This multicenter, randomized, open-label, parallel-group, non-inferiority trial will evaluate whether sequential tapering and discontinuation of beta-blockers is non-inferior to maintenance of the baseline stable beta-blocker dose in adult patients with obstructive hypertrophic cardiomyopathy (oHCM) who have achieved predefined clinical and hemodynamic stability during mavacamten treatment. Eligible participants will be randomly assigned in a 1:1 ratio to a sequential tapering and discontinuation group or a baseline stable-dose maintenance group. In the tapering group, the beta-blocker dose will be reduced stepwise approximately every 4 weeks, with complete discontinuation planned at Week 12 if predefined safety and stability criteria are met. Participants will be followed through Week 24. The primary objective is to compare the proportion of participants who maintain clinical and hemodynamic stability without protocol-defined treatment failure through Week 24. The feasibility and safety of complete beta-blocker discontinuation will also be evaluated.
Age 18 to 75 years.
Diagnosis of obstructive hypertrophic cardiomyopathy (oHCM).
Receiving mavacamten for ≥12 weeks at screening, with the current maintenance dose stable for ≥8 weeks; after completion of the 4-week run-in period, the total duration of mavacamten treatment at randomization should generally be ≥16 weeks.
Receiving one and only one beta-blocker continuously for at least 4 weeks before randomization, with the beta-blocker type, dosing frequency, and daily dose remaining stable, and without concomitant use of a non-dihydropyridine calcium channel blocker.
Previous LVEF <50% during mavacamten treatment, or previous interruption or discontinuation of mavacamten because of reduced left ventricular systolic function.
Heart failure decompensation requiring an emergency department visit, hospitalization, or intravenous treatment within 3 months before randomization; or, within 6 months before randomization, syncope not attributable to a clearly reversible cause, sustained ventricular tachycardia/ventricular fibrillation, or other clinically significant unstable arrhythmia.
Septal reduction therapy within 6 months before randomization, or anticipated need for surgical septal myectomy, alcohol septal ablation, or other septal reduction therapy during the 24-week study period.
A definite indication for beta-blocker therapy other than oHCM for which the investigator considers dose reduction or discontinuation unsafe.
Parallel
Beta-Blocker Sequential Tapering and Discontinuation
DrugParticipants will undergo sequential tapering of their baseline beta-blocker therapy. The daily beta-blocker dose will be reduced approximately every 4 weeks following a planned dose pathway of approximately 100%, 75%, 50%, 25%, and 0% of the randomization baseline daily dose. Complete discontinuation is planned at Week 12 if predefined clinical, hemodynamic, and safety criteria are met. Dose reduction may be paused or delayed, and dose rollback or rescue treatment may be implemented according to protocol-defined criteria.
Beta-Blocker Baseline Stable-Dose Maintenance
DrugParticipants will continue the beta-blocker type, dosing frequency, and daily dose that were stable at randomization throughout the 24-week randomized follow-up period, unless dose modification is clinically required because of efficacy or safety concerns according to the study protocol.
Week 24 Clinical and Hemodynamic Strategy Success Rate
Proportion of participants who maintain clinical and hemodynamic stability through Week 24 without protocol-defined treatment failure. Treatment failure is defined as the occurrence of any of the following: (1) permanent discontinuation or modification of the randomized beta-blocker management strategy, or protocol-defined rescue treatment, due to insufficient efficacy or safety concerns; (2) oHCM-related heart failure hospitalization, septal reduction therapy, or death; (3) resting LVOT peak gradient ≥30 mmHg at Week 24; (4) Valsalva-provoked LVOT peak gradient ≥50 mmHg at Week 24; (5) worsening of NYHA functional class at Week 24 compared with randomization baseline; or (6) LVEF \<50% at Week 24, or confirmed LVEF \<50% during follow-up requiring interruption, dose adjustment, or discontinuation of mavacamten according to its prescribing information or clinical practice.
Change From Baseline in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at Week 24
Change in KCCQ Clinical Summary Score (KCCQ-CSS) from randomization baseline to Week 24. The KCCQ-CSS ranges from 0 to 100, with higher scores indicating better health status.
Change From Baseline in N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) at Week 24
Change in NT-proBNP concentration from randomization baseline to Week 24.
Proportion of Participants With Complete Beta-Blocker Discontinuation at Week 12
Proportion of participants in the sequential tapering group who successfully complete the planned discontinuation of beta-blocker therapy by Week 12.
Proportion of Participants Remaining Off Beta-Blockers at Week 24
Proportion of participants in the sequential tapering group who remain completely off beta-blocker therapy at Week 24 without resumption of beta-blocker treatment.
Incidence of Adverse Events (AEs)
Number and proportion of participants experiencing at least one adverse event during the randomized follow-up period.
Incidence of Serious Adverse Events (SAEs)
Number and proportion of participants experiencing at least one serious adverse event during the randomized follow-up period.
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