Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.
TU Dortmund University, Faculty of Statistics, Dortmund, Germany.
Stat Methods Med Res. 2022 Oct;31(10):2004-2020. doi: 10.1177/09622802221107103. Epub 2022 Jun 13.
Late phase clinical trials are occasionally planned with one or more interim analyses to allow for early termination or adaptation of the study. While extensive theory has been developed for the analysis of ordered categorical data in terms of the Wilcoxon-Mann-Whitney test, there has been comparatively little discussion in the group sequential literature on how to provide repeated confidence intervals and simple power formulas to ease sample size determination. Dealing more broadly with the nonparametric Behrens-Fisher problem, we focus on the comparison of two parallel treatment arms and show that the Wilcoxon-Mann-Whitney test, the Brunner-Munzel test, as well as a test procedure based on the log win odds, a modification of the win ratio, asymptotically follow the canonical joint distribution. In addition to developing power formulas based on these results, simulations confirm the adequacy of the proposed methods for a range of scenarios. Lastly, we apply our methodology to the FREEDOMS clinical trial (ClinicalTrials.gov Identifier: NCT00289978) in patients with relapse-remitting multiple sclerosis.
后期临床试验偶尔会计划进行一次或多次中期分析，以便提前终止或调整研究。虽然已经针对 Wilcoxon-Mann-Whitney 检验制定了广泛的理论来分析有序分类数据，但在群组序贯文献中，关于如何提供重复置信区间和简单的功效公式以方便样本量确定的讨论相对较少。更广泛地处理非参数 Behrens-Fisher 问题，我们专注于比较两个平行的治疗臂，并表明 Wilcoxon-Mann-Whitney 检验、Brunner-Munzel 检验以及基于对数赢率的检验程序，对赢率的一种修改，渐近遵循规范的联合分布。除了基于这些结果开发功效公式外，模拟还证实了所提出的方法在一系列情况下的充分性。最后，我们将我们的方法应用于 FREEDOMS 临床试验（ClinicalTrials.gov 标识符：NCT00289978），该试验涉及复发缓解型多发性硬化症患者。
