Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
Heart Failure
Brief summary
* To evaluate pharmacokinetics (PK) of omecamtiv mecarbil in Japanese subjects with heart failure (HF) with reduced ejection fraction * To evaluate the safety and tolerability of oral omecamtiv mecarbil
Detailed description
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.
Interventions
DRUG25 mg Omecamtiv Mecarbil
oral tablet
DRUGPlacebo
oral tablet
DRUG37.5 mg Omecamtiv Mecarbil
oral tablet
DRUG50 mg Omecamtiv Mecarbil
oral tablet
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Japanese male or female ≥ 20 years and ≤ 85 years of age * History of chronic stable heart failure (HF) with reduced ejection fraction, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening * Treated for HF with optimal pharmacological therapy * Left ventricular ejection fraction ≤ 40% at screening
Exclusion criteria
* Severe uncorrected valvular heart disease * 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 (BP) \> 160 mmHg or \< 90 mmHg, or diastolic BP \> 90 mmHg, or heart rate (HR) \> 110 beats per minute (bpm) or HR \< 50 bpm * Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m\^2 * Total bilirubin (TBL) ≥ 2x upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN Other
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Before morning dose on Week 2 (Day 15), Week 4 (Day 28), Week 12 (Day 84), Week 16 (Day 112) |
| PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8) | Week 8 (Day 56) at predose, at 2 hours ±30 minutes; 4 hours ±30 minutes; 6 hours ±30 minutes; 8 hours ±30 minutes after morning dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 16 in Systolic Ejection Time (SET) | Baseline, Week 16 (Day 112) | LS mean was from the repeated measures model, which included treatment group, stratification factor (from IVRS), scheduled visit, baseline value, and the interaction of treatment group with scheduled visit as covariates. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to Week 20 (Day 140 + 3 days) | An adverse event (AE) is defined as any untoward medical occurrence. Serious AEs are defined as AEs that meets at least 1 of the following serious criteria: fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, other medically important serious event. AEs are graded as: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. TEAEs are defined as events occurring after the first dose of study drug. |
Countries
Japan
Participant flow
Recruitment details
Participants were enrolled at 31 research centers in Japan from 14 April 2016 to 16 December 2016.
Pre-assignment details
Participants were randomized at a ratio of 1:1:1:1 to twice daily (BID) placebo, 25 mg, 25 mg-\>37.5 mg Target Dose, or 25 mg-\>50 mg Target Dose, respectively. Randomization was stratified by presence or absence of atrial fibrillation/flutter.
Participants by arm
| Arm | Count |
|---|---|
| Placebo BID Placebo for omecamtiv mecarbil BID | 21 |
| Omecamtiv Mecarbil 25 mg BID Omecamtiv mecarbil 25 mg BID | 21 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose Omecamtiv mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 37.5 mg BID after Week 4 or Week 8, based on Week 2 PK | 19 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose Omecamtiv Mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 50 mg BID after Week 4 or Week 8, based on Week 2 PK | 20 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo BID | Omecamtiv Mecarbil 25 mg BID | Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 11.5 | 66.9 years STANDARD_DEVIATION 10.3 | 63.6 years STANDARD_DEVIATION 10.8 | 66.5 years STANDARD_DEVIATION 12.2 | 65.4 years STANDARD_DEVIATION 11.1 |
| Atrial Fibrillation/Flutter at Randomization Absent | 17 participants | 17 participants | 16 participants | 16 participants | 66 participants |
| Atrial Fibrillation/Flutter at Randomization Present | 4 participants | 4 participants | 3 participants | 4 participants | 15 participants |
| Race/Ethnicity, Customized Asian | 21 participants | 21 participants | 19 participants | 20 participants | 81 participants |
| Race/Ethnicity, Customized Japanese | 21 participants | 21 participants | 19 participants | 20 participants | 81 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 0 Participants | 1 Participants | 13 Participants |
| Sex: Female, Male Male | 12 Participants | 18 Participants | 19 Participants | 19 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 1 / 21 | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 10 / 21 | 8 / 21 | 10 / 19 | 11 / 20 |
| serious Total, serious adverse events | 3 / 21 | 4 / 21 | 1 / 19 | 3 / 20 |
Outcome results
Primary
Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time
Time frame: Before morning dose on Week 2 (Day 15), Week 4 (Day 28), Week 12 (Day 84), Week 16 (Day 112)
Population: PK Analysis Set: all randomized participants who received at least one dose of omecamtiv mecarbil and had at least one evaluable omecamtiv mecarbil PK concentration at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omecamtiv Mecarbil 25 mg BID | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 12 | 217 ng/mL | Standard Deviation 66.1 |
| Omecamtiv Mecarbil 25 mg BID | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 2 | 239 ng/mL | Standard Deviation 106 |
| Omecamtiv Mecarbil 25 mg BID | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 16 | 206 ng/mL | Standard Deviation 84.5 |
