1/2 Kids MoD PAH Trial: Mono- vs. Duo-Therapy In Pediatric Pulmonary Arterial Hypertension

1/2 Kids MoD PAH 试验：小儿肺动脉高压的单一疗法与双重疗法

• 批准号: 10214935
• 负责人: Steven Herbert Abman
• 金额: $ 95.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214935
• 关键词: Address; Adult; Age; Assessment tool; Brain Injuries; Caring; Case Series; Cessation of life; Child; Child Care; Childhood; Clinical; Clinical Research; Clinical Trials; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Control Groups; Data; Data Coordinating Center; Decision Making; Development; Diagnosis; Disease; Disease Marker; Disease Progression; Drug usage; Early treatment; Effectiveness; Endothelin Receptor Antagonist; Evaluation; Exercise Tolerance; Future; Goals; Heart Diseases; Infant; Life; Lung; Lung diseases; Measures; Medicine; Morbidity - disease rate; Nature; Oral; Outcome; Patients; Performance; Pharmacotherapy; Phosphodiesterase Inhibitors; Pulmonary Heart Disease; Pulmonary Hypertension; Quality of life; Randomized Controlled Trials; Research; Research Institute; Role; Safety; Site; Specialist; Surrogate Endpoint; Systemic disease; Testing; Therapeutic; Therapeutic Intervention; Time; Universities; Validation; actigraphy; active method; base; biobank; bosentan; clinical care; clinical practice; comparative efficacy; evidence base; experience; follow-up; functional outcomes; hemodynamics; improved; improved functioning; inhibitor/antagonist; innovation; mortality; multidisciplinary; novel; optimal treatments; outcome prediction; phosphodiesterase V; predictive modeling; prognostic tool; programs; pulmonary arterial hypertension; sildenafil; standard of care; study population; success; symposium; targeted treatment; treatment group; treatment strategy; trial comparing

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.

摘要 肺动脉高压(PAH)是不同类型儿童高发病率和高死亡率的原因之一 心肺和全身疾病。为儿童PAH确定最佳治疗策略的努力已经 由于缺乏多中心随机对照试验(MRCT)和缺乏定义明确的 经过验证的儿童研究终点。儿科多环芳烃的研究仍然不足，对其了解也相对较少。 儿童的长期结果、适合年龄的临床终点和最佳治疗策略。药效 治疗仍然是次优的，因为MRCT在患有PAH的儿童中很少见，而且目前的决策依赖于 基于成人研究或儿童小病例系列的数据。基于MRCT最近在建立一个 成人PAH患者护理的新标准，我们建议研究初始前期联合治疗的潜在作用 儿童PAH的治疗包括两种针对PAH的口服疗法，已被证明是良好的- 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(AN 内皮素受体拮抗剂)。最近对成人PAH的研究表明，开始与A联合治疗 诊断时的磷酸二酯酶5抑制剂和内皮素受体拮抗剂，而不是 序贯联合治疗，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，对于疾病进展或对单一疗法的不完全反应，没有关于 随着时间的推移，随着时间的推移，更大和更持续的临床改善的潜在好处是更积极的 从初诊时起采用综合治疗方法。儿科多环芳烃的研究已有进一步进展 受限于缺乏协调良好和经验丰富的护理方案，以及这些方案相对罕见的性质 疾病。在儿科肺动脉高压网络(PPHNet)的合作下，高度互动的 和多学科小组的学术PH项目，我们建议检验以下假设： 在诊断为PAH时预先联合使用西地那非和波生坦将导致 与目前的标准方法相比，12个月后的WHO功能分级(FC)有所改善； 也就是单用西地那非疗法。总体而言，这项研究解决了儿科PAH中的关键差距，通过测试临床 具有广泛影响的强大潜力的战略，并通过定义有用的研究终点或将 促进循证决策，加强对帕金森病儿童的护理。