All Times EDT
Keywords: rare disease, adaptive design, sample size re-estimation
Due to highly unmet medical needs in rare disease areas, there is great desire to speed up the drug development process. With extraordinary challenge in recruitment and many uncertainties, adaptive designs may be employed to trials in rare disease areas. A development option of a placebo-controlled registration study through a two-stage adaptive trial design is being evaluated. Stage 1 consists of subjects in ongoing phase 2 study with 48 weeks double blind (DB) treatment and stage 2 includes newly enrolled subjects with 96 weeks DB treatment period. The primary endpoint is the annualized rate of change (slope) for a continuous longitudinal measurement) which will be evaluated through a linear mixed model. An unblinded interim analysis will be performed using Stage 1 data to re-estimate the sample size for Stage 2, followed by another interim analysis for potential early efficacy stopping when all subjects completed the 48 weeks DB treatment. To control the overall type 1 error rate, rather than using a conservative approach, the actual correlation between the interim and final test statistics will be taken into account to determine the final significance level after pre-specifying the significance level for the interim efficacy analysis and the demonstration of the independent increment property for the slope analysis. Other factors such as different longitudinal timepoints for different patients as well as variability assumptions that may impact the type 1 error control and power for the slope analysis will also be discussed. Multiplicity adjustments for secondary endpoints at interim vs. final analysis will also be considered.