A Study of Vericiguat (MK-1242) in Participants With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-035)

Merck Sharp & Dohme LLC6,106 enrolled

Overview

The purpose of this study is to evaluate the efficacy and safety of vericiguat in participants with chronic heart failure with reduced ejection fraction (HFrEF), specifically those with symptomatic chronic HFrEF who have not had a recent hospitalization for heart failure or need for outpatient intravenous (IV) diuretics. The primary hypothesis is that vericiguat is superior to placebo in reducing the risk of cardiovascular death or heart failure hospitalization.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

6,106

Conditions

Chronic Heart Failure With Reduced Ejection Fraction

Interventions

VericiguatDRUG

2.5, 5.0, or 10.0 mg orally once daily

PlaceboDRUG

0 mg matching placebo for 2.5 mg, 5 mg, and 10 mg of vericiguat

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * History of chronic HF \[New York Heart Association (NYHA) Class II to IV\] on guideline-directed medical therapy for heart failure (GDMT) with no HF hospitalization within 6 months or outpatient IV diuretic use within 3 months before randomization. * Left ventricular ejection fraction (LVEF) of ≤40%, assessed within 12 months before randomization by any imaging method. * Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. * A female participant is eligible to participate if she is not pregnant or breastfeeding, is not a woman of childbearing potential (WOCBP), or is a WOCBP and agrees to follow contraceptive guidance during the study intervention period and for at least 1 month after the last dose of study intervention. Exclusion Criteria: * Has SBP \<100 mm Hg or symptomatic hypotension. * Awaiting heart transplantation, is receiving continuous IV infusion of an inotrope, or has or anticipates receiving an implanted ventricular assist device. * Amyloidosis or sarcoidosis. * Primary valvular heart disease requiring surgical procedure or intervention or has undergone a valvular surgical procedure or intervention within 3 months before randomization. * Hypertrophic cardiomyopathy. * Acute myocarditis or Takotsubo cardiomyopathy. * History of heart transplant. * Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia. * Acute coronary syndrome, or undergone coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within 3 months before randomization. * History of symptomatic carotid stenosis, transient ischemic attack (TIA), or stroke within 3 months before randomization. * Malignancy or other noncardiac condition limiting life expectancy to \<3 years. * Requires continuous home oxygen for severe pulmonary disease. * Interstitial lung disease. * Discontinuation or dose modification of GDMT or vericiguat within 4 weeks before randomization. * Recent history (within the last year) of drug or alcohol abuse or dependence.

Locations (519)

Outcomes

Primary Outcomes

Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization: Participants With an Event Per 100 Patient-Years

The time to first occurrence of the composite endpoint of CV death or HF hospitalization was defined as the time from randomization to the first event of CV death or HF hospitalization. Randomized participants without a HF hospitalization or CV death event at the time of analysis were censored at the last available information, when the protocol pre-specified number of total CV death events was achieved (primary completion analysis data cutoff), or the date of their non-CV death, whichever occurred first. Events were confirmed by a clinical events committee (CEC). Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of participants with a CV death or HF hospitalization event per 100 patient-years at risk is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Secondary Outcomes

Time to CV Death: Participants With an Event Per 100 Patient-Years

Time to CV death was defined as the time from randomization to CV death. Randomized participants without a CV death at the time of analysis were censored at their last available information, when the protocol pre-specified number of total CV death events was achieved (primary analysis database cutoff), or the date of their non-CV death, whichever occurred first. CV deaths were confirmed by a CEC. Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of participants with a CV death event per 100 patient-years at risk is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Time to First Occurrence of HF Hospitalization: Participants With an Event Per 100 Patient-Years

Time to first occurrence of HF hospitalization was defined as the time from randomization to the first event of HF hospitalization. Randomized participants without an HF hospitalization at the time of analysis were censored at their last available information, when the protocol pre-specified number of total CV death events was achieved (primary analysis database cutoff), or the date of their death, whichever occurred first. HF hospitalizations were confirmed by a CEC. Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of participants with an HF hospitalization event per 100 patient-years at risk is presented.

