MRC Biostatistics Unit Hub for Trials Methodology Research, Cambridge Institute of Public Health, Cambridge, UK.
Clin Trials. 2017 Oct;14(5):507-517. doi: 10.1177/1740774517716937. Epub 2017 Jun 27.
BACKGROUND/AIMS: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs.
Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored.
We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial's type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate.
The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial.
背景/目的：阶梯式楔形群随机试验设计近年来受到了广泛关注。尽管已经提出了各种对原始设计的扩展，但对于具有中期分析的阶梯式楔形群随机试验的设计尚无指导。在个体随机试验设置中，分组序列方法可以提供显著的效率增益和伦理效益。我们通过讨论如何适应已建立的分组序列方法来解决这个问题。
利用分组序列试验设计的误差消耗方法，详细说明了确定具有中期分析的阶梯式楔形群随机试验所需的假设。我们考虑了因疗效、无效或疗效和无效而提前停止。我们首先描述了如何为数据分析的任何指定线性混合模型来完成这一点。然后，我们将重点放在一个常用的模型上，并使用最近完成的阶梯式楔形群随机试验，将具有中期分析的几种设计与经典的阶梯式楔形设计进行比较。最后，探索了处理未知方差情况的分位数替换程序的性能。
我们证明，在阶梯式楔形群随机试验设计中加入中期分析可以将零假设和备择假设下的预期样本量分别减少 31%和 22%，而不会对试验的 I 型和 II 型错误率造成任何损失。发现使用受限误差最大似然估计比分位数替换对于控制 I 型错误率更为重要。
将中期分析纳入阶梯式楔形群随机试验中可以帮助防止对疗效不佳的治疗进行耗时的试验，并有助于加快有效的治疗方法的实施。未来，试验设计者应根据特定试验的需要考虑在阶梯式楔形群随机试验中加入某种早期停止。
