Noninferiority clinical trials aim to show an experimental treatment is therapeutically no worse than standard of care, particularly if the new treatment is preferred for reasons such as cost, convenience, safety, and so on. Noninferiority trials are by nature less conservative than superiority studies: protocol violations may increase bias toward the alternative hypothesis of noninferiority. Our objective was to compare multiple imputation, a linear mixed model, and other methods for analyzing a longitudinal trial with missing data in intention-to-treat and per-protocol populations. We simulated trials with missing data and noncompliance due to treatment inefficacy under varying trial conditions (e.g., trajectory of treatment effects, correlation between repeated measures, and missing data mechanism), assessing each approach by estimating bias, Type I error, and power. We found that multiple imputation using auxiliary data on noncompliance in the imputation model performed best. A hybrid intention-to-treat/per-protocol multiple imputation approach with a missing not at random imputation model produced low Type I error, was unbiased and maintained reasonable power to detect noninferiority. We conclude that the anti-conservatism of noninferiority trial estimands conforming with the intention-to-treat principle may be offset by imputation models that include variables on intercurrent events. Supplementary materials for this article are available online.

非劣效性临床试验旨在证明实验性治疗在治疗上不比标准治疗差，特别是如果出于成本，便利性，安全性等原因而首选新治疗的情况下。从本质上来说，非劣效性试验不如优势研究那么保守：违反规程可能会增加对非劣效性替代假设的偏见。我们的目标是比较多重插补，线性混合模型和其他方法，以分析有意治疗和按方案人群中缺少数据的纵向试验。我们模拟了在各种试验条件（例如，治疗效果的轨迹，重复措施之间的相关性以及数据机制缺失）下由于治疗无效而导致数据缺失和不合规的试验，通过评估偏倚，类型I错误和电源。我们发现，在插补模型中使用关于不合规性的辅助数据进行多次插补的效果最佳。缺少意向性插补模型的混合意向治疗/按方案多插补方法产生的I型错误率低，无偏见并保持了合理的能力来检测非劣效性。我们得出的结论是，符合意图治疗原则的非劣效性试验估计的反保守性可能会被包含并发事件变量的估算模型所抵消。可在线获得本文的补充材料。缺少意向性插补模型的混合意向治疗/按方案的多插补方法产生的I型错误较低，并且没有偏见并且保持了合理的能力来检测非劣效性。我们得出的结论是，符合意图治疗原则的非劣效性试验估计的反保守性可能会被包含并发事件变量的估算模型所抵消。可在线获得本文的补充材料。缺少意向性插补模型的混合意向治疗/按方案的多插补方法产生的I型错误较低，并且没有偏见并且保持了合理的能力来检测非劣效性。我们得出的结论是，符合意图治疗原则的非劣效性试验估计的反保守性可能会被包含并发事件变量的估算模型所抵消。可在线获得本文的补充材料。