References ........................................................................................................................17
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1 Background and Rationale
Type 1 diabetes (T1D) is a chronic disease caused by the interaction of genetic determinants
and environmental factors resulting in an autoimmune destruction of pancreatic beta cells [1].
T1D accounts for 5-15% of approximately 366 million worldwide patients with diabetes [2] and
its incidence is increasing at a rate of 3.9% per year [3]. T1D is currently treated with life-long
insulin-replacement therapy.
Overnight control is a challenging task for many T1D patients. With the current treatment
strategies, hyper and/or hypoglycemia often occurs at night. Overnight glucose control is further
complicated by the dawn phenomenon which may lead to hyperglycemia in the morning.
Nocturnal hypoglycemia (NH) is a common event in patients with T1D [4, 5]. In 100 adult T1D
patients observed for 287 nights, prolonged non-severe NH (mean 140 min) were observed in
30% of nights, but only 15% of those were symptomatic [6]. Most cases of severe hypoglycemia
events occur at night [7, 8]. Such episodes account for 75% of total hypoglycemic seizures in
children [9], is associated with cardiac dysrhythmia [10] and could be responsible for 6% of
deaths in T1D patients under the age of 40 years [11]. NH is also a significant cause of work
productivity loss [12] and is associated with hypoglycemia unawareness one of the most
important risk factor for recurrent hypoglycemia [13]. NH remains common even in the era of
more physiological insulin delivery, bedtime snacks, or use of sensors with hypoglycemia
alarms [14]. The most significant nocturnal hypoglycemic risk reduction has been documented
while comparing sensor-augmented pump therapy with and without automatic suspension of
insulin delivery in patients with documented nocturnal hypoglycemic episodes [15]. In such
situations, automatic suspension allowed a 38% reduction of hypoglycemic area under the
curve and nocturnal hypoglycemic events occurred 32% less frequently. However, even with
such insulin delivery suspension, patients still presented a mean of 1.5 nocturnal episodes per
week of significant length. There is thus an urgent need to identify technologies and strategies
that will further facilitate regulation of nocturnal glucose levels including prevention of
hypoglycemia.
As with adults, hypoglycemia is a major obstacle for children with T1D and can affect their ability
to achieve glycemic targets. Besides the aforementioned dawn phenomenon, additional factors
are also important in children and adolescents including less reproducible food intake and
exercise patterns as well as the impact of puberty on insulin sensitivity, all factors leading to a
frequent mismatch between injected insulin and actual requirements. The Diabetes Control and
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Complications Trials showed that about 75% of severe hypoglycemia in children occurs during
sleep [22]. Numerous studies have shown that daytime exercise, such as in a camp setting,
increases the risk of NH [15-19]. In some studies conducted in adolescents with T1D, nocturnal
hypoglycaemia has been reported in 56% of nights following daytime exercise. In the pediatric
age range, the relative risk of hyperglycemia as compared to hypoglycemia as a factor of
cognitive disruption is still largely debated. Hypoglycemia in pediatrics has been associated with
impaired cognitive function, impaired intellectual performance and learning difficulties [2, 23,
24]. Hypoglycemia might also be associated with permanent damage to the central nervous
system [25]. Moreover, with frequent hypoglycemias, some patients might develop
hypoglycemia unawareness [26], which leads to increased potential for further acute events.
Since the early 2000s, improved tools for managing T1D have emerged such as continuous
glucose monitoring systems (CGMS) and increasingly sophisticated insulin pumps. CGMS
measures interstitial glucose levels and offers unprecedented insights into overall glucose
profile and its regular use has been shown to improve glucose control [20]. Insulin pumps are
designed to mimic physiological delivery of insulin. In T1D patients with documented nocturnal
hypoglycemia, sensor-augmented pump therapy with automatic shut-off function to prevent
hypoglycemia is an efficient way to reduce the number of episodes and time spent in
hypoglycemia [15]. However, both number and duration of episodes remains unacceptably high.
