Multi-arm multi-stage (MAMS) trials have gained popularity, due to their improved efficiency in evaluating multiple treatments. A traditional MAMS trial often decreases the expected sample size of the trial compared to just running a multi-arm approach, but with the drawback of an increase in maximum sample size. For academic led trials this poses a particular challenge, as funding is typically based on the maximum required sample size. To address this, drop-the-loser designs were introduced, where a fixed number of treatments are dropped at each interim stage, thereby reducing the maximum sample size. In this work, we propose an enhanced multi-stage drop-the-loser design that also allows for early stopping of the entire trial for superiority. This approach aims to retain the benefits of a reduced maximum sample size while also lowering the expected sample size. The proposed design is motivated by a trial in atrial fibrillation. We derive analytical expressions for the type I error rate, power, and expected sample size, and compare the proposed design's performance to alternative methods. We outline the key requirements for implementing the proposed design and discuss the contexts in which it should be considered. For the motivating example the results show that the proposed design substantially reduces the expected sample size compared to a standard drop-the-loser design, while lowering the maximum sample size relative to running a traditional MAMS trial or multiple separate trials.

翻译：多臂多阶段临床试验因能提高评估多种治疗方案的效率而受到广泛关注。相较于仅采用多臂试验设计，传统MAMS试验通常会降低期望样本量，但其代价是最大样本量的增加。对于学术主导的临床试验而言，这带来了特殊挑战——因为经费通常基于所需的最大样本量进行拨付。为解决此问题，学界提出了“淘汰劣效治疗方案”设计，即每个中期分析阶段固定淘汰若干治疗方案，从而降低最大样本量。本研究提出一种增强型多阶段淘汰劣效治疗方案设计，该设计允许因优效性而提前终止整个试验。此方法旨在保留降低最大样本量优势的同时，进一步缩减期望样本量。本研究的提出受到一项心房颤动临床试验的启发。我们推导了I类错误率、检验效能和期望样本量的解析表达式，并将所提设计的性能与替代方法进行比较。我们概述了实施该设计的核心要求，并讨论了其适用的研究情境。以该驱动案例为例，结果表明：相较于标准淘汰劣效治疗方案设计，本研究所提设计能显著降低期望样本量；同时相对于传统MAMS试验或多个独立试验，其最大样本量也有所降低。