A Multi-Center, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 96
- 试验地点
- 22
- 主要终点
- Incidence of Adverse Events (AEs)
研究概览
简要总结
This study is being performed to understand the effect of different doses of CK-3773274 on patients with hypertrophic cardiomyopathy (HCM).
详细描述
This was a Phase 2, multi-center, randomized, placebo-controlled, double-blind, dose-finding study in participants with symptomatic HCM. The study consisted of 4 cohorts. For Cohorts 1 and 2, participants with obstructive HCM (oHCM) and not receiving disopyramide were randomized 2:1 to active or placebo treatment and received up to 3 escalating doses of aficamten (5, 10, and 15 mg once daily in Cohort 1 and 10, 20, and 30 mg once daily in Cohort 2) or placebo based on site-read echocardiographic guidance. Cohort 3 consisted of participants with oHCM whose background HCM therapy included disopyramide. All participants in Cohort 3 received up to 3 escalating doses of aficamten (5, 10, and 15 mg once daily) based on echocardiographic guidance. Cohort 4 consisted of participants with non-obstructive HCM (nHCM) on standard of care background therapy. Cohort 4 participants received up to 3 doses of aficamten (5, 10, and 15 mg once daily), titrated based on site-read echocardiographic guidance.
In all 4 cohorts, treatment duration was 10 weeks with a 4-week follow-up period after the last dose.
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 at screening.
- •Body weight is ≥45 kg at screening.
- •Diagnosed with HCM per the following criteria:
- •Has left ventricular (LV) hypertrophy with non-dilated LV chamber in the absence of other cardiac disease.
- •Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive family history of HCM or with a known disease-causing gene mutation).
- •Adequate acoustic windows for echocardiography.
- •For Cohorts 1, 2 and 3 has LVOT-G during screening as follows:
- •Resting gradient ≥50 mmHg OR
- •Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G ≥50 mmHg
- •For Cohort 4 has resting and post-Valsalva LVOT-G < 30 mmHg at the time of screening
- •For Cohort 4 has elevated NT-proBNP > 300 pg/mL at the time of screening
- •LVEF ≥60% at screening.
- •New York Heart Association (NYHA) Class II or III at screening.
- •Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for >4 weeks prior to randomization and anticipate remaining on the same medication regimen during the study.
- •For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable disopyramide doses for >4 weeks prior to screening and anticipate remaining on the same medication regimen during the study.
排除标准
- •Aortic stenosis or fixed subaortic obstruction.
- •Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- •History of LV systolic dysfunction (LVEF <45%) at any time during their clinical course.
- •Documented history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction.
- •Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy > 12 months prior to screening who remain symptomatic from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort
- •For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening. (For Cohort 3, use of disopyramide is required).
- •Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II).
- •Paroxysmal atrial fibrillation or flutter documented during the screening period.
- •Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for >6 months).
- •History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
- •Has received prior treatment with CK-3773274 or mavacamten.
- •For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with exercise (for subjects who have had prior septal reduction therapy, this exclusion criteria only applies to gradients detected following septal reduction therapy).
研究组 & 干预措施
Cohort 1 (oHCM) - Aficamten
Participants received CK-3773274 doses of 5 - 15 mg once daily with dose levels guided by echocardiography assessments for up to 10 weeks
干预措施: CK-3773274 (5 - 15 mg) (Drug)
Cohort 1 (oHCM) - Placebo
Participants received placebo once daily for up to 10 weeks
干预措施: Placebo for CK-3773274 (Drug)
Cohort 2 (oHCM) - Aficamten
Participants received CK-3773274 doses 10 - 30 mg once daily with dose levels guided by echocardiography assessments for up to 10 weeks
干预措施: CK-3773274 (10 - 30 mg) (Drug)
Cohort 2 (oHCM) - Placebo
Participants received placebo once daily for up to 10 weeks
干预措施: Placebo for CK-3773274 (Drug)
Cohort 3 (oHCM) - Aficamten & Background Disopyramide
Participants received CK-3773274 doses 5 - 15 mg once daily with dose levels guided by echocardiography assessments for up to 10 weeks while taking disopyramide
干预措施: CK-3773274 (5 - 15 mg) (Drug)
Cohort 4 (nHCM) - Aficamten
Participants received CK-3773274 doses of 5 - 15 mg once daily with dose levels guided by echocardiography assessments for up to 10 weeks
干预措施: CK-3773274 (5 - 15 mg) (Drug)
结局指标
主要结局
Incidence of Adverse Events (AEs)
时间窗: 14 weeks
Participant incidence of reported AEs to determine the safety and tolerability of aficamten in participants with HCM.
Incidence of Left Ventricular Ejection Fraction (LVEF) < 50%
时间窗: 14 weeks
Participant incidence of LVEF \< 50% as assessed by the core laboratory assessment.
Incidence of Serious Adverse Events (SAEs)
时间窗: 14 weeks
Participant incidence of reported SAEs to determine the safety and tolerability of aficamten in participants with symptomatic HCM.
次要结局
- Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Resting Left Ventricular Outflow Track Gradient (LVOT-G)(Baseline and 10 weeks)
- Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Post-Valsalva LVOT-G(Baseline and 10 Weeks)
- Change From Baseline in Resting LVOT-G Over Time as a Function of Dose.(Baseline and 10 Weeks)
- Change From Baseline in Post-Valsalva LVOT-G Over Time as a Function of Dose.(10 weeks)
- Slope of the Relationship of the Plasma Concentration of CK-3773274 to the Change From Baseline in the Resting LVEF(Day 1 to End of Study (EOS) (Week 14))