We now have the ability to even further reduce hypoglycemic risk while improving overall
glucose control combining three technologies: CGMS, insulin pumps and a control algorithm.
The combination of these technologies is known as a closed-loop strategy (CLS), or the socalled external artificial pancreas. In a CLS, insulin is delivered according to real-time CGMS
values, with immediate feedback as recommended by a control algorithm, rather than at preprogrammed rates. Several studies have shown that glucose levels regulation with CLS is
feasible in children and adolescents. Current data summarized below indicate that this patient
group could obtain important benefits from CLS. Weinzimer et al. [21] reported that percentage
of time-in-target for glucose levels (3.9-10.0 mmol/L) over 34 hours was increased with the CLS
compared to pre-study home CSII (85% vs. 58%, p < 0.002) in 17 patients aged 13-20 years
old. Moreover, the efficacy of the CLS over conventional CSII to regulate overnight glucose
levels over 12 hours has been assessed in 21 T1D patients aged 5-18 years old [22]. The
results of this study showed that percentage of time-in-target for glucose levels (3.9 to 8.0
mmol/L) was increased with the CLS as compared to CSII (60% vs. 40%, p = 0.002) while
percentage of time of glucose levels < 3.9 mmol/L was also reduced (2.1% vs. 4.1% p = 0.03).
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A study by the same group evaluated the safety and efficacy of CLS for 36 hours in 12
adolescents [23]. It was observed that the CLS increased the percentage of time spent in target
range (84% vs. 49%, p = 0.02) compared to conventional CSII. Dauber et al. [24] compared
CLS with CSII in children aged < 7 years old and reported a trend toward a higher time for
glucose levels in target range (6.1 to 11.1 mmol/L) for CLS vs. CSII (5.3 hours vs. 3.2 hours, p =
NS). The aforementioned studies were all conducted in clinical research facility settings. The
major challenge is the successful implementation of the CLS in daily-life situations in outpatient
settings. Phillip et al. [7] assessed the short-term safety and efficacy of the CLS in controlling
nocturnal glucose levels in pediatric T1D patients at a diabetes camp. On two consecutive
nights, 56 patients were randomly assigned to either receive the CLS or sensor-augmented
pump therapy. On nights when the CLS was used, fewer hypoglycemic episodes were observed
(7 vs. 22, p = 0.003) and time of glucose levels spent below 3.3 mmol/L was reduced (0 minute
vs. 27.5 minutes, p = 0.002) compared to sensor-augmented therapy. Also, results of a
randomized crossover trial in 16 pediatric T1D patients (mean age of 15.4 years) for overnight
control over 21 days were presented at the last World Diabetes Congress in 2013. The study
revealed that the single hormone CLS, compared to sensor-augmented therapy, led to more
time in blood glucose targets (64% vs. 47%) and fewer nights with hypoglycemia (10% vs.
17%). In addition, patients reported greater reassurance, confidence and better sleep with the
CLS.
Small glucagon doses as an adjunct to insulin in a dual-hormone CLS has great potential to
provide additional hypoglycemic risk reduction [25, 26]. In a dual-hormone CLS, insulin is
delivered nearly continuously to treat and prevent hyperglycemia while subcutaneous glucagon
is delivered intermittently to treat and prevent hypoglycemia. We assessed the efficacy of dualhormone CLS compared to conventional insulin pump therapy (CSII) in regulating glucose
levels during exercise, dinner meal, and overnight (15-hour period) in 15 adults with T1D [27]. In
this study, the dual-hormone CLS significantly reduced hypoglycemic risk by 8-fold while
increasing the percentage of time for which plasma glucose levels were in target range by 17%
(3.8 hours/day).
We aim to conduct a randomized three-way crossover trial comparing single-hormone CLS
(insulin), dual-hormone CLS (insulin and glucagon) and conventional pump therapy in regulating
overnight glucose levels in children with T1D in a diabetes camp.The current proposal will also
be the first one to assess the efficacy of the dual-hormone CLS in children in outpatient settings.
