PRJ2429: Effect of inhaled corticosteroid (ICS) particle size on asthma efficacy and safety outcomes: A systematic literature review and meta-analysis

Trial description: Inhaled corticosteroids (ICS) are the primary treatment for chronic asthma. As particle size dictates deposition of a drug in the lungs, different formulations of ICS with different particle sizes may impact the efficacy and safety of a medication. This protocol outlines the methods that will be used to synthesize and analyze the results of a systematic literature review. The objectives of the systematic review were to summarize the comparative efficacy and safety of ICS medications of different particle sizes as assessed in randomized controlled trials. Specifically, large particle formulations of fluticasone propionate (FP) and fluticasone propionate/salmeterol in combination (FCS) were compared to small particle formulations based on available head-to-head controlled clinical trials. The systematic literature review was based on the published peer-reviewed English language literature, unrestricted by geography, in the past 16 years (January 1, 1998 - January 13, 2014). The search strategy yielded 1,655 potentially-relevant articles. All abstracts were reviewed, and 1,567 were excluded and 88 full-text articles were reviewed. Relevant data were extracted from 25 controlled trials in the form of structured electronic summary tables and spreadsheets to be used in data synthesis for this study. This study will take the extracted data and provide summary plots based on available data, including benefit-risk interval plots and meta-analysis forest plots for specific endpoints where possible.To characterize available efficacy data of FP-containing medications relative to small particle size comparator ICS medications, the following endpoints will be 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 will be 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.Treatments to be evaluated include 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).This protocol includes methods used to create summary displays of data across published studies identified by the systematic review.This will include benefit-risk interval plots, which is a graphical display of absolute risk difference or mean treatment difference and 95% confidence interval of multiple endpoints on the same graph across studies, irrespective of differences in study designs, endpoints and units.When appropriate (i.e. if there is sufficient sample size and homogeneity across studies), a formal meta-analysis will be conducted on key efficacy endpoints. Results in children and adolescents/adults will be analyzed separately. If appropriate, meta regression will be used to adjust for relevant differences across studies for each specific outcome.For the meta-analysis, the results of the individual trials: point estimates and 95% confidence intervals, pooled results of study estimates will be presented on a forest plot. A funnel plot will be utilized to examine potential selection bias. Additional sensitivity analysis will be performed when appropriate.