Division of Infectious Diseases, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
BMC Med Res Methodol. 2024 Oct 18;24(1):245. doi: 10.1186/s12874-024-02364-6.
The ICH E9 (R1) addendum on Estimands and Sensitivity analysis in Clinical trials proposes a framework for the design and analysis of clinical trials aimed at improving clarity around the definition of the targeted treatment effect (the estimand) of a study.
We adopt the estimand framework in the context of a study using "trial emulation" to estimate the risk of pneumocystis pneumonia, an opportunistic disease contracted by people living with HIV and AIDS having a weakened immune system, when considering two antibiotic treatment regimes for stopping antibiotic prophylaxis treatment against this disease. A "while on treatment" strategy has been implemented for post-randomisation (intercurrent) events. We then perform a sensitivity analysis using reference based multiple imputation to model a scenario in which patients lost to follow-up stop taking prophylaxis.
The primary analysis indicated a protective effect for the new regime which used viral suppression as prophylaxis stopping criteria (hazard ratio (HR) 0.78, 95% confidence interval [0.69, 0.89], p < 0.001). For the sensitivity analysis, when we apply the "jump to off prophylaxis" approach, the hazard ratio is almost the same compared to that from the primary analysis (HR 0.80 [0.69, 0.95], p = 0.009). The sensitivity analysis confirmed that the new regime exhibits a clear improvement over the existing guidelines for PcP prophylaxis when those lost to follow-up "jump to off prophylaxis".
Our application using reference based multiple imputation demonstrates the method's flexibility and simplicity for sensitivity analyses in the context of the estimand framework for (emulated) trials.
ICH E9（R1）附录中关于临床试验中的目标值和敏感性分析提出了一个框架，旨在提高对研究目标治疗效果（目标值）定义的清晰度，从而设计和分析临床试验。
我们在使用“试验模拟”的研究背景下采用目标值框架，估计在考虑两种停止针对这种疾病的抗生素预防治疗的抗生素治疗方案时，艾滋病毒和艾滋病患者免疫功能减弱的人患机会性肺炎（卡氏肺孢子虫肺炎）的风险。针对随机化后（并发）事件实施了“治疗中”策略。然后，我们使用基于参考的多重插补进行敏感性分析，以模拟患者失访停止预防的情况。
主要分析表明，新方案使用病毒抑制作为预防停药标准具有保护作用（风险比（HR）0.78，95%置信区间[0.69,0.89]，p<0.001）。对于敏感性分析，当我们应用“跳转到停用预防”方法时，与主要分析相比，风险比几乎相同（HR 0.80 [0.69,0.95]，p=0.009）。敏感性分析证实，当失访患者“跳转到停用预防”时，新方案与现有的 PcP 预防指南相比，对 PcP 预防具有明显改善。
我们使用基于参考的多重插补的应用证明了该方法在（模拟）试验的目标值框架下进行敏感性分析的灵活性和简单性。
