论文标题
自适应临床试验设计,盲目选择的二进制复合终点和样本量重新评估
Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment
论文作者
论文摘要
对于一个单一的,主要的二元终点需要不高的样本量的随机临床试验,复合端点被广泛选择为主要终点。尽管通常使用,但复合终点在设计和解释结果时都带来了挑战。鉴于组件可能具有不同的相关性并且具有不同的效果大小,因此必须仔细地选择组件的选择。特别是,复合二进制端点的样本量计算不仅取决于复合组件的预期效应大小和事件概率,还取决于它们之间的相关性。但是,文献中通常不会报告有关端点之间相关性的信息,这可能是计划未来声音试验设计的障碍。我们考虑具有主要复合二进制端点的两臂随机对照试验,并且仅由复合终点的临床上更重要的组成部分组成。我们提出了一种试验设计,该设计允许基于在临时分析中获得的盲目信息对主要终点进行自适应修改。我们考虑一个决策规则,可以在复合端点及其最相关的组件作为主要端点之间进行选择。决策规则以较低的所需样本量选择终点。此外,使用估计的事件概率和相关性以及复合组件的预期效应大小重新评估样本量。我们通过模拟研究了拟议设计下的统计能力和显着性水平。我们表明,自适应设计比在主要终点上没有自适应修改的设计的同等强度或更强大。即使在维持类型1误差的同时,相关性被弄错了,也可以实现目标功率。我们通过两个案例研究来说明该提案。
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.