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2 Hypothesis
Dual-hormone closed-loop strategy reduces the time spent in hypoglycemia in children with type
1 diabetes (T1D) compared to single-hormone closed-loop strategy, which in turn is more
effective than the conventional pump therapy to reduce time spent in hypoglycemia..
3 Trial Objectives
To compare the efficacy of dual-hormone closed-loop strategy, single-hormone closed-loop
strategy and conventional pump therapy in reducing the nocturnal time spent in hypoglycemia in
a diabetic camp for children with T1D.
4 Study Design
4.1 Trial Design
CLASS08 (Closed-loop Assessment Study) is an open-label, randomized, three-way, cross-over
study comparing single-hormone (insulin) closed-loop strategy, dual-hormone (insulin and
glucagon) closed-loop strategy and conventional pump therapy in preventing nocturnal
hypoglycemia in children with T1D.
4.2 Study Population
The trial aims to enroll children with T1D.
4.2.1
Inclusion criteria
To be eligible for the study, all subjects must meet the following criteria:
1. Males or females between the 8 and 17 years of old.
2. Clinical diagnosis of type 1 diabetes for at least one year.
The diagnosis of type 1 diabetes is based on the investigator’s judgment; C peptide level
and antibody determinations are not needed.
3. The subject will have been on insulin pump therapy for at least 3 months.
4. HbA1c ≤ 11.0%.
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4.2.2
Exclusion criteria
Subjects who meet any of the following criteria are not eligible for the study:
1. Clinically significant nephropathy, neuropathy or retinopathy as judged by the investigator.
2. Severe hypoglycemic episode within two weeks of inclusion in the study. A severe
hypoglycemic episode is defined as loss of conscience, seizure or a hospital emergency
visit.
3. Current use of oral glucocorticoid medication (except low stable dose according to
investigator judgement). Stable doses of inhaled steroids are acceptable.
4. Known or suspected allergy to the trial products.
5. Other serious medical illness likely to interfere with study participation or with the ability to
complete the trial by the judgment of the investigator.
6. Failure to comply with team’s recommendations (e.g. not willing to use trial pump, etc).
4.3 Study Interventions
4.3.1
Conventional pump therapy
In control visits, subjects will use conventional pump therapy to regulate glucose levels.
Subcutaneous interstitial glucose levels will be recorded measured by the real time sensor
(Dexcom G4 Platinum, Dexcom).
4.3.2
Single-hormone closed-loop strategy
In single-hormone closed-loop intervention visits, variable subcutaneous insulin infusion rates
will be used to regulate glucose levels. Insulin Aspart (Novorapid, Novo Nordisk) will be infused
using a subcutaneous infusion pump (Accu-Check Combo, Roche). Subcutaneous interstitial
glucose levels as measured by the real time sensor (Dexcom G4 Platinum, Dexcom) will be
entered manually into the computer every 10 minutes. The pumps’ infusion rate will then be
changed manually based on the computer generated recommended infusion rates. The
computer generated recommendations are based on a predictive algorithm [28]. Predictive
algorithms have been successfully used in closed-loop studies in children, adolescents,
pregnant women and adults [28].
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4.3.3
Dual-hormone closed-loop strategy
In dual-hormone closed-loop intervention visits, variable subcutaneous insulin and glucagon
infusion rates will be used to regulate glucose levels. Insulin Aspart (Novorapid, Novo Nordisk)
and Glucagon (Paladin) will be infused using two separate subcutaneous infusion pumps (AccuCheck Combo, Roche). Subcutaneous interstitial glucose levels as measured by the real time
sensor (Dexcom G4 Platinum, Dexcom) will be entered manually into the computer every 10
minutes. The pumps’ infusion rate will then be changed manually based on the computer
generated recommended infusion rates. The computer generated recommendations are also
based on a predictive algorithm [28].
