Design and powering of cystic fibrosis clinical trials using rate of FEV1 decline as an efficacy endpoint

BackgroundRate of lung function decline (RLFD) (as FEV₁ percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements.MethodsSample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV₁ 1–4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥ 6 years with FEV₁ ≥ 70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5 years using semi-annual FEV₁ measures.ResultsIncreasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements.ConclusionsCF RLFD studies of 1.5 years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates.