Chronic Heart Failure With Reduced Ejection Fraction, Heart Failure
Conditions
Brief summary
This is a randomized, placebo-controlled, parallel-group, multi-center, double-blind, event driven study of vericiguat (MK-1242) in participants with heart failure with reduced ejection fraction (HFrEF). The primary hypothesis is vericiguat (MK-1242) is superior to placebo in increasing the time to first occurrence of the composite of cardiovascular (CV) death or heart failure (HF) hospitalization in participants with HFrEF.
Interventions
DRUGVericiguat
2.5, 5.0, or 10.0 mg orally once daily
DRUGPlacebo for vericiguat
2.5, 5.0, or 10.0 mg orally once daily
Sponsors
Bayer
Canadian VIGOUR Centre
Duke Clinical Research Institute
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of chronic HF (New York Heart Association \[NYHA\] Class II-IV) on standard therapy before qualifying HF decompensation * Previous HF hospitalization within 6 months prior to randomization or intravenous (IV) diuretic treatment for HF (without hospitalization) within 3 months. * Brain natriuretic peptide (BNP) levels: sinus rhythm-≥ 300 pg/mL; atrial fibrillation-≥ 500 pg/mL and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels: sinus rhythm- ≥ 1000 pg/mL; atrial fibrillation - ≥ 1600 pg/mL within 30 days prior to randomization * Left ventricular ejection fraction (LVEF) of \<45% assessed within 12 months prior to randomization by any method * If female, is not of reproductive potential or agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: practice abstinence from heterosexual activity or use (or have her partner use) acceptable contraception during heterosexual activity.
Exclusion criteria
* Clinically unstable at the time of randomization as defined by either the administration of any IV treatment within 24 hours prior to randomization, and/or systolic blood pressure (SBP) \<100 mmHg or symptomatic hypotension * Current or anticipated use of long-acting nitrates or nitric oxide (NO) donors including isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine * Current or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as vardenafil, tadalafil, and sildenafil * Current use or anticipated use of a soluble guanylate cyclase (sGC) stimulator such as riociguat * Known allergy or sensitivity to any sGC stimulator * Awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or equivalent), receiving continuous IV infusion of an inotrope, or has/anticipates receiving an implanted ventricular assist device * Primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention * Hypertrophic obstructive cardiomyopathy * Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy * Post-heart transplant cardiomyopathy * Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia * Acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction \[NSTEMI\], or ST elevation myocardial infarction \[(STEMI\]) or coronary revascularization (coronary artery bypass grafting \[CABG\] or percutaneous coronary intervention \[PCI\]) within 60 days, or indication for coronary revascularization at time of randomization * Symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days * Complex congenital heart disease * Active endocarditis or constrictive pericarditis * Estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m2 or chronic dialysis * Severe hepatic insufficiency such as with hepatic encephalopathy * Malignancy or other non-cardiac condition limiting life expectancy to \<3 years * Require continuous home oxygen for severe pulmonary disease * Current alcohol and/or drug abuse * Participated in another interventional clinical study and treatment with another investigational product ≤30 days prior to randomization or plans to participate in any other trial/investigation during the duration of this study * Mental or legal incapacitation and is unable to provide informed consent * Immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is involved with this study * Interstitial Lung Disease * Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to First Occurrence of Composite Endpoint of CV Death or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization or CV death event at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A clinical events committee (CEC) reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of HF Hospitalization | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to the First Occurrence of HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided. |
| Time to Total HF Hospitalizations (Including First and Recurrent Events) | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to Total HF Hospitalizations (including first and recurring) was analyzed using an Andersen-Gill model. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years of follow-up) is provided. |
| Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event or HF hospitalization at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided. |
| Time to All-Cause Mortality | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to All-Cause Mortality was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results: the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided. |
| Time to the First Occurrence of CV Death | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Time to First Occurrence of CV Death was analyzed using a one-sided stratified log-rank test. Randomized participants without a CV death at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided. |
| Number of Participants Who Discontinued Treatment Due to an Adverse Event | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
| Percentage of Participants Who Experienced Symptomatic Hypotension | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Study participants were monitored for symptomatic hypotension, an event of clinical interest, and results were reported. |
| Percentage of Participants Who Experienced Syncope | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | Study participants were monitored for syncope, an event of clinical interest, and results were reported. |
| Number of Participants Who Experienced One or More Adverse Events | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vericiguat Participants received a starting dose of 2.5 mg of vericiguat taken orally once daily with food, on a background of heart failure (HF) standard of care. The vericiguat dose was uptitrated to 5 mg and to 10 mg. | 2,526 |
| Placebo Participants received a starting matching placebo dose of 2.5 mg taken orally once daily with food, on a background of HF standard of care. The matching placebo dose was uptitrated to 5 mg and to 10 mg. | 2,524 |
| Total | 5,050 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 541 | 552 |
| Overall Study | Lost to Follow-up | 14 | 14 |
