Sildenafil (REVATIO^®) was approved for the treatment of adult Pulmonary Arterial Hypertension (PAH) in the US and the EU. A pediatric study has been performed and sildenafil was approved in the EU for pediatric PAH. The long-term extension of this study revealed good survival but also an increased mortality with the high dose of sildenafil compared to lower doses. As a consequence, FDA required Pfizer to evaluate REVATIO^®’s effect on the risk of death in adults with PAH. Following FDA’s rationale a survival model was developed to characterize the exposure–mortality relationship and assess its potential impact on an ongoing survival trial in adults in the context of confounding factors. Clinical trial simulations were performed to assess the design of the survival trial in adults (AFFILIATE, NCT02060487), expected to last approximately 8 years according to both assumptions: absence or presence of an exposure–mortality relationship and to quantify the impact of confounding factors on its readout. Simulations showed that the trial would be robust in most conditions. But its interpretation will depend on the number of confounding factors such as additional treatments attempting to control disease progression.Clinical trial identifier NCT00159913 for STARTS-1, NCT00159874 for STARTS-2

中文翻译：

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基于模型和仿真的混杂因素对肺动脉高压中西地那非生存试验的读数影响的评估。

西地那非（Revatio的^®）被批准在美国和欧盟的治疗成人肺动脉高压（PAH）的。儿科研究已经完成，西地那非在欧盟被批准用于儿科PAH。与低剂量相比，高剂量西地那非的长期扩展显示了良好的生存率，但也增加了死亡率。因此，FDA要求辉瑞公司评估Revatio的^®对成人PAH死亡风险的影响。遵循FDA的基本原理，开发了生存模型，以表征暴露与死亡率的关系，并评估其在混杂因素背景下对正在进行的成人生存试验的潜在影响。进行了临床试验模拟，以评估成人生存试验的设计（AFFILIATE，NCT02060487），该试验根据以下两个假设预计将持续约8年：暴露与死亡的关系是否存在，以及量化混杂因素对患者的影响。它的读数。仿真表明，该试验在大多数情况下都是可靠的。但是其解释将取决于混杂因素的数量，例如试图控制疾病进展的其他治疗方法。临床试验标识符 适用于STARTS-1的NCT00159913，适用于STARTS-2的NCT00159874