In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between-treatment difference in population means of a clinical endpoint that is free from the confounding effects of "rescue" medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post-rescue data. We caution that the commonly used mixed-effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for "dropouts" (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient-level imputation is not required. A supplemental "dropout = failure" analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between-treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.

译文

在一些随机 (药物与安慰剂) 临床试验中,感兴趣的估计是临床终点的人群治疗间差异,该临床终点不受 “抢救” 药物的混杂作用 (例如,hbA1c在24周时与基线相比的变化,无论是否或何时终止分配的治疗,在没有抢救药物的情况下都会观察到).在这种情况下,如果某些患者在试验中过早退出试验或开始使用抢救药物,则会出现数据丢失的问题,后者需要丢弃抢救后的数据。我们警告说,常用的混合效应模型重复测量分析与随机假设的嵌入缺失可以提供对上述感兴趣估计的夸大估计。发生这种情况的部分原因是对药物组中 “辍学” (即缺少感兴趣的终点数据的患者) 过于乐观的均值进行了隐含的估算。我们提出了一种替代方法,其中将药物组辍学的缺失平均值明确替换为安慰剂下的整个终点分布的估计平均值 (主要分析) 或在临界点框架内的一系列越来越保守的平均值 (敏感性分析); 不需要患者水平的估算。考虑了补充的 “辍学 = 失败” 分析,其中对所有辍学进行了共同的不良结果估算,然后使用分位数回归进行治疗之间的比较。所有分析都针对相同的估计,并且可以针对基线协变量进行调整。使用了三个示例和仿真结果来支持我们的建议。

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