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: 10505262
• 负责人: Steven Herbert Abman
• 金额: $ 129.89万
• 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 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505262
• 关键词: Address; Adult; Age; Assessment tool; Brain Injuries; Caring; Case Series; Cessation of life; Child; Child Care; Childhood; Classification; 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; biobank; bosentan; clinical care; clinical practice; comparative efficacy; efficacy evaluation; evidence base; experience; follow-up; functional improvement; functional outcomes; hemodynamics; improved; inhibitor; 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）是导致多种疾病儿童发病率和死亡率高的原因之一。 心肺和全身性疾病。为确定儿童PAH的最佳治疗策略所做的努力， 由于缺乏多中心随机对照试验（MRCT）和缺乏定义明确的 在儿童中进行的研究的已证实终点。儿童PAH仍未得到充分研究，对以下方面的了解相对较少： 长期结果、适合儿童年龄的临床终点和最佳治疗策略。药物 治疗仍不理想，因为PAH儿童中MRCT罕见，当前决策依赖于 成人研究或儿童小病例系列的数据。基于MRCT最近在建立 作为成人PAH患者的新标准治疗，我们建议研究初始前期联合治疗的潜在作用 治疗儿童PAH，包括两种PAH特异性口服疗法，已被证明效果良好- 儿童耐受的单药治疗：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）。最近在成人PAH中的研究表明，开始联合治疗 磷酸二酯酶5抑制剂和内皮素受体拮抗剂在诊断时，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。PAH儿童在以下情况下，随着时间的推移通常需要额外的治疗： 疾病进展或对单药治疗的不完全应答，但是，没有关于 随着时间的推移，更大和更持续的临床改善的潜在受益， 联合治疗方法从最初的诊断时间。儿童PAH的研究已进一步 由于缺乏协调良好和经验丰富的护理方案， 疾病与儿科肺动脉高压网络（PPHNet）合作， 和多学科小组的学术PH计划，我们建议测试的假设， 在PAH诊断时，西地那非和波生坦的前期联合治疗将导致 与当前标准方法相比，12个月时WHO功能分级（FC）改善， 也就是西地那非单独治疗总体而言，本研究通过测试一项临床研究， 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新的替代品， 促进循证决策，加强对PAH儿童的护理。