For randomized clinical trials where a single, primary, binary endpoint would require unfeasibly large sample sizes, composite endpoints are widely chosen as the primary endpoint. Despite being commonly used, composite endpoints 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 planning of future sound trial design. 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 composite endpoint. We propose a trial design that allows an adaptive modification of the primary endpoint based on blinded information obtained at an interim analysis. We consider a decision rule to select between a composite endpoint 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. The targeted power is achieved even if the correlation is misspecified while maintaining the type 1 error. We illustrated the proposal by means of two case studies.
翻译:对于随机临床试验,如果单一的、初级的、二进制的端点需要大量样本,那么综合端点通常被广泛选为主要的端点。尽管混合端点通常被广泛选为主要的端点。尽管使用频繁,但复合端点在设计和解释结果方面带来挑战。鉴于各组成部分的相关性可能不同,而且影响大小也不同,因此必须谨慎地选择各组成部分。特别是,复合二进端点的抽样规模计算不仅取决于复合组成部分的预期影响大小和事件概率,而且还取决于它们之间的关联性。然而,文献中通常没有报告关于终点之间相互关系的信息,而这种信息可能妨碍未来健全的试验设计的规划。我们考虑采用两种武器随机随机控制的试验,使用初级复合端点的端点,我们提议试点的试点是根据在临时分析中获得的盲点信息对初级端点进行适应性调整。我们考虑在综合端点和最相关的端点之间选择一个决定规则,而目标端点的端点则可能妨碍未来健全的试验设计设计设计。我们决定规则选择了一种精确度,同时通过估计的精确度,我们用精确度来估计的标定点,然后用精确度来显示估计的标值,然后用精确度,然后用精确的标点来显示的标值来显示,然后用精确度,然后用精确度来显示,然后用精确度来显示。