BACKGROUND Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder which frequently leads to symptoms such as dyspnea and exercise intolerance, often due to severe dynamic left ventricular outflow tract obstruction (LVOTO). Current guideline-recommended pharmacotherapies have variable therapeutic responses to relieve LVOTO. In recent phases 2 and 3, clinical trials for symptomatic obstructive HCM (oHCM), mavacamten, a small molecule inhibitor of β-cardiac myosin has been shown to improve symptoms, exercise capacity, health status, reduce LVOTO, along with having a beneficial impact on cardiac structure and function. METHODS VALOR-HCM is designed as a multicenter (approximately 20 centers in United States) phase 3, double-blind, placebo-controlled, randomized study. The study population consists of approximately 100 patients (≥18 years old) with symptomatic oHCM who meet 2011 American College of Cardiology/American Heart Association and/or 2014 European Society of Cardiology HCM-guideline criteria and are eligible and willing to undergo septal reduction therapy (SRT). The study duration will be up to 138 weeks, including an initial 2-week screening period, followed by16 weeks of placebo-controlled treatment, 16 weeks of active blinded treatment, 96 weeks of long-term extension, and an 8-week posttreatment follow-up visit. The primary endpoint will be a composite of the decision to proceed with SRT prior to or at Week 16 or remain guideline eligible for SRT at Week 16. Secondary efficacy endpoints will include change (from baseline to Week 16 in the mavacamten group vs placebo) in postexercise LVOT gradient, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire clinical summary score, NT-proBNP, and cardiac troponin. Exploratory endpoints aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS In severely symptomatic drug-refractory oHCM patients meeting guideline criteria of eligibility for SRT, VALOR-HCM will primarily study if a 16-week course of mavacamten reduces or obviates the need for SRT using clinically driven endpoints.

中文翻译：

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VALOR-HCM 的研究设计和基本原理：评估 mavacamten 在有症状的阻塞性肥厚型心肌病适合进行室间隔减少治疗的成人中。

背景肥厚型心肌病(HCM)是一种原发性心肌病，其经常导致呼吸困难和运动不耐受等症状，通常是由于严重的动态左心室流出道阻塞(LVOTO)。当前指南推荐的药物疗法对缓解 LVOTO 具有不同的治疗反应。在最近的第 2 和第 3 阶段，症状性阻塞性 HCM (oHCM) 的临床试验表明，mavacamten 是一种 β-心肌肌球蛋白小分子抑制剂，可改善症状、运动能力、健康状况、减少 LVOTO 并产生有益影响关于心脏结构和功能。方法 VALOR-HCM 被设计为一项多中心（美国约 20 个中心）3 期、双盲、安慰剂对照、随机研究。研究人群由大约 100 名有症状的 oHCM 患者（≥18 岁）组成，他们符合 2011 年美国心脏病学会/美国心脏协会和/或 2014 年欧洲心脏病学会 HCM 指南标准，并且有资格并愿意接受间隔减少治疗(SRT)。研究持续时间将长达 138 周，包括最初的 2 周筛选期，随后是 16 周的安慰剂对照治疗、16 周的主动盲法治疗、96 周的长期扩展和 8 周的治疗后随访上访。主要终点将是在第 16 周之前或之时继续进行 SRT 或在第 16 周时继续符合 SRT 指南的决定的综合。次要疗效终点将包括变化（mavacamten 组与安慰剂组从基线到第 16 周）运动后 LVOT 梯度，纽约心脏协会课程、堪萨斯城心肌病问卷临床总结评分、NT-proBNP 和心肌肌钙蛋白。探索性终点旨在表征 mavacamten 对 oHCM 病理生理学多个方面的影响。结论 在符合 SRT 资格指南标准的严重症状性药物难治性 oHCM 患者中，VALOR-HCM 将主要研究 16 周的 mavacamten 疗程是否减少或消除了使用临床驱动终点对 SRT 的需要。