5 Study Procedures
5.1 Recruitment
Flyers with information on the study will be sent by mail to families who have registered for the
diabetic camp (Camp Carowanis, 5000 Des Pins Sainte-Agathe-des-Monts, https://diabeteschildren.ca/fr/?/camp/C13). Families interested in participating will be able to contact the
research team for further information. Inclusion and exclusion criteria will be reviewed over the
phone. Subjects that meet basic eligibility criteria will be included.
5.2 Visit Schedule
5.2.1
Verbal consent
Once verbal consent of both parents/guardian and child has been obtained, the following
procedures will be taken:

Inclusion and exclusion criteria will be reviewed

Medical history (i.e. date of diagnosis, recent severe hypo- and hyperglycemia episodes,
micro- and macrovascular complications, comorbidities and precise list of all medications)
will be recorded.

Subject’s parent or guardian will be asked to sign the consent form that will be sent to them.
Subjects will also have to sign an assent form1.
1
As bus transportation is organized from main cities, a significant number of patients will arrive to the camp without their parents
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
A formal visit at the research centre will be offered but is not mandatory
5.2.2
Day 1 – Diabetic camp
When subjects will arrive at the camp, the following procedures will be undertaken by our
research nurse:

Verification that signatures of consent and assent forms have been obtained.

Records of the previous 3 days of insulin therapy (total daily dose, carbohydrate to insulin
ratios, basal rates).

HbA1c will be retrieved from the subject’s medical file kept at the camp.

Body weight and height will be measured.

A real-time sensor will be inserted in the abdominal/arm tissue.
5.2.3
Intervention Night Procedures
For each intervention arm, there will be three consecutive nights. A total of 9 nights per subject
will be done. The first night is planned on the second day of the camp (e.g. arrival on Monday,
first study night on Tuesday evening). A member of the research team will be present at the
diabetic camp to ensure protocol implementation and patient’s safety. At bedtime, for closedloop visits, subject’s pump will be substituted with the study pump and fast acting insulin
Novorapid® (Aspart) will be placed. On the next morning, the subject’s pump will be reinstalled.
The life duration of the sensor is 7 days. Therefore, the sensor will have to be replaced at least
once during the study. As recommended by the manufacturer, the sensor will be calibrated at
least twice a day using capillary glucose as measured by the glucose meter.
During intervention visits, closed-loop strategy will start at 22:00 until 7:00 next morning.
Protocol insulin pumps will be substituted to patient’s insulin pump at the time of usual bedtime
capillary glucose check. To facilitate this process, a catheter compatible with various insulin
pump models will be sued and provided by the research team. A glucose sensor reading will be
entered manually into the computer every 10 minutes. The computer will generate a
recommendation for the basal rates of insulin delivery and glucagon mini-boluses (glucagon
recommendations will only be generated during the dual-hormone closed-loop visits). Pumps’
parameters will then be changed manually to implement the computer generated
recommendations. The subject and the camp’s healthcare staff will be blinded to sensor
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readings. At the time of usual morning capillary glucose check, the patient will be switched back
to his usual insulin pump.
On dual-hormone closed-loop visits, glucagon will be reconstituted according to the
manufacturer’s instructions for each night and an Accu-Check Combo insulin pump containing
the glucagon solution will be installed. Fresh glucagon will be used each night. A specific
catheter will be inserted and used for this second pump. At the time of usual morning capillary
glucose check, this pump will be uninstalled by the research team.
During control visits, subjects will carry on with their normal conventional insulin pump therapy
and will be allowed to freely implement therapeutic adjustments. Subjects and the camp’s
healthcare staff will also have access to the sensor values and will freely use them for glucose
control. Subjects will use their insulin pump and the research team will record the amount of
insulin given during the night.
Finger-stick glucose measurements will be done as per camp protocol and will be retrieved from
the subject’s medical file kept at the diabetes camp.
