Heart Failure With Reduced Ejection Fraction
Conditions
Brief summary
The purpose of this study is to evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on exercise capacity as determined by cardiopulmonary exercise testing following 20 weeks of treatment with omecamtiv mecarbil or placebo
Detailed description
Oversight Authorities: United States: Food and Drug Administration Canada: Health Canada France: National Agency for the Safety of Medicine and Health Products Germany: Federal Institute for Drugs and Medical Devices Hungary: National Institute of Pharmacy and Nutrition Italy: Italian Medicines Agency Netherlands: Medicines Evaluation Board Poland: Chief Pharmaceutical Inspectorate Sweden: Medical Products Agency
Interventions
Oral omecamtiv mecarbil twice daily for up to 20 weeks with dose level determined by periodic blood testing
DRUGPlacebo
Oral placebo twice daily for up to 20 weeks
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, greater than or equal to 18 to lesser than or equal to 85 years of age * History of chronic HF, defined as requiring continuous treatment with medications for HF for a minimum of 3 months before screening * New York Heart Association (NYHA) class II or III at screening * Left ventricular ejection fraction less than or equal to 35% * On maximally tolerated HF standard of care (SoC) therapies consistent with regional clinical practice guidelines, if not contraindicated and according to investigator judgment of the subject's clinical status. Beta blocker dose must be stable for 30 days prior to randomization. * N-terminal (NT)-proBNP level greater than or equal to 200 pg/mL * Peak VO2 less than or equal to 75% of the predicted normal value with respiratory exchange ratio (RER) greater than or equal to 1.05 on a screening CPET, confirmed by a CPET core laboratory
Exclusion criteria
* Severe uncorrected valvular heart disease * Paroxysmal atrial fibrillation or flutter documented within the previous 6 months, direct-current (DC) cardioversion or ablation procedure for atrial fibrillation within 6 months, or plan to attempt to restore sinus rhythm within 6 months of randomization. Subjects with persistent atrial fibrillation and no sinus rhythm documented in the prior 6 months are permitted. * Symptomatic bradycardia, second-degree Mobitz type II, or third-degree heart block without a pacemaker. * History of gastrointestinal bleeding requiring hospitalization, urgent procedure or transfusion in the prior year, or received intravenous (IV) iron, blood transfusion, or an erythropoiesis-stimulating agent (ESA) within 3 months prior to screening, or planned blood transfusion or ESA use during the study screening or treatment period. Chronic, stable use of oral iron is permitted. * Ongoing or planned enrollment in cardiac rehabilitation. * Requires assistance to walk or use of mobility assistive devices such as motorized devices, wheelchairs, or walkers. The use of canes for stability while ambulating is acceptable if the subject is deemed capable of performing CPET. * Major medical event or procedure within 3 months prior to randomization, including: hospitalization, surgery, renal replacement therapy or cardiac procedure. This includes episodes of decompensated HF that require IV HF treatment. * At screening: Resting systolic BP greater than 140 mmHg or less than 85 mmHg, or diastolic BP greater than 90 mmHg (mean of triplicate readings); Resting heart rate greater than 90 beats per minute, or less than 50 beats per minute (mean of triplicate readings); Estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m2 (by the modified Modification of Diet in Renal Disease equation); Hepatic impairment defined by a total bilirubin (TBL) greater than or equal to 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times ULN. Patients with documented Gilbert syndrome and TBL greater than or equal to 2 times ULN due to unconjugated hyperbilirubinemia, without other hepatic impairment, are permitted. * Room air oxygen saturation under 90% at screening * Hemoglobin less than 10.0 g/dL at screening * Significant adverse finding (e.g., exercise-induced early ischemic changes, abnormal decrease in BP \[systolic BP falls by more than 10 mmHg\], unexpected arrhythmia or other serious finding) during CPET at screening that precludes safe participation in the study, per investigator * Chronotropic incompetence (including inadequate pacemaker rate response) during CPET at screening, defined as a maximum heart rate \<60% of the maximum predicted heart rate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Oxygen Uptake on Cardiopulmonary Exercise Testing From Baseline to Week 20 | Baseline and Week 20 | The effect of treatment on exercise capacity, as assessed by peak oxygen uptake, was assessed during cardiopulmonary exercise testing (CPET) with gas-exchange analysis. Cycle ergometry was the preferred modality for exercise testing; treadmill exercise testing was an acceptable alternative. Participants were to use the same testing modality for all exercise tests during the study. Whenever possible, CPET was administered by the same study personnel using the same equipment throughout the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Workload During Cardiopulmonary Exercise Testing From Baseline to Week 20 | Baseline and Week 20 | Total workload was measured during CPET (cycle ergometry \[preferred\] or treadmill exercise testing) and represents the maximum load to which a participant was subjected during CPET in order to produce work. |
| Change in Ventilatory Efficiency During Cardiopulmonary Exercise Testing From Baseline to Week 20 | Baseline and Week 20 | Ventilatory efficiency (ventilation \[VE\]/volume of exhaled carbon dioxide \[VCO2\]) was measured through CPET with gas exchange analysis. |
| Change in the Average Daily Activity Units Measured Over a 2-week Period From Baseline (Week -2 to Day 1) to Weeks 18-20 | Baseline (Week -2 to Day 1) to Weeks 18-20 | The effect of treatment on daily activity, as assessed by average daily activity units, was evaluated by actigraphy. Actigraphy was collected during 4 sessions throughout the study for 2 week intervals. |
Countries
Canada, France, Germany, Hungary, Italy, Netherlands, Poland, Sweden, United States
Participant flow
Recruitment details
Participants with heart failure with reduced ejection fraction (HFrEF) were enrolled at 63 sites in Canada, France, Germany, Hungary, Italy, Netherlands, Poland, Sweden, and the United States. The first participant enrolled on 09 April 2019, and the last participant completed follow-up on 06 January 2022.
