A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study to Select and Evaluate an Oral Modified Release Formulation of Omecamtiv Mecarbil in Subjects With Heart Failure and Left Ventricular Systolic Dysfunction
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 544
- 试验地点
- 1
- 主要终点
- Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
研究概览
简要总结
The primary objectives of this study are (i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil for chronic twice daily (BID) dosing in adults with heart failure and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) over 20 weeks of treatment.
详细描述
Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that increases cardiac contractility by selectively and directly activating the enzymatic domain of cardiac myosin heavy chain, the force-generating motor protein of the cardiac sarcomere. This is a randomized, placebo-controlled, multicenter, phase 2 study, consisting of a dose escalation phase to select 1 of 3 omecamtiv mecarbil oral formulations in 2 dose escalation cohorts, followed by an expansion phase to evaluate 20 weeks of administration of the selected omecamtiv mecarbil formulation at 2 target dose levels, compared with placebo.
This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 4 weeks prior to screening
- •Treated with stable, optimal pharmacological therapy for ≥ 4 weeks
- •History of left ventricular ejection fraction (LVEF) ≤ 40%
- •Elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP)
- •Exclusion criteria:
- •Severe uncorrected valvular heart disease
- •Hospitalization within 30 days prior to enrollment
- •Hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease
- •Acute myocardial infarction, unstable angina or persistent angina at rest within 30 days prior to randomization
- •Systolic blood pressure > 160 mmHg or < 90 mmHg or diastolic blood pressure > 90 mmHg
- •Total bilirubin ≥ 2 x upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 x ULN
- •Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2
排除标准
- 未提供
研究组 & 干预措施
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Matrix F2 Formulation (Drug)
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Swellable Core Technology F2 (Drug)
Expansion Phase: Placebo
Participants received placebo tablets twice a day for 20 weeks.
干预措施: Placebo (Drug)
Dose-escalation Cohort 1: Placebo
Participants received placebo tablets twice a day (BID) for 7 days.
干预措施: Placebo (Drug)
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Matrix F1 Formulation (Drug)
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Matrix F2 Formulation (Drug)
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Swellable Core Technology F2 (Drug)
Dose-escalation Cohort 2: Placebo
Participants received placebo tablets twice a day for 7 days.
干预措施: Placebo (Drug)
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.
干预措施: Omecamtiv Mecarbil Matrix F1 Formulation (Drug)
Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1
Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.
干预措施: Omecamtiv Mecarbil Matrix F1 Formulation (Drug)
Expansion Phase: OM M-F1 PK-based Titration
All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL.
干预措施: Omecamtiv Mecarbil Matrix F1 Formulation (Drug)
结局指标
主要结局
Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
时间窗: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.
Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
时间窗: Day 7 at predose
Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
时间窗: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
时间窗: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.
Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
时间窗: Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
时间窗: Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
次要结局
- Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20(Baseline and week 20)
- Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20(Baseline and week 20)
- Expansion Phase: Number of Participants With Treatment-emergent Adverse Events(From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.)
- Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20(Baseline and week 20)
- Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20(Baseline and week 20)
- Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events(From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.)
- Expansion Phase: Change From Baseline in Stroke Volume at Week 20(Baseline and week 20)
- Expansion Phase: Change From Baseline in Heart Rate at Week 20(Baseline and week 20)