Heart Failure
Conditions
Brief summary
The purpose of this study is to determine if treatment with omecamtiv mecarbil when added to standard of care is well tolerated and superior to placebo in reducing the risk of cardiovascular death or heart failure events in adults with chronic heart failure with reduced ejection fraction (HFrEF).
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
Omecamtiv mecarbil tablets for oral administration
DRUGPlacebo
Matching placebo tablets
DRUGStandard of Care
Participants were required to be optimally managed with standard of care therapies for chronic HF (eg, beta blockers, renin angiotensin aldosterone system inhibitors), consistent with regional clinical practice guidelines, unless contraindicated.
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subject has provided informed consent * Male or female, ≥ 18 to ≤ 85 years * History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 30 days before randomization * Left ventricle ejection fraction (LVEF) ≤ 35%, per subjects most recent medical record, within 12 months prior to screening. * New York Heart Association (NYHA) class II to IV at most recent screening assessment. * Managed with HF standard of care (SoC) therapies consistent with regional clinical practice guidelines according to investigator judgment of subject's clinical status * Current hospitalization with primary reason of HF OR one of the following events within 1 year of screening: hospitalization with primary reason of HF; urgent visit to emergency department (ED) with primary reason of HF. * Elevated B-type natriuretic peptide (BNP) or n-terminal-prohormone brain natriuretic peptide (NT-proBNP) Other Inclusion Criteria May apply Key
Exclusion criteria
* Currently receiving treatment in another investigational device or drug study, or \< 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. * Malignancy within 5 years prior to randomization with the following exceptions: localized basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, stage 1 prostate carcinoma, breast ductal carcinoma in situ. * Subject has known sensitivity to any of the products or components to be administered during testing Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cardiovascular Death or First Heart Failure Event | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | The primary outcome was a composite of a heart-failure (HF) event or cardiovascular (CV) death, whichever occurred first, in a time-to-event analysis. A heart-failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. All deaths and HF events were adjudicated by an independent external clinical events committee (CEC) at the Duke Clinical Research Institute, using standardized definitions based on the recent American College of Cardiology/American Heart Association (ACC/AHA) standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death or first HF event was analyzed using Kaplan-Meier (KM) methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cardiovascular Death | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | Cardiovascular death includes acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. All deaths were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported. |
| Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | Baseline and Week 24 | The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire with a 2-week recall period that includes 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy (the patient's understanding of how to manage their heart failure). The symptom frequency and symptom burden domains are merged into a total symptom score. Scores are represented on a 0-to-100-point scale, where lower scores represent more frequent and severe symptoms and scores of 100 indicate no symptoms. The change from baseline in KCCQ TSS was analyzed separately for each randomization setting (inpatient and outpatient). Least squares means are from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates. |
| Time to First Heart Failure Hospitalization | From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | A HF hospitalization is defined as an event that met all of the following criteria: 1. The participant was admitted to the hospital with a primary diagnosis of HF; 2. The length of stay in the hospital extended for at least 24 hours; 3. The participant exhibited documented new or worsening symptoms due to HF on presentation; 4. The participant had objective evidence of new or worsening HF; 5. The participant received initiation or intensification of treatment specifically for HF, including an intravenous diuretic or vasoactive agent, mechanical or surgical intervention, or mechanical fluid removal. Events were adjudicated by an independent external CEC at the Duke Clinical Research Institute using standardized definitions based on the ACC/AHA standards for endpoint definitions in CV clinical trials. Time to first HF hospitalization was analyzed using KM methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event is reported. |
| Time to All-cause Death | From randomization up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months. | All events were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to all-cause death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with an event are reported. Events that occurred up to the earliest of last confirmed survival status date or analysis cut-off date (07 August 2020) are included. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Lithuania, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 11,121 patients underwent screening at 944 sites in 35 countries. Of these patients, 8,256 were randomized, but 24 patients from one site were excluded because of Good Clinical Practice violations and are not included in the data reported below.
