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A novel estimand to adjust for rescue treatment in randomized clinical trials
Statistics in Medicine ( IF 2 ) Pub Date : 2021-02-10 , DOI: 10.1002/sim.8901
Hege Michiels 1 , Cristina Sotto 2 , An Vandebosch 2 , Stijn Vansteelandt 1, 3
Affiliation  

The interpretation of randomized clinical trial results is often complicated by intercurrent events. For instance, rescue medication is sometimes given to patients in response to worsening of their disease, either in addition to the randomized treatment or in its place. The use of such medication complicates the interpretation of the intention‐to‐treat analysis. In view of this, we propose a novel estimand defined as the intention‐to‐treat effect that would have been observed, had patients on the active arm been switched to rescue medication if and only if they would have been switched when randomized to control. This enables us to disentangle the treatment effect from the effect of rescue medication on a patient's outcome, while tempering the strong extrapolations that are typically needed when inferring what the intention‐to‐treat effect would have been in the absence of rescue medication. We propose a novel inverse probability weighting method for estimating this effect in settings where the decision to initiate rescue medication is made at one prespecified time point. This estimator relies on specific untestable assumptions, in view of which we propose a sensitivity analysis. We use the method for the analysis of a clinical trial conducted by Janssen Pharmaceuticals, in which patients with type 2 diabetes mellitus can switch to rescue medication for ethical reasons. Monte Carlo simulations confirm that the proposed estimator is unbiased in moderate sample sizes.

中文翻译:

在随机临床试验中调整抢救治疗的新方法

随机临床试验结果的解释通常由于并发事件而变得复杂。例如,除了随机治疗或其替代方法外,有时会根据患者病情恶化向患者提供急救药物。这种药物的使用使治疗意向分析的解释变得复杂。有鉴于此,我们提出了一个新的估计,即当且仅当在随机分配时将患者切换为对照时,主动臂上的患者才转用抢救药物时,会观察到意向性治疗效果。这使我们能够将治疗效果与急救药物对患者预后的影响区分开来,同时调整推断在没有急救药物的情况下会有意向性治疗效果时通常需要的强推论。我们提出了一种新颖的逆概率加权方法,用于估计在一个预先确定的时间点做出启动急救药物的决定的情况下的这种影响。该估计器依赖于无法测试的特定假设,因此我们建议进行敏感性分析。我们使用该方法对Janssen Pharmaceuticals进行的一项临床试验进行分析,在该试验中,出于伦理原因,2型糖尿病患者可以改用抢救药物。蒙特卡洛模拟证实了在中等样本量下所提出的估计量是无偏的。我们提出了一种新颖的逆概率加权方法,用于估计在一个预先确定的时间点做出启动急救药物的决定的情况下的这种影响。该估计器依赖于无法测试的特定假设,因此我们建议进行敏感性分析。我们使用该方法对Janssen Pharmaceuticals进行的一项临床试验进行分析,在该试验中,出于伦理原因,2型糖尿病患者可以改用抢救药物。蒙特卡洛模拟证实了在中等样本量下所提出的估计量是无偏的。我们提出了一种新颖的逆概率加权方法,用于估计在一个预先确定的时间点做出启动急救药物的决定的情况下的这种影响。该估计器依赖于无法测试的特定假设,因此我们建议进行敏感性分析。我们使用该方法对Janssen Pharmaceuticals进行的一项临床试验进行分析,在该试验中,出于伦理原因,2型糖尿病患者可以改用抢救药物。蒙特卡洛模拟证实了在中等样本量下所提出的估计量是无偏的。我们使用该方法对Janssen Pharmaceuticals进行的一项临床试验进行分析,在该试验中,出于伦理原因,2型糖尿病患者可以改用抢救药物。蒙特卡洛模拟证实了在中等样本量下所提出的估计量是无偏的。我们使用该方法对Janssen Pharmaceuticals进行的一项临床试验进行分析,在该试验中,出于伦理原因,2型糖尿病患者可以改用抢救药物。蒙特卡洛模拟证实了在中等样本量下所提出的估计量是无偏的。
更新日期:2021-04-06
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