Variable Duration Trial as an Alternative Design for Continuous Endpoints

Abstract

ABSTRACTClinical trials with continuous primary endpoints typically measure outcomes at baseline, at a fixed timepoint (denoted Tmin), and at intermediate timepoints. The analysis is commonly performed using the mixed model repeated measures method. It is sometimes expected that the effect size will be larger with follow‐up longer than Tmin. But extending the follow‐up for all patients delays trial completion. We propose an alternative trial design and analysis method that potentially increases statistical power without extending the trial duration or increasing the sample size. We propose following the last enrolled patient until Tmin, with earlier enrollees having variable follow‐up durations up to a maximum of Tmax. The sample size at Tmax will be smaller than at Tmin, and due to staggered enrollment, data missing at Tmax will be missing completely at random. For analysis, we propose an alpha‐adjusted procedure based on the smaller of the p values at Tmin and Tmax, termed . This approach can provide the highest power when the powers at Tmin and Tmax are similar. If the power at Tmin and Tmax differ significantly, the power of is modestly reduced compared with the larger of the two powers. Rare disease trials, due to the limited size of the patient population, may benefit the most with this design.