5.3 Randomization
Each study participant will be assigned a unique anonymous identification number (ID), which
will be used throughout the study. A block balanced randomization will be used to determine the
order of the interventions. Randomization envelopes will be opened once consent has been
obtained.
5.4 Treatment of Hypoglycemia and Hyperglycemia
In open-loop and closed-loop nights, during the intervention period (22:00 to 7:00), if the sensor
reads less than 3.1 mmol/L or over 20 mmol/L for 15 consecutive minutes, we will inform the
camp’s healthcare staff and they will act based on the camp protocols for hypoglycemia and
hyperglycemia. The same treatment protocols will be used by the camp’s healthcare staff for
both open-loop and closed-loop nights.
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6 Statistical Analysis
6.1 Study Endpoints
6.1.1
Primary endpoint
Percentage of time (23:00-7:00) of glucose levels (as measured by the glucose sensor) spent
below 4.0 mmol/L.
6.1.2
Secondary endpoints
6.1.2.1 Continuous measures:
1. Percentage of time (23:00-7:00) of glucose levels (as measured by the glucose sensor)
spent a. between 4.0 and 8.0 mmol/L; b. between 4.0 and 10.0 mmol/L; c. below 3.5
mmol/L; d. below 3.3 mmol/L; e. above 8 mmol/L; f. above 10 mmol/L.
2. Area under the curve of glucose levels a. below 4.0 mmol/L; b. below 3.5 mmol/L; c. below
3.3 mmol/L; d. above 8.0 mmol/L; e. above 10.0 mmol/L.
3. Mean glucose levels.
4. Standard deviation of glucose levels as a measure of glucose variability.
5. Total insulin delivery.
6.1.2.2 Binary measures:
1. Hypoglycemic risk assessed by: a) Total number of hypoglycemic event (> 15 minutes)
below 3.1 mmol/L; b) Number of patients experiencing at least one hypoglycemic event (>
15 minutes) below 3.1 mmol/L.
6.2 Sample Size and Power Calculations
The trial aims to recruit more than 22 children to complete the study according to the protocol.
Sample size is calculated to achieve enough power as pertained to the primary endpoint (time
spent below 4.0 mmol/L). Data from our CLASS01, CLASS03, and CLASS04 studies and data
from other investigators’ studies were used as guidelines to determine the sample size. It is
anticipated that as compared to single-hormone CLS, dual-hormone strategy will reduce
absolute time spent at glucose levels below 4.0 mmol/L by 2.4%. The standard deviation of
paired differences is estimated to be 3.0%. After correcting for multiple comparisons, twenty two
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subjects are needed to achieve 80% statistical power to detect this level of improvement at 5%
significance threshold.
From our previous studies, the difference between single-hormone CLS and dual-hormone CLS
was less than the difference between any of the CLS strategies and CSII while having similar
standard deviation (for example, in CLASS03, time < 4.0 mmol/L was 16.2% in CSII, 3.1% in
single-hormone CLS, and 0.8% in dual-hormone CLS). Therefore, the sample size calculated
based on the predicted difference between the two CLSs will be sufficient to detect higher
differences between any of the CLSs and CSII.
Preliminary analysis from 22 subjects from our ongoing CLASS03 study indicated statistical
significance in the time below 4.0 mmol/L endpoint between single- and dual-hormone CLS,
supporting our power calculations. Also, as we will be observing over multiple nights in this
study, we expect to observe a higher difference between the treatments compared to the data in
CLASS03 and CLASS04. Subjects failing to complete at least two nights in two intervention
arms will not be included in the analysis.
Additional subjects would be required to achieve enough power to detect differences in the
secondary endpoint time below 3.5 mmol/L. It is anticipated that as compared to single-hormone
CLS, dual-hormone strategy will reduce absolute time spent at glucose levels below 3.5 mmol/L
by 1.5%. The standard deviation of paired differences is estimated to be 2.4%. After correcting
for multiple comparisons, thirty five subjects are needed to achieve 80% statistical power to
detect this level of improvement at 5% significance threshold.