| Overall Study | Site Terminated by Sponsor | 4 | 3 |
| Overall Study | Withdrawal by Subject | 15 | 18 |
Baseline characteristics
| Characteristic | Placebo | Total | Vericiguat |
|---|---|---|---|
| Age, Continuous | 67.2 Years STANDARD_DEVIATION 12.2 | 67.3 Years STANDARD_DEVIATION 12.2 | 67.5 Years STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 28 Participants | 52 Participants | 24 Participants |
| Race (NIH/OMB) Asian | 561 Participants | 1132 Participants | 571 Participants |
| Race (NIH/OMB) Black or African American | 126 Participants | 249 Participants | 123 Participants |
| Race (NIH/OMB) More than one race | 180 Participants | 363 Participants | 183 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 11 Participants | 14 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 1618 Participants | 3239 Participants | 1621 Participants |
| Sex: Female, Male Female | 603 Participants | 1208 Participants | 605 Participants |
| Sex: Female, Male Male | 1921 Participants | 3842 Participants | 1921 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 553 / 2,526 | 561 / 2,524 |
| other Total, other adverse events | 958 / 2,519 | 925 / 2,515 |
| serious Total, serious adverse events | 852 / 2,519 | 897 / 2,515 |
Outcome results
Primary
Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization
Time to First Occurrence of Composite Endpoint of CV Death or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization or CV death event at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A clinical events committee (CEC) reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | 33.6 Parts w/ event per 100 part-yrs at risk |
| Placebo | Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | 37.8 Parts w/ event per 100 part-yrs at risk |
p-value: 0.01995% CI: [0.82, 0.98]Cox proportional hazard model
Secondary
Number of Participants Who Discontinued Treatment Due to an Adverse Event
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vericiguat | Number of Participants Who Discontinued Treatment Due to an Adverse Event | 167 Participants |
| Placebo | Number of Participants Who Discontinued Treatment Due to an Adverse Event | 158 Participants |
Secondary
Number of Participants Who Experienced One or More Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vericiguat | Number of Participants Who Experienced One or More Adverse Events | 2027 Participants |
| Placebo | Number of Participants Who Experienced One or More Adverse Events | 2036 Participants |
Secondary
Percentage of Participants Who Experienced Symptomatic Hypotension
Study participants were monitored for symptomatic hypotension, an event of clinical interest, and results were reported.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants who received at least 1 dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Percentage of Participants Who Experienced Symptomatic Hypotension | 9.1 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced Symptomatic Hypotension | 7.9 Percentage of participants |
p-value: 0.12195% CI: [-0.3, 2.8]Miettinen & Nurminen method
Secondary
Percentage of Participants Who Experienced Syncope
Study participants were monitored for syncope, an event of clinical interest, and results were reported.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants who received at least 1 dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Percentage of Participants Who Experienced Syncope | 4.0 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced Syncope | 3.5 Percentage of participants |
p-value: 0.30395% CI: [-0.5, 1.6]Miettinen & Nurminen method
Secondary
Time to All-Cause Mortality
Time to All-Cause Mortality was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results: the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to All-Cause Mortality | 16.0 Parts w/ event per 100 part-yrs at risk |
| Placebo | Time to All-Cause Mortality | 16.9 Parts w/ event per 100 part-yrs at risk |
p-value: 0.37795% CI: [0.84, 1.07]Cox proportional hazard model
Secondary
Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization
Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any all-cause mortality event or HF hospitalization at the time of analysis were censored at their last available information or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization | 35.9 Parts w/ event per 100 part-yrs at risk |
| Placebo | Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization | 40.1 Parts w/ event per 100 part-yrs at risk |
p-value: 0.02195% CI: [0.83, 0.98]Cox proportional hazard model
Secondary
Time to the First Occurrence of CV Death
Time to First Occurrence of CV Death was analyzed using a one-sided stratified log-rank test. Randomized participants without a CV death at the time of analysis were censored at their last available information, the date of their non-CV death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to the First Occurrence of CV Death | 12.9 Parts w/ event per 100 part-yrs at risk |
| Placebo | Time to the First Occurrence of CV Death | 13.9 Parts w/ event per 100 part-yrs at risk |
p-value: 0.26995% CI: [0.81, 1.06]Cox proportional hazard model
Secondary
Time to the First Occurrence of HF Hospitalization
Time to the First Occurrence of HF Hospitalization was analyzed using a one-sided stratified log-rank test. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years at risk) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to the First Occurrence of HF Hospitalization | 25.9 Parts w/ event per 100 part-yrs at risk |
| Placebo | Time to the First Occurrence of HF Hospitalization | 29.1 Parts w/ event per 100 part-yrs at risk |
p-value: 0.04895% CI: [0.81, 1]Cox proportional hazard model
Secondary
Time to Total HF Hospitalizations (Including First and Recurrent Events)
Time to Total HF Hospitalizations (including first and recurring) was analyzed using an Andersen-Gill model. Randomized participants without any HF hospitalization at the time of analysis were censored at their last available information, the date of their death, or the primary analysis database cutoff date of 18-June-2019, whichever occurred first. A CEC reviewed and adjudicated the endpoint events. A time-to-event methodology was used to evaluate the results; the incidence rate of participants with an event (number of participants with an event per 100 participant-years of follow-up) is provided.
Time frame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vericiguat | Time to Total HF Hospitalizations (Including First and Recurrent Events) | 38.3 Parts w/ event per 100 part-yrs |
| Placebo | Time to Total HF Hospitalizations (Including First and Recurrent Events) | 42.4 Parts w/ event per 100 part-yrs |
p-value: 0.02395% CI: [0.84, 0.99]Andersen-Gill model