Pre-assignment details
A total of 276 participants were randomized in a 2:1 ratio to treatment: 185 to omecamtiv mecarbil and 91 to placebo.
Participants by arm
| Arm | Count |
|---|---|
| Omecamtiv Mecarbil Omecamtiv mecarbil was administered as an oral modified-release tablet twice daily for up to 20 weeks. Participants randomized to this arm started at an omecamtiv mecarbil dose of 25 mg twice daily. The dose could be increased based on plasma concentrations at Weeks 2 and 6. | 185 |
| Placebo Participants randomized this arm received placebo tablets (matching the appearance of the omecamtiv mecarbil tablets) twice daily for up to 20 weeks. | 91 |
| Total | 276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 4 |
| Overall Study | Consistently forgot to bring study drug kits to site visits (for compliance check) | 1 | 0 |
| Overall Study | Death | 2 | 1 |
| Overall Study | No longer able to take medicines | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Stopped taking study drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Omecamtiv Mecarbil | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 9.64 | 64.4 years STANDARD_DEVIATION 11.41 | 63.6 years STANDARD_DEVIATION 10.25 |
| Primary cause of heart failure: ischemic heart disease | 117 Participants | 48 Participants | 165 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 6 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 163 Participants | 82 Participants | 245 Participants |
| Sex: Female, Male Female | 27 Participants | 15 Participants | 42 Participants |
| Sex: Female, Male Male | 158 Participants | 76 Participants | 234 Participants |
| Time since HFrEF diagnosis | 7.6 years STANDARD_DEVIATION 6.14 | 7.8 years STANDARD_DEVIATION 6.88 | 7.7 years STANDARD_DEVIATION 6.38 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 185 | 1 / 91 |
| other Total, other adverse events | 126 / 185 | 58 / 91 |
| serious Total, serious adverse events | 30 / 185 | 13 / 91 |
Outcome results
Primary
Change in Peak Oxygen Uptake on Cardiopulmonary Exercise Testing From Baseline to Week 20
The effect of treatment on exercise capacity, as assessed by peak oxygen uptake, was assessed during cardiopulmonary exercise testing (CPET) with gas-exchange analysis. Cycle ergometry was the preferred modality for exercise testing; treadmill exercise testing was an acceptable alternative. Participants were to use the same testing modality for all exercise tests during the study. Whenever possible, CPET was administered by the same study personnel using the same equipment throughout the study.
Time frame: Baseline and Week 20
Population: Full Analysis Set (all randomized participants who received at least 1 dose of randomized study drug)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil | Change in Peak Oxygen Uptake on Cardiopulmonary Exercise Testing From Baseline to Week 20 | -0.239 mL/min/kg | Standard Error 0.1718 |
| Placebo | Change in Peak Oxygen Uptake on Cardiopulmonary Exercise Testing From Baseline to Week 20 | 0.207 mL/min/kg | Standard Error 0.2412 |
p-value: 0.1395% CI: [-1.024, 0.131]ANCOVA
Secondary
Change in the Average Daily Activity Units Measured Over a 2-week Period From Baseline (Week -2 to Day 1) to Weeks 18-20
The effect of treatment on daily activity, as assessed by average daily activity units, was evaluated by actigraphy. Actigraphy was collected during 4 sessions throughout the study for 2 week intervals.
Time frame: Baseline (Week -2 to Day 1) to Weeks 18-20
Population: The analysis population included participants in the Full Analysis Set with available data at both assessment time frames (ie, baseline \[Week -2 to Day 1\] and Weeks 18-20).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil | Change in the Average Daily Activity Units Measured Over a 2-week Period From Baseline (Week -2 to Day 1) to Weeks 18-20 | -0.2 10^5 activity units | Standard Error 0.3 |
| Placebo | Change in the Average Daily Activity Units Measured Over a 2-week Period From Baseline (Week -2 to Day 1) to Weeks 18-20 | -0.5 10^5 activity units | Standard Error 0.38 |
p-value: 0.5495% CI: [-0.6, 1.1]Repeated measures mixed model
Secondary
Change in Total Workload During Cardiopulmonary Exercise Testing From Baseline to Week 20
Total workload was measured during CPET (cycle ergometry \[preferred\] or treadmill exercise testing) and represents the maximum load to which a participant was subjected during CPET in order to produce work.
Time frame: Baseline and Week 20
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil | Change in Total Workload During Cardiopulmonary Exercise Testing From Baseline to Week 20 | -3.798 Watt | Standard Error 1.3352 |
| Placebo | Change in Total Workload During Cardiopulmonary Exercise Testing From Baseline to Week 20 | 1.590 Watt | Standard Error 1.9477 |
p-value: 0.02595% CI: [-10.108, -0.0668]ANCOVA
Secondary
Change in Ventilatory Efficiency During Cardiopulmonary Exercise Testing From Baseline to Week 20
Ventilatory efficiency (ventilation \[VE\]/volume of exhaled carbon dioxide \[VCO2\]) was measured through CPET with gas exchange analysis.
Time frame: Baseline and Week 20
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Omecamtiv Mecarbil | Change in Ventilatory Efficiency During Cardiopulmonary Exercise Testing From Baseline to Week 20 | 0.277 slope | Standard Error 0.3616 |
| Placebo | Change in Ventilatory Efficiency During Cardiopulmonary Exercise Testing From Baseline to Week 20 | -0.138 slope | Standard Error 0.5065 |
p-value: 0.5195% CI: [-0.81, 1.639]ANCOVA