A Case Study of 2-Stage Seamless Adaptive Sample Size Re-Estimation Design with Efficacy Interim Analysis When Slope Is the Primary Endpoint

Abstract

Due to highly unmet medical needs in rare disease areas, there is great desire to speed up the drug development process. A two-stage adaptive design option for a placebo-controlled registration study is being evaluated. Stage 1 consists of participants in an ongoing phase 2 study with 1-year double blinded (DB) treatment and Stage 2 includes newly enrolled participants with 2-year DB treatment period. The primary endpoint is the annualized rate of change (slope) for a continuous longitudinal measurement, which will be evaluated through a random coefficient 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 participants completed the 1-year 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 given the pre-specified significance level for the interim efficacy analysis. Multiplicity adjustments for secondary endpoints including considerations for order switching between interim and final analysis in this specific case study will also be discussed.

Keywords:

• Efficacy interim analysis
• Multiplicity adjustment
• Sample size re-estimation
• Slope
• Type I error

Supplementary Materials

Supplementary materials contain the proofs of the results stated in the main text.

Acknowledgments

We would like to thank the two referees and associate editor for their helpful comments and suggestions that have greatly improved the presentation of this article.

Disclosure Statement

Qi Zhang, Yuqian Shen, Hui Quan and Pascal Minini are employees of Sanofi and may hold shares and/or stock options in the company. Lin Wang was an employee of Sanofi at the time of this manuscript preparation and held shares in Sanofi.