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

REHAB-PH 试验：重新利用组胺拮抗剂使肺动脉高压患者受益

• 批准号: 9791474
• 负责人: Peter J Leary
• 金额: $ 69.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791474
• 关键词: Activities of Daily Living; Address; Adult; Animals; Apoptosis; Biochemical Markers; Cardiac; Cardiac Myocytes; Caring; Clinical; Communities; Development; Disease; Diuretics; Dose; EFRAC; Etiology; Evaluation; Famotidine; Fibrosis; Frequencies; Goals; HRH2 gene; Heart; Heart failure; Histamine; Histamine Antagonists; Histamine H2 Receptors; Incidence; Individual; Left; Longevity; Lung; Measures; Mediator of activation protein; Morbidity - disease rate; Morphology; Muscle Cells; Myocardial; Natriuretic Peptides; Natural History; New York; Participant; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Placebos; Progressive Disease; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Vascular Resistance; Randomized; Randomized Controlled Trials; Right Ventricular Function; Right ventricular structure; Safety; Signal Transduction; Societies; Stress; Symptoms; Testing; United States National Institutes of Health; Vasodilator Agents; Ventricular; Veterans; Walking; Work; clinical efficacy; cohort; coronary fibrosis; cost; effective therapy; exercise capacity; health related quality of life; improved; innovation; instrument; mortality; novel; novel strategies; primary endpoint; pulmonary arterial hypertension; randomized placebo controlled trial; routine therapy; secondary endpoint; targeted treatment; therapeutic target; therapy development; tool

Project(Summary( 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.

项目（概要（ 尽管降低肺功能的药物开发已取得实质性进展 肺动脉高压（PAH）的血管阻力，目前尚无已知的治疗方法 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 是 PAH 患者发病率和死亡率的关键驱动因素，但也使一系列其他问题复杂化 常见疾病如肺气肿、左心衰竭等。 我们正在寻求一种针对 PAH 患者的组胺 H2 受体的新方法， 心脏衰竭。先前的动物研究表明心肌 H2 受体有助于心肌纤维化 是重要的心力衰竭介质。先前的随机对照试验显示法莫替丁 改善心脏病参与者的 B-钠尿肽、左心室形态和症状 衰竭和射血分数降低（左心衰竭）。我们的工作已经显示出正确的差异 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 患有肺动脉高压者使用H2受体拮抗剂。这些初步结果提高了 H2 受体拮抗剂很有可能是治疗右心衰竭的有效方法。 H2 受体拮抗是一个有吸引力的治疗靶点，与当前 NIH 的优先事项非常一致 将现有的、廉价且耐受性良好的药物重新用于其他疾病的新用途 州。治疗肺动脉高压的药物特别昂贵。如果辅助治疗 H2 受体拮抗剂是有效的，这将使 PAH 患者和整个社会受益。 我们提出了法莫替丁（一种 H2 受体）的 2 期、单中心、随机安慰剂对照试验 拮抗剂）用于成人 PAH 患者。该研究将评估为期 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 6 分钟步行距离。中学 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），纽约心脏协会功能等级，健康相关的生活质量，由 疾病特异性 emPHasi-10 仪器，以及常规治疗的频率 PAH 患者在试验期间的情况会逐步升级。