REVAMP-PH: REpurposing Valsartan May Protect against Pulmonary Hypertension

REVAMP-PH：重新利用缬沙坦可以预防肺动脉高压

基本信息

批准号：
10642368
负责人：
Peter J Leary
金额：
$ 76.18万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642368
关键词：
Activities of Daily Living Address Adult Angiotensin II Angiotensin II Receptor Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Animals Apoptosis Area Biochemical Markers Cardiac Cardiac Myocytes Caring Clinical Development Diameter Diastole Disease Diuretics Dose Etiology Evaluation Failure Fibrosis Frequencies Goals Heart Heart failure Individual Interstitial Lung Diseases Left Lung Measures Morbidity - disease rate Muscle Cells Natural History New York Outcome Participant Pathogenesis 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 Role Safety Signal Transduction Societies Stress Testing United States National Institutes of Health Vasodilator Agents Ventricular Veterans Walking Work 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 pro-brain natriuretic peptide (1-76)pulmonary arterial hypertension pulmonary vascular remodeling randomized placebo controlled trial receptor right ventricular failure routine therapy secondary endpoint success targeted treatment therapeutic target tool valsartan

项目摘要

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 in patients with PAH. 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, interstitial lung disease, and left heart failure. We are pursuing a novel approach that targets angiotensin receptors in patients with PAH and right heart failure. Previous animal studies suggest angiotensin signaling may contribute to myocardial fibrosis and could also be important in the pathogenesis of PAH and pulmonary vascular remodeling. Angiotensin receptor blockers are well established in left heart failure where their benefit is not merely a result of improvement in left heart afterload. Our work has shown a substantially lower all-cause mortality in veterans with pulmonary hypertension who use angiotensin converting enzyme inhibitors or angiotensin receptor blockers. These mechanistic and observational results raise the strong possibility that angiotensin receptor blockade might be an effective treatment for right heart failure. Angiotensin receptor blockade 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 PAH are particularly expensive. If adjunctive therapy with an angiotensin receptor blockers are efficacious, this would benefit PAH patients and society at-large. We propose a Phase 2, single-center, randomized placebo-controlled trial of valsartan (an angiotensin receptor blocker) in adults with PAH. The study will evaluate the safety and clinical efficacy of a 24- week course of valsartan. The primary endpoint is change in six-minute walk distance at 24 weeks. Secondary endpoints include differences in right ventricular function, biochemical markers of right heart failure (NT-proBNP), 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 PAH 患者右心室后负荷没有变化的情况下，对右心有益。正确的心力衰竭是 PAH 患者发病率和死亡率的关键驱动因素，但也使疾病复杂化其他常见疾病，如肺气肿、间质性肺病和左心衰竭。我们正在寻求一种针对 PAH 患者和右肺患者血管紧张素受体的新方法。心脏衰竭。先前的动物研究表明血管紧张素信号传导可能有助于心肌纤维化，并且在 PAH 和肺血管重塑的发病机制中也可能很重要。血管紧张素受体阻滞剂在左心衰竭中已得到广泛应用，其益处不仅在于左心后负荷改善的结果。我们的工作表明，全因事故的发生率大大降低使用血管紧张素转换酶抑制剂或患有肺动脉高压的退伍军人的死亡率血管紧张素受体阻滞剂。这些机械和观察结果提出了很强的可能性血管紧张素受体阻断可能是治疗右心衰竭的有效方法。血管紧张素受体阻断是一个有吸引力的治疗靶点，与当前的 NIH 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领域的新用途的优先事项疾病状态。治疗 PAH 的药物特别昂贵。如果使用血管紧张素进行辅助治疗受体阻滞剂是有效的，这将使 PAH 患者和整个社会受益。我们提出了一项缬沙坦（一种血管紧张素）的 2 期、单中心、随机安慰剂对照试验。受体阻滞剂）用于患有 PAH 的成人。该研究将评估 24- 缬沙坦的一周疗程。主要终点是 24 周时六分钟步行距离的变化。次要终点包括右心室功能、右心生化标志物的差异心力衰竭 (NT-proBNP)、纽约心脏协会功能分级、健康相关生活质量（如通过疾病特异性 emPHasi-10 仪器进行评估），以及常规治疗的频率在试验期间，对 PAH 患者的治疗不断升级。