Data from ClinicalTrials.gov

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Advanced Cardiovascular - Alexander City ( Site 0038)

Alexander City, Alabama, United States

University of Alabama at Birmingham - School of Medicine-Cardiology ( Site 0153)

Birmingham, Alabama, United States

Heart Center Research, LLC ( Site 0156)

Huntsville, Alabama, United States

Mercy Gilbert Medical Center-Dignity Health Cardiology ( Site 0075)

Gilbert, Arizona, United States

Valley Clinical Trials, Inc. ( Site 0085)

Covina, California, United States

VA West Los Angeles Medical Center-Cardiology ( Site 0149)

Los Angeles, California, United States

Valley Clinical Trials Inc ( Site 0006)

Northridge, California, United States

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center ( Site 0010)

Torrance, California, United States

Blue Coast Research Center ( Site 0053)

Vista, California, United States

Excel Medical Clinical Trials ( Site 0008)

Boca Raton, Florida, United States

...and 509 more locations

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Time to Total HF Hospitalizations (Including First and Recurrent Events): Total Events Per 100 Patient-Years

Time to total HF hospitalizations was defined as the time from randomization to all HF hospitalization events, including time to first event and time increments between events. Randomized participants without an HF hospitalization at the time of analysis were censored at their last available information, when the protocol pre-specified number of total CV death events was achieved (primary analysis database cutoff), or the date of their death, whichever occurred first. HF hospitalizations were confirmed by a CEC. Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of total HF hospitalization events per 100 patient-years at risk is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization: Participants With an Event Per 100 Patient-Years

The time to first occurrence of the composite endpoint of all-cause mortality or HF hospitalization was defined as the time from randomization to the first event of all-cause mortality or HF hospitalization. Randomized participants without an all-cause mortality or HF hospitalization event at the time of analysis were censored at the last available information or when the protocol pre-specified number of total CV death events is achieved (primary analysis database cutoff), whichever occurred first. Events were confirmed by a CEC. Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of participants with an all-cause mortality or HF hospitalization event per 100 patient-years at risk is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Time to All-Cause Mortality: Participants With an Event Per 100 Patient-Years

Time to all-cause mortality was defined as the time from randomization to all-cause mortality. Randomized participants without an all-cause mortality event at the time of analysis were censored at their last available information or when the protocol pre-specified number of total CV death events was achieved (primary analysis database cutoff), whichever occurred first. All-cause mortality was confirmed by a CEC. Protocol-specified final analyses are reported here with a primary completion data cutoff. Time-to-event methodology was used to evaluate the results and the number of participants with an all-cause mortality event per 100 patient-years at risk is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Selected Nonserious Adverse Events (NSAEs)

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Selected NSAEs are defined as nonserious AEs that meet any of the following criteria: AEs that lead to study intervention dose modification or discontinuation, AEs that lead to withdrawal from the study, or Coronavirus Disease 2019 (COVID-19) disease-related AEs. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more selected NSAEs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Serious Adverse Events (SAEs)

An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, or other important medical events as determined by the investigator. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more SAEs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Events of Clinical Interest (ECIs)

ECIs were determined and reported based on the clinical judgment of the investigator. As pre-specified in the protocol, ECIs included the following: 1) Events of potential drug-induced liver injury (DILI), defined as an elevated aspartate aminotransferase or alanine aminotransferase laboratory value that is greater than or equal to 3X the upper limit of normal (ULN) and an elevated total bilirubin laboratory value that is greater than or equal to 2X the ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X the ULN, 2) Events associated with symptomatic hypotension, or 3) Events associated with anemia, regardless of etiology. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more ECIs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Potential DILI ECIs

Potential DILI ECIs were determined and reported based on the clinical judgment of the investigator. Potential DILI ECIs were defined as an elevated aspartate aminotransferase or alanine aminotransferase laboratory value that is greater than or equal to 3X the ULN and an elevated total bilirubin laboratory value that is greater than or equal to 2X the ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X the ULN. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more potential DILI ECIs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Symptomatic Hypotension ECIs

Symptomatic hypotension ECIs were determined and reported based on the clinical judgment of the investigator. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more symptomatic hypotension ECIs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)

Percentage of Participants Who Experienced One or More Anemia ECIs

Anemia ECIs were determined and reported based on the clinical judgment of the investigator, regardless of etiology. Protocol-specified final analyses are reported here with a primary completion data cutoff. The percentage of participants who experienced one or more anemia ECIs is presented.

Time frame: Up to approximately 36 months (from randomization to the primary completion data cutoff)