Bowden Jack, Madsen Jesper, Goldman Bryan, Thorn Iversen Aske, Liang Xiaoran, Vansteelandt Stijn
Novo Nordisk Research Centre (NNRCO), Oxford, UK.
Biostatistics, Novo Nordisk, Bagsvaerd, Denmark.
Stat Med. 2025 Mar 30;44(7):e70076. doi: 10.1002/sim.70076.
The STEP 1 randomized trial evaluated the effect of taking semaglutide versus placebo on body weight over a 68-week duration. As with any study evaluating an intervention delivered over a sustained period, nonadherence was observed. This was addressed in the original trial analysis within the Estimand Framework by viewing nonadherence as an intercurrent event. The primary analysis applied a treatment policy strategy which viewed it as an aspect of the treatment regimen, and thus made no adjustment for its presence. A supplementary analysis used a hypothetical strategy, targeting an estimand that would have been realized had all participants adhered, under the assumption that no post-baseline variables confounded adherence and change in body weight. In this article, we propose an alternative instrumental variable (IV) method to adjust for nonadherence which does not rely on the same "unconfoundedness" assumption and is less vulnerable to positivity violations (e.g., it can give valid results even under conditions where nonadherence is guaranteed). Unlike many previous IV approaches, it makes full use of the repeatedly measured outcome data, and allows for a time-varying effect of treatment adherence on a participant's weight. We show that it provides a natural vehicle for defining two distinct hypothetical estimands: the treatment effect if all participants would have adhered to semaglutide, and the treatment effect if all participants would have adhered to both semaglutide and placebo. When applied to the STEP 1 study, they suggest a sustained, slowly decaying weight loss effect of semaglutide treatment.
STEP 1随机试验评估了在68周的时间里服用司美格鲁肽与服用安慰剂相比对体重的影响。与任何评估长期实施的干预措施的研究一样，观察到了不依从情况。在最初的试验分析中，在估计框架内将不依从视为并发事件来解决这个问题。主要分析采用了一种治疗策略，将其视为治疗方案的一个方面，因此没有对其存在进行调整。一项补充分析使用了一种假设策略，目标是一个在所有参与者都依从的情况下本可实现的估计量，前提是没有基线后变量混淆依从性和体重变化。在本文中，我们提出了一种替代的工具变量（IV）方法来调整不依从情况，该方法不依赖于相同的“无混杂”假设，并且不太容易受到正性违背的影响（例如，即使在保证不依从的情况下也能给出有效结果）。与许多先前的IV方法不同，它充分利用了重复测量的结果数据，并考虑了治疗依从性对参与者体重的随时间变化的影响。我们表明，它为定义两个不同的假设估计量提供了一个自然的工具：如果所有参与者都依从司美格鲁肽时的治疗效果，以及如果所有参与者都依从司美格鲁肽和安慰剂两者时的治疗效果。当应用于STEP 1研究时，它们表明司美格鲁肽治疗具有持续、缓慢衰减的体重减轻效果。
