2011 - Athens - Greece

PAGE 2011: Study design
Shuying Yang

Using Placebo FEV1 Response to Improve the efficiency of clinical trials in Asthma

Shuying Yang (1), Roberto Gomeni (2) and Misba Beerahee (1)

(1) Clinical Pharmacology Modelling and Simulation, GSK, UK; (2) Pharmacometrics, GSK, US

Objectives: To evaluate the efficiency of new clinical trial design in asthma where subjects are randomised to study treatments based on their placebo response at the end of a run-in period.

Methods: A novel approach based on population enrichment for designing and analysing clinical trials for asthma is proposed. The study design consists of two parts: a two-week run-in period where all subjects are treated with placebo, and a randomised period where subjects follow their randomised treatment (active/placebo) for certain period of time. The selection of subjects for second part of the trial is based on their FEV1 response at the end of run-in period. Clinical trial simulations (CTS) are utilised to investigate the validity and the benefits of the proposed study design. The advantage and gain of the proposed design over the conventional approach where all subjects included in the analysis regardless are explored. The simulations are conducted in R (1) with the aid of functions in MSToolKit (2).

Results: Outcomes from the clinical trial simulations suggested that the study power was significantly improved under the proposed study design. Similar study efficiency was attained with about half of the subjects with this new design when compared to the conventional method. The benefit of the new design was more evident for scenarios where the true effective size (active-placebo) depends on the effect of placebo at the run-in period. The risk of an inflated Type I error associated with the proposed trial design was assessed using Clinical Trial Simulation. Randomised two-arm placebo controlled trials were simulated under the assumption that the active drug was ineffective (effect size equals to 0). The results obtained in absence of population enrichment were compared to the results obtained after population enrichment. The results indicated that the proposed methodology preserved the Type I error showing no estimation bias.

Conclusions: The new design with a two-week placebo run-in period in asthma trials is valid, sufficient, and more efficient in terms of study power or sample size for detecting the potential drug effects.

[1]. R project for statistical computing, http://www.r-project.org/
[2]. The MSToolkit library for clinical trial design, v2 (2010), http://cran.r-project.org/web/packages/MSToolkit/index.html

Reference: PAGE 20 (2011) Abstr 2049 [www.page-meeting.org/?abstract=2049]
Poster: Study design