Feasibility and Safety of Sequential Tapering and Discontinuation of Beta-blockers in Patients With Obstructive Hypertrophic Cardiomyopathy After Achieving Hemodynamic Targets With Mavacamten: a Multicenter, Randomized, Open-label, Parallel-group, Non-inferiority Trial (STEP-oHCM)
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 286
- 试验地点
- 1
- 主要终点
- Week 24 Clinical and Hemodynamic Strategy Success Rate
研究概览
简要总结
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.
详细描述
Mavacamten can substantially reduce left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). However, many patients continue to receive beta-blockers as background therapy after achieving clinical and hemodynamic stability, and prospective randomized evidence regarding whether beta-blockers can be safely tapered or discontinued in this setting is limited.
After a 4-week screening and run-in period, eligible participants receiving stable mavacamten and beta-blocker therapy will be randomized 1:1 to either sequential beta-blocker tapering and discontinuation or maintenance of the baseline stable beta-blocker dose. In the sequential tapering group, the daily beta-blocker dose will be reduced by approximately 25% of the baseline daily dose every 4 weeks, with complete discontinuation planned at Week 12 in participants who continue to meet predefined clinical and hemodynamic stability criteria. Participants in the maintenance group will generally continue their baseline stable beta-blocker dose throughout the 24-week randomized follow-up period.
Clinical status, heart rate, blood pressure, left ventricular ejection fraction (LVEF), and resting and Valsalva-provoked LVOT gradients will be monitored during follow-up. Prespecified criteria for pausing dose reduction, dose re-escalation, and rescue treatment will be used to protect participant safety. Key echocardiographic assessments will be centrally evaluated by an independent core echocardiography laboratory, and major clinical events and treatment failure events will be adjudicated by an independent Clinical Endpoint Committee. An independent Data and Safety Monitoring Board will review accumulated safety data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Participants and treating investigators will be aware of treatment assignment because beta-blocker dose adjustments are readily identifiable. Key echocardiographic outcomes, including resting and Valsalva-provoked LVOT peak gradients and LVEF, will be assessed centrally by an independent core echocardiography laboratory blinded to treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •The last qualified echocardiographic assessment before randomization shows a resting left ventricular outflow tract (LVOT) peak gradient <30 mmHg and a Valsalva-provoked LVOT peak gradient <50 mmHg.
- •Left ventricular ejection fraction (LVEF) ≥55% at randomization baseline.
- •Clinically stable and considered by the investigator to be suitable for sequential tapering and discontinuation of beta-blocker therapy.
排除标准
- •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.
- •An HCM phenocopy or another disease clearly responsible for left ventricular hypertrophy, including cardiac amyloidosis, Fabry disease, or other infiltrative, storage, or metabolic cardiomyopathies.
- •Moderate-to-severe valvular heart disease, fixed left ventricular outflow tract obstruction, or another structural heart disease that may substantially affect LVOT gradients or assessment of the primary outcome.
- •Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), end-stage renal disease, or ongoing dialysis.
- •Severe hepatic impairment (Child-Pugh class C), decompensated liver disease, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal at screening, or other severe hepatic dysfunction considered by the investigator to potentially affect the safe use of mavacamten.
- •Active malignancy, ongoing systemic anticancer therapy that may substantially interfere with study assessments, or an anticipated life expectancy <1 year because of a serious comorbid condition.
- •Pregnancy or breastfeeding, planned pregnancy during the study, or, for participants of childbearing potential, inability or unwillingness to use effective contraception.
- •A drug interaction that cannot be adequately modified or avoided and may substantially affect mavacamten exposure, or anticipated need for continued use of a protocol-prohibited medication during the study.
- •Other serious systemic disease, inability to complete the required follow-up or comply with the study protocol, or any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.
研究组 & 干预措施
Sequential Tapering and Discontinuation Group
Participants 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 and hemodynamic stability and safety criteria are met. Dose reduction may be paused, delayed, or reversed, and rescue treatment may be initiated according to protocol-defined safety criteria.
干预措施: Beta-Blocker Sequential Tapering and Discontinuation (Drug)
Baseline Stable-Dose Maintenance Group
Participants will continue their beta-blocker at the stable dose used 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.
干预措施: Beta-Blocker Baseline Stable-Dose Maintenance (Drug)
结局指标
主要结局
Week 24 Clinical and Hemodynamic Strategy Success Rate
时间窗: From randomization through Week 24
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.
次要结局
- Change From Baseline in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at Week 24(Randomization baseline to Week 24)
- Change From Baseline in N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) at Week 24(Randomization baseline to Week 24)