Milind Y Desai1, Kathy Wolski2, Anjali Owens3, Srihari S Naidu4, Jeffrey B Geske5, Nicholas G Smedira6, Hartzell Schaff7, Kathy Lampl8, Ellen McErlean2, Christina Sewell2, David Zhang8, Jay M Edelberg8, Amy J Sehnert8, Steven E Nissen2. 1. Hypertrophic Cardiomyopathy Center, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH; Department of cardiovascular medicine, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH; Cleveland Clinic Coordinating Center for Clinical Research, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH. Electronic address: desaim2@ccf.org. 2. Department of cardiovascular medicine, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH; Cleveland Clinic Coordinating Center for Clinical Research, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH. 3. Department of Cardiothoracic Surgery, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH; Division of Cardiology, University of Pennsylvania, U Penn, Philadelphia, PA Westchester, NY. 4. Division of Cardiology, Westchester Medical Center, U Penn, Philadelphia, PA Westchester, NY. 5. Division of Cardiology, Mayo Clinic, Rochester, MN. 6. Hypertrophic Cardiomyopathy Center, Heart and Vascular Institute, Cleveland CLinic, Cleveland OH; Department of Cardiothoracic Surgery, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH. 7. Division of Cardiac Surgery, Mayo Clinic, Rochester, MN. 8. Bristol Myers Squibb, Brisbane, CA.
Abstract
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 Associationand/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 CardiomyopathyQuestionnaire 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.
RCT Entities:
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.