Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of MYK-491 in Patients With Stable Heart Failure With Reduced Ejection Fraction
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 52
- 试验地点
- 17
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The purpose of this Phase 1b/2a study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MYK-491 in patients with stable heart failure.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has stable chronic heart failure with reduced ejection fraction
- •Has adequate acoustic windows for echocardiography
排除标准
- •Any significant structural cardiac abnormalities on Screening TTE
- •At Screening, symptomatic hypotension or hypertension or bradycardia.
- •Routinely scheduled outpatient intravenous (IV) infusions for heart failure (e.g., inotropes, vasodilators [e.g., nesiritide], diuretics) or routinely scheduled ultrafiltration.
- •Presence of protocol specified laboratory abnormalities at Screening.
研究组 & 干预措施
Part 1/SAD and Part 2/MAD - drug
Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo
Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo
干预措施: MYK-491 (Drug)
Part 1/SAD and Part 2/MAD - placebo
Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo
Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From first dose to 30 days post last dose (Up to 2 months)
Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).
Number of Participants With a Troponin I Increase - MAD Cohorts
时间窗: Baseline, pre-dose and 7hr post dose on treatment day 1, day 2, day 5 and pre-dose and at 7-, 24-, and 48-hours post final dose
Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing \>2×ULN for the specific assay (\>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase \>0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
Number of Participants With Clinically Significant Laboratory Abnormalities
时间窗: From first dose to 30 days post last dose (Up to 2 months)
Number of participants with clinically significant laboratory abnormalities.
Number of Participants With Clinically Significant Physical Examinations Abnormalities
时间窗: From first dose to 30 days post last dose (Up to 2 months)
Number of participants with clinically significant physical examinations abnormalities.
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts
时间窗: Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to the corresponding period.
Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts
时间窗: Baseline and at 6-hours post-dose
Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts
时间窗: Baseline and at 6-hours post-dose
Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.
Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts
时间窗: Baseline and at 6-hours post-dose
Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts
时间窗: Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose
Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to first randomized dose.
Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts
时间窗: Baseline and at 6-hours post-dose
Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.
Number of Participants With a Troponin I Increase - SAD Cohorts
时间窗: Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose
Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing \>2×ULN for the specific assay (\>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase \>0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16.
次要结局
- Apparent First-order Terminal Elimination Half-life (t1/2)(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Danicamtiv Maximum Observed Plasma Concentration (Cmax)(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts(Baseline, predose and at 3, 6, 9, and 24 hours post dose)
- Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts(Baseline, predose and at 3, 6, 9, and 24 hours post dose)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts(Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11)
- Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Area Under the Plasma Concentration-Time Curve (AUC)(1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts(Baseline, predose and at 3, 6, 9, and 24 hours post dose)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts(Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11)
- Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts(Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11)