The study listed may include approved and non-approved uses, formulations or treatment regimens. The results
reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any
product mentioned in this Register, healthcare professionals should consult prescribing information for the product
approved in their country.
GSK Medicine: Fluticasone propionate/salmeterol, Fluticasone propionate
Study Number: e-track WWE202012, protocol number PRJ2429
Title: Effect of inhaled corticosteroid (ICS) particle size on asthma efficacy and safety outcomes: A systematic
literature review and meta-analysis
Rationale: Inhaled corticosteroids (ICS) are the primary treatment for persistent asthma. Currently available ICS have
differing particle size, due both to the formulation and propellant, and it has been postulated that this may impact
patient outcomes. Beclomethasone dipropionate (HFA-BDP) and ciclesonide are considered small particle ICS and
fluticasone propionate-containing medications are considered standard size (HFA-FP and DISKUS® inhaler).
Study Period: 13October2014 to 27Nov2014 (final protocol to statistical analysis complete)
Objectives: The objective of this structured literature review and analysis was to evaluate if particle size has an impact
on patient outcomes by synthesizing the comparative efficacy and safety of ICS for both small and standard particle
sizes as assessed in head-to-head randomized controlled trials.
Indication: Asthma
Study Investigators/Centers: GSK conducted study
Research Methods: A systematic review (previously completed) identified published controlled trials appropriate for
this study. Efficacy and safety data were extracted to produce benefit-risk plots.
Data Source: Published literature. English language published peer-reviewed literature (Jan 1, 1998 to Feb 13, 2014)
with FP-containing medications yielded 1,655 potentially relevant articles: 1,575 were excluded, 80 full-text articles
were reviewed with 25 randomised controlled trials with a small particle size comparator in asthma included in final
evidence tables.
Study Design: Comparative effectiveness and safety of key outcomes were examined for standard and small particle
size ICS medications. Where appropriate, meta-analysis methods were applied.
Study Population: Adult and child participants with asthma in published randomized, controlled, trials (Jan 1, 1998 to
Feb 13, 2014) with FP-containing medications vs. small particle size medications.
Study Exposures, Outcomes: Treatments evaluated included fluticasone propionate vs. ICS small particle size
comparators (beclomethasone dipropionate HFA or ciclesonide), fluticasone propionate/salmeterol (FSC) vs. ICS small
particle size comparators (beclomethasone dipropionate HFA or beclomethasone/formoterol HFA in combination).
To characterize available efficacy data of FP-containing medications relative to small particle size comparator ICS
medications, the following efficacy endpoints were considered: Forced expiratory volume in 1 second (FEV1), morning
peak expiratory flow (PEF), symptom scores (on 4-8 point scales where a lower score corresponds to less symptoms),
% predicted forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%), and rescue
medication use per day.
To characterize available safety data, the following endpoints were considered: any adverse events (at least one), local
steroid effects (oral candidiasis, hoarseness), upper respiratory tract infections, growth and bone metabolism, cortisol
levels to assess adrenal suppression.
Data Analysis Methods:
Benefit-risk interval plots were created for key efficacy and safety outcomes. These plots are a graphical display of
estimated differences between treatments and their 95% confidence intervals for multiple endpoints on the same
graph across studies, irrespective of differences in study designs, endpoints and units. Meta-analysis methods were
applied for efficacy endpoints: Forced expiratory volume in 1 second (FEV1), morning peak expiratory flow (PEF), and
% predicted forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%).Random and fixed
effects models were fit, with random effects considered as the primary model. Results in children and
adolescents/adults were analyzed separately.
Other effectiveness and safety endpoints were not considered for meta-analysis due to heterogeneity, potential
publication bias and disparity of endpoint definitions and/or timing of collection.
For the meta-analysis, the results of the individual trials (point estimates and 95% confidence intervals, pooled results
of study estimates) were presented on forest plots. Absolute treatment differences between FP and small particle ICS
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were tabulated. For continuous measures, adjusted mean differences were used when available and calculated when
not directly available. For binary measures, the risk difference and its 95% CI were estimated using the normal
approximation to the binomial distribution.
A funnel plot was utilized to examine potential selection bias. Additional sensitivity analysis was performed when
appropriate.
