Market Access, Janssen, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
Statistics and Decision Sciences, Global Development, Actelion Pharmaceuticals Ltd, 4123, Allschwil, Switzerland.
Adv Ther. 2022 Sep;39(9):4346-4358. doi: 10.1007/s12325-022-02253-8. Epub 2022 Aug 1.
Evaluating overall survival in randomized controlled trials (RCTs) can often be confounded by bias introduced by treatment switching. SERAPHIN was a large RCT that evaluated the effects of long-term treatment with the endothelin receptor antagonist macitentan in patients with pulmonary arterial hypertension. In an intent-to-treat (ITT) analysis, a non-significant decrease in the risk of all-cause mortality up to study closure was reported with macitentan 10 mg versus placebo. As patients could switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects on overall survival.
The inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no treatment switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as patients in the placebo group switching to open-label macitentan 10 mg, and patients in the macitentan 10 mg group prematurely discontinuing macitentan.
By study closure, 73.2% (183/250) of patients in the placebo group had switched to macitentan 10 mg. Among these patients, exposure time to macitentan 10 mg represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). At study closure, 24.8% (60/242) of patients in the macitentan 10 mg group were not receiving open-label macitentan; mean time not receiving macitentan was 44.3 weeks. The adjusted hazard ratios (HR) for overall survival using the IPCW and RPSFT methods were lower (HR 0.42, 95% confidence interval [CI] 0.22, 0.81; p = 0.009, and HR 0.33, 95% CI 0.04, 2.83, respectively) than the ITT unadjusted HR (0.80, 95% CI 0.51, 1.24).
These results from the current analyses indicate that in SERAPHIN, the standard ITT analysis was confounded by treatment switching resulting in an underestimation of the benefit of macitentan 10 mg on overall survival. By adjusting for switching, the IPCW and RPSFT models estimated a 58% and 67% reduction in risk of mortality, respectively, with macitentan 10 mg versus placebo.
ClinicalTrials.gov identifier: NCT00660179.
在随机对照试验（RCT）中评估总生存时间往往会受到因治疗转换而引入的偏倚的影响。SERAPHIN 是一项大型 RCT，评估了长期使用内皮素受体拮抗剂马西替坦治疗肺动脉高压患者的效果。在意向治疗（ITT）分析中，报告了马西替坦 10 毫克与安慰剂相比，全因死亡率风险有非显著性下降，直至研究关闭。由于患者在出现疾病进展症状时可以转换治疗，因此该分析试图调整治疗转换对总生存的混杂影响。
使用逆概率 censoring 加权（IPCW）和秩保持结构失效时间（RPSFT）模型来估计在 SERAPHIN 中没有治疗转换的情况下，治疗对总死亡率的影响。评估了所有原因死亡的时间，直至研究关闭。治疗转换定义为安慰剂组的患者转换为开放标签马西替坦 10 毫克，以及马西替坦 10 毫克组的患者过早停止马西替坦治疗。
截至研究关闭时，安慰剂组 73.2%（183/250）的患者已转换为马西替坦 10 毫克。在这些患者中，马西替坦 10 毫克的暴露时间占总研究治疗暴露时间的 28.2%（累计暴露 134.6 患者年）。截至研究关闭时，马西替坦 10 毫克组 24.8%（60/242）的患者未接受开放标签马西替坦治疗；未接受马西替坦治疗的平均时间为 44.3 周。使用 IPCW 和 RPSFT 方法的总生存调整后的危险比（HR）较低（HR 0.42，95%置信区间 [CI] 0.22，0.81；p = 0.009，以及 HR 0.33，95% CI 0.04，2.83）与 ITT 未调整 HR（0.80，95% CI 0.51，1.24）相比。
当前分析的结果表明，在 SERAPHIN 中，标准的 ITT 分析因治疗转换而受到混杂影响，导致对马西替坦 10 毫克对总生存的益处的低估。通过调整转换，IPCW 和 RPSFT 模型估计马西替坦 10 毫克与安慰剂相比，死亡率风险分别降低了 58%和 67%。
ClinicalTrials.gov 标识符：NCT00660179。
