2/2 Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric Pulmonary Arterial Hypertension-DCC

摘要 肺动脉高压（PAH）导致患有多种疾病的儿童的高发病率和死亡率 心肺及全身疾病。确定儿科 PAH 最佳治疗策略的努力已取得进展 由于缺乏多中心随机对照试验（MRCT）以及缺乏明确定义和 儿童研究的经过验证的终点。儿科 PAH 仍未得到充分研究，人们对其知之甚少 儿童的长期结果、适合年龄的临床终点和最佳治疗策略。药物 治疗仍然不够理想，因为 MRCT 在 PAH 儿童中很少见，并且当前的决策取决于 来自成人研究或儿童小病例系列的数据。基于 MRCT 最近在建立 成人 PAH 患者的新护理标准，我们建议研究初始预先组合的潜在作用 儿童 PAH 的治疗包括两种 PAH 特异性口服疗法，这两种疗法已被证明效果良好 儿童可耐受的单一疗法：西地那非（一种 V 型磷酸二酯酶抑制剂）和波生坦（一种 内皮素受体拮抗剂）。最近对成人 PAH 的研究表明，开始联合治疗 诊断时服用磷酸二酯酶 5 抑制剂和内皮素受体拮抗剂，而不是 序贯联合治疗可改善肺血流动力学、运动耐量和生活质量 与单一疗法相比。随着时间的推移，患有 PAH 的儿童通常需要额外的治疗 然而，没有关于疾病进展或对单一疗法的不完全反应的数据 随着时间的推移，更积极的治疗会带来更大、更持续的临床改善的潜在好处 从初次诊断时开始采用联合治疗方法。儿科PAH研究已深入 由于缺乏协调良好且经验丰富的护理计划以及这些计划相对稀有的性质而受到限制 疾病。在小儿肺动脉高压网络 (PPHNet) 的合作下，一个高度互动的网络 和学术 PH 项目的多学科小组，我们建议检验以下假设： 在 PAH 诊断时进行西地那非和波生坦的前期联合治疗将导致 与现行标准方法相比，12 个月时世界卫生组织功能等级 (FC) 得到改善， 这是单独的西地那非疗法。总体而言，这项研究通过测试临床研究解决了儿科 PAH 的关键差距 具有广泛影响潜力的战略，并通过定义有用的研究终点或新颖的替代品， 促进基于证据的决策并加强对 PAH 儿童的护理。

ABSTRACT Pulmonary arterial hypertension (PAH) contributes to high morbidity and mortality in children with diverse cardiopulmonary and systemic diseases. Efforts to define optimal treatment strategies for pediatric PAH have been limited by the absence of multicenter randomized controlled trials (MRCTs) and the lack of well-defined and proven endpoints for studies in children. Pediatric PAH remains understudied and relatively little is known about long-term outcomes, age-appropriate clinical endpoints and optimal therapeutic strategies for children. Drug treatment remains suboptimal as MRCTs are rare in children with PAH and current decision-making is dependent on data from adult studies or small case series in children. Based on recent success of MRCTs in establishing a new standard of care for adult PAH patients, we propose to study the potential role for initial up-front combination treatment of PAH in children consisting of two PAH-specific oral therapies that have been shown to be well- tolerated in children as monotherapies: sildenafil (a type V phosphodiesterase inhibitor) and bosentan (an endothelin receptor antagonist). Recent studies in adult PAH suggest that initiation of combined therapy with a phosphodiesterase 5 inhibitor and an endothelin receptor antagonist at the time of diagnosis, rather than sequential combination therapy, improves pulmonary hemodynamics, exercise tolerance and quality of life when compared with monotherapy. Children with PAH often require additional therapies over time in the setting of disease progression or incomplete responsiveness to monotherapy, however, there are no data regarding the potential benefits of greater and more sustained clinical improvement over time with the more aggressive combination therapy approach from the time of initial diagnosis. Studies of pediatric PAH have been further limited by the lack of well-coordinated and experienced care programs and the relative rare nature of these diseases. With the collaboration of the Pediatric Pulmonary Hypertension Network (PPHNet), a highly interactive and multidisciplinary group of academic PH programs, we propose to test the hypothesis that initiation of up-front combination therapy with sildenafil and bosentan at the time of PAH diagnosis will result in improved WHO Functional Class (FC) at 12 months in comparison with the current standard approach, which is sildenafil therapy alone. Overall, this study addresses critical gaps in pediatric PAH by testing a clinical strategy with strong potential for broad impact, and by defining useful study endpoints or novel surrogates that will facilitate evidence-based decision-making and enhance the care of children with PAH.