Limitations: This study was based on the available literature. Study populations, duration of treatment, and efficacy
and safety endpoints varied across studies. There were few studies in children.
Study Results:
The following studies were included in the analysis.
FPmedication
Fluticasone
Propionate
(FP)
Fluticasone
Propionate/
Salmeterol
(FSC)
Small Particle
Comparator
HFABeclomethasone
dipropionate
(BDP)
Unique
Studies
N= 25
10
No. controlled trials
References
Efficacy
N=24
Safety
N=21
10
9
[Aubier, 2001; Currie, 2002; Fairfax,
2001; Moghaddam, 2012; Niitsuma,
2003; Ohbayashi, 2008; Robroeks,
2008; Thongngarm, 2005; Tunonde-Lara, 2007; van Aalderen, 2007]
Ciclesonide
(CIC)
11
10
9
[Bateman, 2008; Boulet, 2007; Buhl,
2006; Cohen, 2011; Dahl, 2010;
Lee, 2004; Lee, 2005; Magnussen,
2007; Pedersen, 2006; Pedersen,
2009; van der Molen, 2010]
HFA-BDP
1
1
1
[Fowler, 2002]
Beclomethasone
dipropionate/
formoterol (BFC)
3
3
2
[Papi, 2007; Papi, 2012; Scichilone,
2010]
Primary and Secondary Outcome(s)
Meta Analysis – Efficacy
 In adults, no significant differences were observed for change in FEV1, morning peak flow, or FEF25–75 using
random effects models (Fig. 1).
 Data suggested that for morning PEF the treatment difference between small and standard particles is dose
dependent so the results were separated by dose (using GINA estimate of clinical comparability).
 Treatment differences in FEF25–75 were significant in favour of FP using a fixed effects model (–2.85; 95% CI
–5.58, –0.13].
 Funnel plots did not exhibit asymmetry, suggesting no publication bias nor a systematic difference between
studies included.
 In children, the small number of studies with disparate endpoints and results did not allow for meta analysis
(Fig. 2).
Benefit-Risk Plots – Efficacy and Safety (Figs. 1 & 2)
 Efficacy: no clinically meaningful differences were noted across the 5 efficacy endpoints considered.
 Safety: no appreciable differences were noted for most endpoints. Most studies were not designed to test
treatment differences for safety endpoints.
 Subjects receiving FP experienced more local ICS effects than those receiving ciclesonide.
 Cortisol data were variable, with no clear differentiation between treatments.
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Figure 1- Benefit Risk Plot in Adolescents & Adults by Particle Size
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Figure 2- Benefit Risk Plot in Children by Particle Size
Conclusion: This systematic review suggests no differences in efficacy and no appreciable differences in safety
between FP-containing medications and small particle size ICS medications for the treatment of asthma.ICS-containing
medications with a small particle size do not confer additional clinical benefits over those with a standard particle size.
References
Aubier M, Wettenger R, Gans SJ. Efficacy of HFA-beclomethasone dipropionate extra-fine aerosol (800 microg day(1)) versus HFA-fluticasone propionate (1000 microg day(-1)) in patients with asthma. Respiratory medicine
2001;95:212-20.
Bateman ED, Linnhof AE, Homik L, Freudensprung U, Smau L, Engelstatter R. Comparison of twice-daily inhaled
ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma. Pulmonary
pharmacology & therapeutics 2008;21:264-75.
Boulet LP, Bateman ED, Voves R, Muller T, Wolf S, Engelstatter R. A randomized study comparing ciclesonide and
fluticasone propionate in patients with moderate persistent asthma. Respiratory medicine 2007;101:1677-86.
Buhl R, Vinkler I, Magyar P, et al. Comparable efficacy of ciclesonide once daily versus fluticasone propionate twice
daily in asthma. Pulmonary pharmacology & therapeutics 2006;19:404-12.
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Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NH. Particle size matters: diagnostics and
treatment of small airways involvement in asthma. The European respiratory journal 2011;37:532-40.
Currie GP, Fowler SJ, Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Airway and systemic effects of hydrofluoroalkane
fluticasone and beclomethasone in patients with asthma. Thorax 2002;57:865-8.
