The STEP 1 randomized trial evaluated the effect of taking semaglutide vs placebo on body weight over a 68 week duration. As with any study evaluating an intervention delivered over a sustained period, non-adherence was observed. This was addressed in the original trial analysis within the Estimand Framework by viewing non-adherence 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 realised had all participants adhered, under the assumption that no post-baseline variables confounded adherence and change in body weight. In this paper we propose an alternative Instrumental Variable method to adjust for non-adherence 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 non-adherence is guaranteed). Unlike many previous Instrumental Variable 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 both suggest a sustained, slowly decaying weight loss effect of semaglutide treatment.

翻译：STEP 1随机对照试验评估了在68周内使用司美格鲁肽对比安慰剂对体重的效果。与任何评估长期干预措施的研究一样，该试验观察到了不依从现象。原始试验分析在估计量框架内将不依从视为一种中间事件来处理。主要分析采用了治疗策略方案，将其视为治疗方案的一部分，因此未对其存在进行调整。一项补充分析使用了假设性策略，旨在估计若所有参与者均依从时本应实现的估计量，其前提是假设不存在基线后变量同时混淆依从性与体重变化。本文提出了一种替代性的工具变量方法来调整不依从性，该方法不依赖于相同的“无混淆”假设，且对正性假设违例更稳健（例如，即使在依从性无法保证的条件下仍能给出有效结果）。与以往的许多工具变量方法不同，该方法充分利用了重复测量的结局数据，并允许治疗依从性对参与者体重的影响随时间变化。我们证明，该方法为定义两种不同的假设性估计量提供了自然的载体：一是若所有参与者均依从司美格鲁肽时的治疗效果，二是若所有参与者均同时依从司美格鲁肽和安慰剂时的治疗效果。应用于STEP 1研究时，两者均表明司美格鲁肽治疗具有持续且缓慢衰减的减重效果。