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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Pivotal Phase 3 Randomized, Placebo-controlled Clinical Study to Evaluate the Efficacy and Safety of the sGC Stimulator Vericiguat/MK-1242 in Adults With Chronic Heart Failure With Reduced Ejection Fraction

Conditions
-----------------
Chronic Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
-----------------
* Drug: Vericiguat
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vericiguat<br>Participants receive a starting dose of 2.5 mg of vericiguat taken orally once daily. The vericiguat dose will be titrated to 5 mg and to 10 mg. | Drug: Vericiguat<br>* 2.5, 5.0, or 10.0 mg orally once daily<br>* Other names: BAY 1021189;|
| Placebo Comparator: Placebo<br>Participants receive a starting matching placebo to vericiguat dose of 2.5 mg taken orally once daily. The matching placebo dose will be sham titrated to 5 mg and to 10 mg. | Drug: Placebo<br>* 0 mg matching placebo for 2.5 mg, 5 mg, and 10 mg of vericiguat<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | The first event of CV death or HF hospitalization as confirmed by a clinical events committee (CEC). | From date of randomization until the date of first occurrence of a CV death or HF hospitalization, assessed up to approximately 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of CV Death | The first event of CV death as confirmed by a CEC. | From date of randomization until the date of first occurrence of a CV death, assessed up to approximately 40 months | 
| Time to First Occurrence of HF Hospitalization | The first event of HF hospitalization as confirmed by a CEC. | From date of randomization until the date of first occurrence of a HF hospitalization, assessed up to approximately 40 months | 
| Time to Total HF Hospitalizations (Including First and Recurrent Events) | All events of HF hospitalization as confirmed by a CEC. | Up to approximately 40 months | 
| Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization | The first event of death due to any cause or HF hospitalization as confirmed by a CEC. | From date of randomization until the date of first occurrence of death or HF hospitalization, assessed up to approximately 40 months | 
| Time to All-Cause Mortality | The first event of death due to any cause as confirmed by a CEC. | From date of randomization until the date of death, assessed up to approximately 40 months | 
| 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Selected NSAEs are 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 (COVID-19) disease-related AEs. | Up to approximately 40 months | 
| 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/birth defect, or is another important medical event, as judged medically or scientifically, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above. | Up to approximately 40 months | 
| Percentage of Participants Who Experienced One or More Events of Clinical Interest (ECIs) | Events of clinical interest will include: 1) Potential drug-induced liver injury (DILI) events defined as: elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 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, as determined by way of protocol specified laboratory testing or unscheduled laboratory testing, 2) Symptomatic hypotension 3) Anemia. | Up to approximately 40 months |