Dahl R, Engelstatter R, Trebas-Pietras E, Kuna P. A 24-week comparison of low-dose ciclesonide and fluticasone
propionate in mild to moderate asthma. Respiratory medicine 2010;104:1121-30.
Fairfax A, Hall I, Spelman R. A randomized, double-blind comparison of beclomethasone dipropionate extrafine
aerosol and fluticasone propionate. Annals of allergy, asthma & immunology : official publication of the American
College of Allergy, Asthma, & Immunology 2001;86:575-82.
Fowler SJ, Currie GP, Lipworth BJ. Step-down therapy with low-dose fluticasone-salmeterol combination or mediumdose hydrofluoroalkane 134a-beclomethasone alone. The Journal of allergy and clinical immunology 2002;109:929-35.
Lee DK, Fardon TC, Bates CE, Haggart K, McFarlane LC, Lipworth BJ. Airway and systemic effects of
hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma. Chest
2005;127:851-60.
Lee DK, Haggart K, Currie GP, Bates CE, Lipworth BJ. Effects of hydrofluoroalkane formulations of ciclesonide 400
microg once daily vs fluticasone 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate
persistent asthma. British journal of clinical pharmacology 2004;58:26-33.
Magnussen H, Hofman J, Staneta P, Lawo JP, Hellwig M, Engelstatter R. Similar efficacy of ciclesonide once daily
versus fluticasone propionate twice daily in patients with persistent asthma. The Journal of asthma : official journal of
the Association for the Care of Asthma 2007;44:555-63.
Moghaddam KG, Rashidi N, Meybodi HA, et al. The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal
axis. Indian journal of pharmacology 2012;44:314-8.
Niitsuma T, Okita M, Sakurai K, et al. Adrenal function as assessed by low-dose adrenocorticotropin hormone test
before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate. The Journal of
asthma : official journal of the Association for the Care of Asthma 2003;40:515-22.
Ohbayashi H, Adachi M. Hydrofluoroalkane-beclomethasone dipropionate effectively improves airway eosinophilic
inflammation including the distal airways of patients with mild to moderate persistent asthma as compared with
fluticasone propionate in a randomized open double-cross study. Allergology international : official journal of the
Japanese Society of Allergology 2008;57:231-9.
Papi A, Nicolini G, Crimi N, et al. Step-down from high dose fixed combination therapy in asthma patients: a
randomized controlled trial. Respiratory research 2012;13:54.
Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled
combination in moderate to severe asthma. Allergy 2007;62:1182-8.
Pedersen S, Engelstatter R, Weber HJ, et al. Efficacy and safety of ciclesonide once daily and fluticasone propionate
twice daily in children with asthma. Pulmonary pharmacology & therapeutics 2009;22:214-20.
Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160
microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatric pulmonology 2006;41:954-61.
Robroeks CM, van de Kant KD, van Vliet D, et al. Comparison of the anti-inflammatory effects of extra-fine
hydrofluoroalkane-beclomethasone vs fluticasone dry powder inhaler on exhaled inflammatory markers in childhood
asthma. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, &
Immunology 2008;100:601-7.
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Scichilone N, Battaglia S, Sorino C, et al. Effects of extra-fine inhaled beclomethasone/formoterol on both large and
small airways in asthma. Allergy 2010;65:897-902.
Thongngarm T, Silkoff PE, Kossack WS, Nelson HS. Hydrofluoroalkane-134A beclomethasone or chlorofluorocarbon
fluticasone: effect on small airways in poorly controlled asthma. The Journal of asthma : official journal of the
Association for the Care of Asthma 2005;42:257-63.
Tunon-de-Lara JM, Laurent F, Giraud V, et al. Air trapping in mild and moderate asthma: effect of inhaled
corticosteroids. The Journal of allergy and clinical immunology 2007;119:583-90.
van Aalderen WM, Price D, De Baets FM, Price J. Beclometasone dipropionate extrafine aerosol versus fluticasone
propionate in children with asthma. Respiratory medicine 2007;101:1585-93.
van der Molen T, Foster JM, Caeser M, Muller T, Postma DS. Difference between patient-reported side effects of
ciclesonide versus fluticasone propionate. Respiratory medicine 2010;104:1825-33.
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