A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 282
- 试验地点
- 114
- 主要终点
- Change From Baseline in pVO2 at Week 24
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction.
详细描述
CY 6031 was a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in participants with symptomatic oHCM. Eligible participants were randomized in a 1:1 ratio to receive aficamten or placebo. Randomization was stratified by use of beta-blockers (yes or no) and cardiopulmonary exercise testing (CPET) exercise modality (treadmill or bicycle). Enrollment limits were applied as follows: participants taking beta-blockers were capped at approximately 70% of total enrollment; participants taking disopyramide were capped at approximately 10% of total enrollment; participants with persistent atrial fibrillation (AF) at screening were capped at approximately 15% of total enrollment; and participants using the bicycle CPET exercise modality were capped at approximately 50% of total enrollment.
Investigational product (IP) was administered orally once daily (QD) with or without food for 24 weeks. During the initial 6 weeks of the treatment period, IP doses were individually titrated at Weeks 2, 4, and 6 based on echocardiography-guided criteria. Dose escalation at Weeks 2, 4, and 6 occurred only if a participant had a Valsalva left ventricular outflow tract gradient (LVOT-G) ≥ 30 mmHg and a biplane left ventricular ejection fraction (LVEF) ≥ 55%. Echocardiograms were performed at each subsequent visit during the trial, and the IP dose was down-titrated if the LVEF was < 50%. The primary endpoint of peak oxygen uptake (pVO2) was measured by CPET at screening and at the end of treatment (Week 24). A participant's background HCM therapy was individually optimized according to local practice prior to enrollment in the study.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females between 18 and 85 years of age, inclusive, at screening.
- •Body mass index <35 kg/m
- •Diagnosed with HCM per the following criteria:
- •Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and
- •Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
- •≥15 mm in one or more myocardial segments OR
- •≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM
- •Has resting LVOT-G ≥30 mmHg and post-Valsalva LVOT G ≥50 mmHg during screening as determined by the echocardiography core laboratory.
- •LVEF ≥60% at screening as determined by the echocardiography core laboratory.
- •New York Heart Association (NYHA) Functional Class II or III at screening.
- •Hemoglobin ≥10g/dL at screening.
- •Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory.
- •Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.
排除标准
- •Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- •Significant valvular heart disease (per investigator judgment).
- •Moderate-severe valvular aortic stenosis.
- •Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
- •History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course.
- •Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations).
- •Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
- •Documented paroxysmal atrial fibrillation during the screening period.
- •Paroxysmal or permanent atrial fibrillation is only excluded IF:
- •rhythm restoring treatment (eg, direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) has been required ≤6 months prior to screening.
- •rate control and anticoagulation have not been achieved for at least 6 months prior to screening.
- •History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
- •Has received prior treatment with CK-3773274 or mavacamten.
研究组 & 干预措施
Aficamten up to 20 mg
Participants received 5 mg, 10 mg, 15 mg, or 20 mg of aficamten; dose levels were guided by echocardiography assessments. Treatment was administered for up to 24 weeks.
干预措施: Aficamten (5 mg, 10 mg, 15 mg, and 20 mg) (Drug)
Placebo to match aficamten
Participants received placebo for up to 24 weeks.
干预措施: Placebo to match aficamten (Drug)
结局指标
主要结局
Change From Baseline in pVO2 at Week 24
时间窗: Baseline to Week 24
The effect of CK-3773274 on exercise capacity in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) was determined through changes in peak oxygen uptake (pVO2) after 24 weeks of treatment. pVO2 was measured by cardiopulmonary exercise testing (CPET) on a treadmill or bicycle. A higher pVO2 indicates better cardiorespiratory fitness.
次要结局
- Change From Baseline in KCCQ-CSS at Week 24(Baseline to Week 24)
- Change From Baseline in KCCQ-CSS at Week 12(Baseline to Week 12)
- Proportion of Participants With ≥1 Class Improvement in New York Heart Association (NYHA) Functional Class From Baseline to Week 24(Baseline to Week 24)
- Proportion of Participants With ≥1 Class Improvement in NYHA Functional Class From Baseline to Week 12(Baseline to Week 12)
- Change From Baseline in Valsalva Left Ventricular Outflow Tract Gradient (LVOT-G) at Week 24(Baseline to Week 24)
- Change From Baseline in Valsalva LVOT-G at Week 12(Baseline to Week 12)
- Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 24(Baseline to Week 24)
- Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 12(Baseline to Week 12)
- Duration of SRT Eligibility During the 24-week Treatment Period for Participants Who Were SRT Eligible at Baseline(Baseline to Week 24)
- Change From Baseline to Week 24 in Total Workload During CPET(Baseline to Week 24)