Pre-assignment details
Participants were randomly assigned in a 1:1 ratio to receive either oral omecamtiv mecarbil (OM) or placebo. Randomization was stratified by randomization setting (currently hospitalized for heart failure \[HF\] or recently and not currently hospitalized for HF) and region (United States and Canada; Latin America; Western Europe, South Africa, and Australasia; Eastern Europe including Russia; Asia).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo tablets (BID). | 4,112 |
| Omecamtiv Mecarbil Participants received oral omecamtiv mecarbil BID. The starting dose was 25 mg; the dose may have been adjusted at week 4 to 37.5 or 50 mg based on the predose plasma concentration measured at week 2. | 4,120 |
| Total | 8,232 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1,054 | 1,051 |
| Overall Study | Lost to Follow-up | 26 | 20 |
| Overall Study | Withdrawal by Subject | 24 | 21 |
Baseline characteristics
| Characteristic | Placebo | Total | Omecamtiv Mecarbil |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 11.4 | 64.5 years STANDARD_DEVIATION 11.4 | 64.5 years STANDARD_DEVIATION 11.3 |
| Age, Customized 18 to 64 years | 1873 Participants | 3747 Participants | 1874 Participants |
| Age, Customized 65 to 84 years | 2211 Participants | 4431 Participants | 2220 Participants |
| Age, Customized 85 years and over | 28 Participants | 54 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 885 Participants | 1771 Participants | 886 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3227 Participants | 6461 Participants | 3234 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 38 Participants | 73 Participants | 35 Participants |
| Race/Ethnicity, Customized Asian | 355 Participants | 710 Participants | 355 Participants |
| Race/Ethnicity, Customized Black or African American | 277 Participants | 562 Participants | 285 Participants |
| Race/Ethnicity, Customized Multiple | 96 Participants | 195 Participants | 99 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 6 Participants | 13 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 139 Participants | 282 Participants | 143 Participants |
| Race/Ethnicity, Customized White | 3201 Participants | 6397 Participants | 3196 Participants |
| Randomization Setting Currently hospitalized for heart failure | 1050 Participants | 2101 Participants | 1051 Participants |
| Randomization Setting Recently and not currently hospitalized for heart failure | 3062 Participants | 6131 Participants | 3069 Participants |
| Region Asia | 335 Participants | 670 Participants | 335 Participants |
| Region Eastern Europe including Russia | 1337 Participants | 2681 Participants | 1344 Participants |
| Region Latin America | 787 Participants | 1574 Participants | 787 Participants |
| Region United States and Canada | 693 Participants | 1386 Participants | 693 Participants |
| Region Western Europe, South Africa, and Australasia | 960 Participants | 1921 Participants | 961 Participants |
| Sex: Female, Male Female | 874 Participants | 1749 Participants | 875 Participants |
| Sex: Female, Male Male | 3238 Participants | 6483 Participants | 3245 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1,078 / 4,112 | 1,078 / 4,120 |
| other Total, other adverse events | 1,146 / 4,101 | 1,129 / 4,110 |
| serious Total, serious adverse events | 2,435 / 4,101 | 2,373 / 4,110 |
Outcome results
Primary
Time to Cardiovascular Death or First Heart Failure Event
The primary outcome was a composite of a heart-failure (HF) event or cardiovascular (CV) death, whichever occurred first, in a time-to-event analysis. A heart-failure event was defined as an urgent clinic visit, emergency department visit, or hospitalization for subjectively and objectively worsening heart failure leading to treatment intensification beyond a change in oral diuretic therapy. All deaths and HF events were adjudicated by an independent external clinical events committee (CEC) at the Duke Clinical Research Institute, using standardized definitions based on the recent American College of Cardiology/American Heart Association (ACC/AHA) standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death or first HF event was analyzed using Kaplan-Meier (KM) methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported.
Time frame: From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cardiovascular Death or First Heart Failure Event | 39.1 percentage of participants |
| Omecamtiv Mecarbil | Time to Cardiovascular Death or First Heart Failure Event | 37.0 percentage of participants |
p-value: 0.025295% CI: [0.86, 0.99]Regression, Cox
p-value: 0.0211Stratified log-rank test
Comparison: Competing risk subdistribution hazard ratio and associated 95% confidence intervals for treatment were computed. Deaths not included in the endpoint were considered as the competing risk.95% CI: [0.86, 0.99]
Secondary
Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24
The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire with a 2-week recall period that includes 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy (the patient's understanding of how to manage their heart failure). The symptom frequency and symptom burden domains are merged into a total symptom score. Scores are represented on a 0-to-100-point scale, where lower scores represent more frequent and severe symptoms and scores of 100 indicate no symptoms. The change from baseline in KCCQ TSS was analyzed separately for each randomization setting (inpatient and outpatient). Least squares means are from the mixed model which includes baseline total symptom score value, region, baseline eGFR, scheduled visit, treatment group and interaction of treatment with scheduled visit as covariates.
