论文标题

COVID-19治疗的随机对照临床试验的终点

Endpoints for randomized controlled clinical trials for COVID-19 treatments

论文作者

Dodd, Lori E, Follmann, Dean, Wang, Jing, Koenig, Franz, Korn, Lisa L, Schoergenhofer, Christian, Proschan, Michael, Hunsberger, Sally, Bonnett, Tyler, Makowski, Mat, Belhadi, Drifa, Wang, Yeming, Cao, Bin, Mentre, France, Jaki, Thomas

论文摘要

简介:COVID-19的随机对照试验的终点选择很复杂。一种新疾病会带来许多不确定性,但试验必须迅速开始。 COVID-19是异质的,范围从温和的疾病到几天内改善到可能持续数周的关键疾病,可能以死亡结束。虽然死亡率的改善将提供有关治疗的临床意义的毫无疑问的证据,但评估死亡率的研究样本量很大,可能是不切实际的。此外,患者在“治愈”和“死亡”之间表示有意义的区别。已经提出了临床严重程度评分作为替代方案。但是,对严重程度得分的适当摘要措施一直是辩论的主题,特别是关于Covid-19的时间顺序的不确定性。在固定时间点测量的结果可能会丢失临床益处的时间。诸如解决时间(或恢复)之类的终点避免了时间问题。但是,有人认为,将序数量减少到“回收”与“未恢复”的二元状态会导致功率损失。 方法:我们使用模拟模型和两个最近的COVID-19治疗试验的数据评估了COVID-19治疗试验的可能试验终点的统计能力。 结果:固定时间点方法的功率在很大程度上取决于选择的评估时间。提交时间(或恢复)分析未指定时间点。即使与在最佳时间评估的固定时间点方法相比,活动时间方法具有合理的统计能力。 讨论:事实分析方法在COVID-19设置中具有优势,除非预先知道评估治疗效果的最佳时间。即使知道最佳时间,事件时间的方法也可能增加临时分析的功率。

Introduction: Endpoint choice for randomized controlled trials of treatments for COVID-19 is complex. A new disease brings many uncertainties, but trials must start rapidly. COVID-19 is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks and can end in death. While improvement in mortality would provide unquestionable evidence about clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly in relating to the uncertainty about the time-course of COVID-19. Outcomes measured at fixed time-points may risk missing the time of clinical benefit. An endpoint such as time-to-improvement (or recovery), avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" vs "not recovered." Methods: We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials. Results: Power for fixed-time point methods depends heavily on the time selected for evaluation. Time-to-improvement (or recovery) analyses do not specify a time-point. Time-to-event approaches have reasonable statistical power, even when compared to a fixed time-point method evaluated at the optimal time. Discussion: Time-to-event analyses methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.

扫码加入交流群

加入微信交流群

微信交流群二维码

扫码加入学术交流群,获取更多资源