Adaptive promising zone design for sequential parallel comparison design with continuous outcomes.

Introduction: The sequential parallel comparison design has emerged as a valuable tool in clinical trials with high placebo response rates. To further enhance its efficiency and effectiveness, adaptive strategies, such as sample size adjustment and allocation ratio modification can be employed.

Methods: We compared the performance of Jennison and Turnbull's method and the Promising Zone approach for sample size adjustment in a two-phase sequential parallel comparison design study. We also evaluated the impact of allocation ratio adjustments using Neyman and Optimal allocation strategies. Various scenarios were simulated to assess the effects of different design parameters, including weight in the test statistic, initial randomization ratio, and interim analysis timing.

Results: The Promising Zone approach demonstrated superior or comparable power to Jennison and Turnbull's method at equivalent expected sample sizes while maintaining the intuitive property that more promising interim results lead to smaller required follow-up sample sizes. However, the Promising Zone approach may require a larger maximum possible sample size in some cases. The addition of allocation ratio adjustments offered minimal improvements overall, but showed potential benefits when the variance in the treatment group was larger than that in the placebo group. We also applied our findings to a real-world example from the AVP-923 trial in patients with Alzheimer's disease-related agitation, demonstrating the practical implications of adaptive sequential parallel comparison designs in clinical research.

Discussion: Adaptive strategies can significantly enhance the efficiency of sequential parallel comparison designs. The choice between sample size adjustment methods should consider trade-offs between power, expected sample size, and maximum adjusted sample size. Although allocation ratio adjustments showed limited overall impact, they may be beneficial in specific scenarios. Future research should explore the application of these adaptive strategies to binary and survival outcomes in sequential parallel comparison designs.