Design and analysis of three‐arm trials with negative binomially distributed endpoints
Design and analysis of three‐arm trials with negative binomially distributed endpoints
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DOI：
10.1002/sim.6738
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发表时间：
2016-02
影响因子：
2
通讯作者：
Tobias Mütze;A. Munk;T. Friede
中科院分区：
文献类型：
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作者：
Tobias Mütze;A. Munk;T. Friede
三组临床试验设计包括实验治疗、活性对照和安慰剂对照，通常称为金标准设计，可检验实验治疗与活性对照相比的非劣效性或优效性。在本文中，我们提出了设计和分析具有负二项分布终点的三臂试验的方法。特别是，我们开发了一个Wald型检验，其中包含一个限制性最大似然方差估计量，用于检验非劣效性或优效性。对于该检验，将推导样本量和把握度公式以及最佳样本量分配。将在一项广泛的模拟研究中评估拟定检验的性能，包括I类错误率、把握度、样本量和样本量分配。为了进行比较，模拟研究中包括了具有样本方差估计量和无限制最大似然估计量的Wald型统计量。我们发现，拟议的Wald-型检验与限制性方差估计在所考虑的情况下表现良好，因此建议在临床试验中应用。提出的方法的动机和说明了最近的临床试验多发性硬化症。实现本文讨论的方法的R包ThreeArmedTrials在CRAN上可用。版权所有© 2015约翰威利父子有限公司
A three‐arm clinical trial design with an experimental treatment, an active control, and a placebo control, commonly referred to as the gold standard design, enables testing of non‐inferiority or superiority of the experimental treatment compared with the active control. In this paper, we propose methods for designing and analyzing three‐arm trials with negative binomially distributed endpoints. In particular, we develop a Wald‐type test with a restricted maximum‐likelihood variance estimator for testing non‐inferiority or superiority. For this test, sample size and power formulas as well as optimal sample size allocations will be derived. The performance of the proposed test will be assessed in an extensive simulation study with regard to type I error rate, power, sample size, and sample size allocation. For the purpose of comparison, Wald‐type statistics with a sample variance estimator and an unrestricted maximum‐likelihood estimator are included in the simulation study. We found that the proposed Wald‐type test with a restricted variance estimator performed well across the considered scenarios and is therefore recommended for application in clinical trials. The methods proposed are motivated and illustrated by a recent clinical trial in multiple sclerosis. The R package ThreeArmedTrials, which implements the methods discussed in this paper, is available on CRAN. Copyright © 2015 John Wiley & Sons, Ltd.