采用盲法选择二元复合终点和样本量重新评估的适应性临床试验设计。

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Marta Bofill Roig, Guadalupe Gómez Melis, Martin Posch, Franz Koenig
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引用次数: 0

摘要

在随机临床试验中,如果采用单一、主要、二元终点,样本量将大得难以承受,因此,人们普遍选择复合终点(CE)作为主要终点。尽管复合终点被广泛使用,但在设计和解释结果方面仍存在挑战。鉴于各组成部分可能具有不同的相关性和效应大小,因此必须谨慎选择各组成部分。特别是,二元复合终点的样本量计算不仅取决于复合成分的预期效应大小和事件概率,还取决于它们之间的相关性。然而,文献中通常没有关于终点之间相关性的信息,这可能会成为未来设计合理试验的障碍。我们考虑进行双臂随机对照试验,试验的主要终点是二元复合终点,而终点只包括 CE 中临床上更重要的部分。我们提出的试验设计允许根据中期分析获得的盲法信息对主要终点进行自适应修改。特别是,我们考虑采用一种决策规则,在 CE 及其最相关的组成部分之间选择一个作为主要终点。决策规则选择估计所需样本量较少的终点。此外,我们还使用估计的事件概率和相关性以及复合成分的预期效应大小来重新评估样本量。我们通过模拟研究了拟议设计下的统计功率和显著性水平。结果表明,在主要终点上,自适应设计与未进行自适应修改的设计相比,具有同等或更大的作用力。此外,即使在规划阶段对相关性进行了错误设置,在保持类型 1 误差的情况下,也能达到目标功率。所有计算均用 R 语言实现,并通过腹膜透析试验加以说明。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment.

For randomized clinical trials where a single, primary, binary endpoint would require unfeasibly large sample sizes, composite endpoints (CEs) are widely chosen as the primary endpoint. Despite being commonly used, CEs entail challenges in designing and interpreting results. Given that the components may be of different relevance and have different effect sizes, the choice of components must be made carefully. Especially, sample size calculations for composite binary endpoints depend not only on the anticipated effect sizes and event probabilities of the composite components but also on the correlation between them. However, information on the correlation between endpoints is usually not reported in the literature which can be an obstacle for designing future sound trials. We consider two-arm randomized controlled trials with a primary composite binary endpoint and an endpoint that consists only of the clinically more important component of the CE. We propose a trial design that allows an adaptive modification of the primary endpoint based on blinded information obtained at an interim analysis. Especially, we consider a decision rule to select between a CE and its most relevant component as primary endpoint. The decision rule chooses the endpoint with the lower estimated required sample size. Additionally, the sample size is reassessed using the estimated event probabilities and correlation, and the expected effect sizes of the composite components. We investigate the statistical power and significance level under the proposed design through simulations. We show that the adaptive design is equally or more powerful than designs without adaptive modification on the primary endpoint. Besides, the targeted power is achieved even if the correlation is misspecified at the planning stage while maintaining the type 1 error. All the computations are implemented in R and illustrated by means of a peritoneal dialysis trial.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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