REHAB-PH Trial: Repurposing a Histamine Antagonist to Benefit Patients with Pulmonary Hypertension

尽管在降低肺动脉压的药物开发方面取得了实质性进展， 肺动脉高压（PAH）的血管阻力，目前还没有已知的治疗方法， 在右心室后负荷没有变化的情况下，有益于右心。右心衰竭是 PAH患者发病率和死亡率的关键驱动因素，但也使一系列其他 常见疾病如肺气肿和左心衰。 我们正在寻求一种新的方法，靶向PAH患者的组胺H2受体， 心衰先前的动物研究表明心肌H2受体促进心肌纤维化 并且是重要的心力衰竭介质。先前的一项随机对照试验显示法莫替丁 心脏病患者的B型利钠肽、左心室形态和症状改善 心力衰竭和射血分数降低（左心衰竭）。我们的研究表明， 社区居住成年人的心室形态和退伍军人较低的全因死亡率 使用H2受体拮抗剂的肺动脉高压患者。这些初步结果提高了 H2受体拮抗剂可能是治疗右心衰竭有效方法。 H2受体拮抗剂是一个有吸引力的治疗靶点，与当前NIH的优先事项完全一致 将现有的、廉价的、耐受性良好的药物重新用于其他疾病的新用途， states.治疗肺动脉高压的药物特别昂贵。如果连续治疗 与H2受体拮抗剂联合使用是有效的，这将使PAH患者和整个社会受益。 我们提出了一个2期，单中心，随机安慰剂对照试验法莫替丁（H2受体 拮抗剂）。这项研究将评估24周的安全性和临床疗效， 法莫替丁疗程主要终点是24周时的6分钟步行距离。二次 终点包括右心室功能的差异，右心衰竭的生化标志物（NT， pro-BNP）、纽约心脏协会功能分级、健康相关生活质量评估 疾病特异性emPHasis-10仪器，以及常规治疗的频率 PAH患者在试验期间递增。

Although there has been substantial progress in the development of medications to lower pulmonary vascular resistance in pulmonary arterial hypertension (PAH), there are no therapies that are known to benefit the right heart in the absence of changes in right ventricular afterload. Right heart failure is the key driver for morbidity and mortality in patients with PAH, but also complicates a range of other common diseases such as emphysema and left heart failure. We are pursuing a novel approach that targets histamine H2 receptors in patients with PAH and right heart failure. Previous animal studies suggest myocardial H2 receptors contribute to myocardial fibrosis and are important heart failure mediators. A previous randomized controlled trial showed famotidine improved b-natriuretic peptide, left ventricular morphology, and symptoms in participants with Heart Failure and Reduced Ejection Fraction (left heart failure). Our work has shown differences in right ventricular morphology among community dwelling adults and a lower all-cause mortality in veterans with pulmonary hypertension who use H2 receptor antagonists. These preliminary results raise the strong possibility that H2 receptor antagonism might be an effective treatment for right heart failure. H2 receptor antagonism is an appealing therapeutic target that is well aligned with current NIH priorities of repurposing existing, inexpensive, and well-tolerated medications for novel use in other disease states. Medications for pulmonary arterial hypertension are particularly expensive. If adjunctive therapy with an H2 receptor antagonist is efficacious this would benefit PAH patients and society at-large. We propose a Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) in adults with PAH. The study will evaluate the safety and clinical efficacy of a 24-week course of famotidine. The primary end-point is six-minute walk distance at 24 weeks. Secondary endpoints include differences in right ventricular function, biochemical markers of right heart failure (nt- pro-BNP), New York Heart Association Functional Class, health related quality of life as assessed by the disease specific emPHasis-10 instrument, and the frequency with which routine therapies for patients with PAH are escalated during the trial.