| Omecamtiv Mecarbil 25 mg BID | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 4 | 222 ng/mL | Standard Deviation 63.5 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 12 | 228 ng/mL | Standard Deviation 56.9 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 4 | 196 ng/mL | Standard Deviation 44 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 2 | 179 ng/mL | Standard Deviation 77.1 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 16 | 244 ng/mL | Standard Deviation 67.7 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 16 | 292 ng/mL | Standard Deviation 118 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 2 | 208 ng/mL | Standard Deviation 61.6 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 4 | 209 ng/mL | Standard Deviation 61.9 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time | Week 12 | 282 ng/mL | Standard Deviation 120 |
Primary
PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8)
Time frame: Week 8 (Day 56) at predose, at 2 hours ±30 minutes; 4 hours ±30 minutes; 6 hours ±30 minutes; 8 hours ±30 minutes after morning dose
Population: PK Analysis Set: all randomized participants who received at least one dose of omecamtiv mecarbil and had at least one evaluable omecamtiv mecarbil PK concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil 25 mg BID | PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8) | 1850 hr*ng/mL | Standard Deviation 563 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8) | 1850 hr*ng/mL | Standard Deviation 383 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8) | 2360 hr*ng/mL | Standard Deviation 465 |
Secondary
Change From Baseline at Week 16 in Systolic Ejection Time (SET)
LS mean was from the repeated measures model, which included treatment group, stratification factor (from IVRS), scheduled visit, baseline value, and the interaction of treatment group with scheduled visit as covariates.
Time frame: Baseline, Week 16 (Day 112)
Population: All participants who received at least one dose of study drug with observed data. The 4 active treatment arms include only those participants who had a minimum investigational product exposure period of 25 days.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil 25 mg BID | Change From Baseline at Week 16 in Systolic Ejection Time (SET) | -1.7 msec | Standard Error 4.7 |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Change From Baseline at Week 16 in Systolic Ejection Time (SET) | 20.5 msec | Standard Error 4.9 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Change From Baseline at Week 16 in Systolic Ejection Time (SET) | 27.6 msec | Standard Error 5.4 |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Change From Baseline at Week 16 in Systolic Ejection Time (SET) | 23.8 msec | Standard Error 5.2 |
p-value: 0.000895% CI: [9.6, 34.7]Repeated Measures Model
p-value: <0.000195% CI: [16.3, 42.3]Repeated measures model
p-value: 0.000295% CI: [12.6, 38.4]Repeated measures model
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is defined as any untoward medical occurrence. Serious AEs are defined as AEs that meets at least 1 of the following serious criteria: fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, other medically important serious event. AEs are graded as: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. TEAEs are defined as events occurring after the first dose of study drug.
Time frame: From first dose of study drug up to Week 20 (Day 140 + 3 days)
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All TEAEs | 14 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs Leading to Withdrawal of Study Drug | 0 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 3 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 2 TEAEs | 10 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fata Adverse Events | 0 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 3 TEAEs | 3 Participants |
| Omecamtiv Mecarbil 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 4 TEAEs | 0 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs Leading to Withdrawal of Study Drug | 2 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 4 TEAEs | 1 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 3 TEAEs | 4 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 4 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fata Adverse Events | 1 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 2 TEAEs | 6 Participants |
| Omecamtiv Mecarbil 25 mg to 37.5 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All TEAEs | 10 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 4 TEAEs | 0 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All TEAEs | 10 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 2 TEAEs | 6 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 3 TEAEs | 1 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 1 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs Leading to Withdrawal of Study Drug | 1 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fata Adverse Events | 0 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 3 TEAEs | 2 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fata Adverse Events | 0 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs Leading to Withdrawal of Study Drug | 0 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 2 TEAEs | 7 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All TEAEs | 12 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 3 Participants |
| Omecamtiv Mecarbil 25 mg to 50 mg BID Target Dose | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Grade >= 4 TEAEs | 0 Participants |