Time frame: Baseline and Week 24
Population: Full analysis set with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | 6.29 scores on a scale | Standard Error 0.34 |
| Omecamtiv Mecarbil | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | 5.83 scores on a scale | Standard Error 0.34 |
| Placebo: Inpatients | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | 21.15 scores on a scale | Standard Error 0.71 |
| Omecamtiv Mecarbil: Inpatients | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at Week 24 | 23.65 scores on a scale | Standard Error 0.7 |
95% CI: [-1.4, 0.48]
95% CI: [0.54, 4.46]
p-value: 0.0278Omnibus F-test
95% CI: [-2.55, 4.51]
Comparison: As a sensitivity for missing data due to death, joint longitudinal and survival models were fit using KCCQ TSS observed values with random subject slopes and intercepts for the longitudinal models with terms for baseline eGFR, region, and treatment by slope. The survival models were fit for all-cause death with baseline eGFR and treatment in the proportional hazard part of the models, KCCQ TSS modeled values as the shared parameterization, stratified by region with Weibull baseline functions.95% CI: [-1.62, 0.2]
Comparison: As a sensitivity for missing data due to death, joint longitudinal and survival models were fit using KCCQ TSS observed values with random subject slopes and intercepts for the longitudinal models with terms for baseline eGFR, region, and treatment by slope. The survival models were fit for all-cause death with baseline eGFR and treatment in the proportional hazard part of the models, KCCQ TSS modeled values as the shared parameterization, stratified by region with Weibull baseline functions.95% CI: [0.8, 3.82]
Secondary
Time to All-cause Death
All events were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to all-cause death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with an event are reported. Events that occurred up to the earliest of last confirmed survival status date or analysis cut-off date (07 August 2020) are included.
Time frame: From randomization up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to All-cause Death | 25.9 percentage of participants |
| Omecamtiv Mecarbil | Time to All-cause Death | 25.9 percentage of participants |
p-value: 0.963395% CI: [0.92, 1.09]Regression, Cox
Secondary
Time to Cardiovascular Death
Cardiovascular death includes acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. All deaths were adjudicated by an independent external clinical-events committee at the Duke Clinical Research Institute, using standardized definitions based on the recent ACC/AHA standards for endpoint definitions in cardiovascular clinical trials. Time to cardiovascular death was analyzed using Kaplan-Meier methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event during the study is reported.
Time frame: From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cardiovascular Death | 19.4 percentage of participants |
| Omecamtiv Mecarbil | Time to Cardiovascular Death | 19.6 percentage of participants |
p-value: 0.855595% CI: [0.92, 1.11]Regression, Cox
Comparison: Competing risk subdistribution hazard ratio and associated 95% confidence intervals for treatment were computed. Deaths not included in the endpoint were considered as the competing risk.95% CI: [0.92, 1.11]
Secondary
Time to First Heart Failure Hospitalization
A HF hospitalization is defined as an event that met all of the following criteria: 1. The participant was admitted to the hospital with a primary diagnosis of HF; 2. The length of stay in the hospital extended for at least 24 hours; 3. The participant exhibited documented new or worsening symptoms due to HF on presentation; 4. The participant had objective evidence of new or worsening HF; 5. The participant received initiation or intensification of treatment specifically for HF, including an intravenous diuretic or vasoactive agent, mechanical or surgical intervention, or mechanical fluid removal. Events were adjudicated by an independent external CEC at the Duke Clinical Research Institute using standardized definitions based on the ACC/AHA standards for endpoint definitions in CV clinical trials. Time to first HF hospitalization was analyzed using KM methods. Since the median was not calculated, the percentage of participants with a positively adjudicated event is reported.
Time frame: From randomization to up to earliest of last confirmed survival status date or analysis cut-off date (07 August 2020); the overall median duration of follow-up was 21.8 months up to a maximum of 42 months.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Heart Failure Hospitalization | 28.7 percentage of participants |
| Omecamtiv Mecarbil | Time to First Heart Failure Hospitalization | 27.7 percentage of participants |
p-value: 0.190295% CI: [0.87, 1.03]Regression, Cox
Comparison: Competing risk subdistribution hazard ratio and associated 95% confidence intervals for treatment were computed. Deaths not included in the endpoint are considered as the competing risk.95% CI: [0.88, 1.04]