Therefore, our recruitment goal is 22 but more subjects will be recruited if became available in
the recruitment phase with a maximum recruitment limit of 36 subjects.
6.3 Level of Significance
5% significance threshold will be used to declare statistical significance. Bonferroni correction
will be used for multiple testing whenever it applies.
6.4 Statistical Tests
The effect of the treatment (Dual-Hormone CLS vs. Single-hormone CLS vs. CSII) on the main
outcome (% of time glucose levels during the night below 4.0 mmol/L) will be estimated using a
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multivariate linear mixed effect model (LMEM) with the treatment sequence (fixed effect),
subject nested within sequence (random effect), period (fixed effect) and treatment (fixed effect)
entered as covariables. The hypothesis of no sequence effect in the LMEM will be tested to
check for carry-over effects. The model is suited for repeated observations, i.e., adjusts for
patient-level intra-correlation. Comparison between any two arms will be performed using
pairwise comparison where the significance level will be adjusted using a conservative
Bonferroni correction. Residual values from the regression model will be examined for an
approximate normal distribution. If values are highly skewed, a transformation will be used to
normalize the distribution. A similar statistical strategy employed for the analysis of the primary
outcome will be used to compare treatment effects for all continuous secondary outcomes while
a LMEM with logit link will be used for the dichotomous ones. Adjustment for multiple
comparisons will be implemented using Bonferroni correction.
7 Ethical and Legal Consideration
7.1 Good Clinical Practice
This study is to be conducted according to globally accepted standards of good clinical practice
(as defined in the International Conference on Harmonisation E6 Guideline for Good Clinical
Practice, 1 May 1996), in agreement with the Declaration of Helsinki and in keeping with local
regulations.
7.2 Delegation of Investigators Duties
The investigator shall ensure that all persons assisting with the trial are adequately qualified,
informed about the protocol, any amendments to the protocol, the study treatments, and their
trial-related duties and functions.
The investigator shall maintain a list of sub-investigators and other appropriately qualified
persons to whom he or she has delegated significant trial-related duties.
7.3 Participant Information and Informed Consent:
After reading the relevant documents, the participant’s parent must give consent in writing. This
consent must be confirmed by the personally dated signature of the participant’s parent and by
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the personally dated signature of the person conducting the informed consent discussions. The
participant must also sign an assent form.
A copy of the signed consent documents must be given to the participant. The original signed
consent documents will be retained by the investigator.
The investigator will not undertake any measures specifically required only for the clinical study
until valid consent has been obtained.
With the parents’ and participant’s authorization. a letter will be sent to the usual healthcare
team provider about the participant’s participation in the trial.
7.4 Confidentiality
Participant names will be kept in strictest confidence. Participants will be identified by their
participant identification numbers which does not contain date of birth or initials. Study data
stored on a computer will be stored in accordance with local data protection laws.
The investigator will maintain a personal participant identification list (participant numbers with
the corresponding participant names) to enable records to be identified. Participants’ identifiers
and contact details will be stored locally under strict security.
7.5 Approval of the Clinical Study Protocol and Amendments
Before the start of the study, the clinical study protocol, informed consent document, and any
other appropriate documents will be submitted to the IEC/IRB with a cover letter or a form listing
the documents submitted, their dates of issue, and the site for which approval is sought.
Before the first participant is enrolled in the study, formal written approval from the IEC/IRB
must be obtained and all ethical and legal requirements must be met.
The IEC/IRB must be informed of all subsequent protocol amendments and administrative
changes, in accordance with local legal requirements.
The investigator must keep a record of all communication with the IEC/IRB.
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7.6 Record Retention
All study records must be kept according to International Conference on Harmonisation
guidelines (details are provided in the IRCM Manual of Operations).
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