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: 10482344
• 负责人: Peter J Leary
• 金额: $ 59.07万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482344
• 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; H2 gene; Heart; Heart failure; Histamine; Histamine Antagonists; 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; antagonist; clinical efficacy; cohort; coronary fibrosis; cost; effective therapy; efficacy evaluation; exercise capacity; health related quality of life; improved; innovation; instrument; mortality; novel; novel strategies; primary endpoint; pulmonary arterial hypertension; randomized placebo controlled trial; right ventricular failure; routine therapy; secondary endpoint; targeted treatment; therapeutic target; therapy development; tool

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.

尽管在降低肺部的药物开发方面取得了重大进展 肺动脉高压（PAH）中的血管耐药性，没有已知的疗法 在没有右心室后负荷变化的情况下使右心脏受益。正确的心力衰竭是 PAH患者发病率和死亡率的主要驱动力，但也使许多其他 常见疾病，例如肺气肿和左心衰竭。 我们正在采用一种新型方法，该方法针对PAH和右患者的组胺H2受体 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 并且是重要的心力衰竭介体。先前的随机对照试验显示Famotidine 改善了B-催生肽，左心室形态和心脏参与者的症状 失败和射血分数减少（左心衰竭）。我们的工作显示了正确的差异 社区居住成年人的心室形态和退伍军人的全因死亡率较低 使用H2受体拮抗剂的肺动脉高压。这些初步结果提高了 H2受体拮抗作用可能是对正确心力衰竭的有效治疗方法。 H2受体拮抗作用是一个有吸引力的治疗靶标，与当前的NIH优先级很好 重新利用现有，廉价且耐受性良好的药物，以在其他疾病中使用 国家。肺动脉高压的药物特别昂贵。如果辅助治疗 使用H2受体拮抗剂有效，这将使PAH患者和社会一般会受益。 我们提出了Famotidine的2阶段，单中心，随机安慰剂对照试验（H2受体 拮抗剂）在患有PAH的成年人中。该研究将评估24周的安全性和临床功效 Famotidine的过程。主要终点是24周的步行距离为6分钟。次要 终点包括右心功能的差异，右心衰竭的生化标记（NT- Pro-BNP），纽约心脏协会功能类别，与健康相关的生活质量评估 疾病特定的重点-10仪器以及常规疗法的频率 在试验期间，患有PAH的患者升级。

项目成果

An expert panel delphi consensus statement on patient selection and management for transitioning between oral and inhaled treprostinil.

关于口服和吸入曲前列环素之间转换的患者选择和管理的专家小组德尔菲共识声明。

• DOI: 10.1016/j.pupt.2020.101979
• 发表时间: 2021
• 期刊: Pulmonary pharmacology & therapeutics
• 影响因子: 3.2
• 作者: Rahaghi,FranckF;Allen,RobleeP;Balasubramanian,VijayP;Chakinala,MuraliM;Elwing,JeanM;Feldman,Jeremy;Leary,PeterJ;Rischard,Franz;Safdar,Zeenat;Sood,Namita;Oudiz,RonaldJ
• 通讯作者: Oudiz,RonaldJ