A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-001)

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction (VICTORIA)

Conditions
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Heart Failure, Chronic Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Vericiguat
* Drug: Placebo for vericiguat


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


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 with food, on a background of HF standard of care. The vericiguat dose will be uptitrated to 5 mg and to 10 mg. | Drug: Vericiguat<br>* 2.5, 5.0, or 10.0 mg orally once daily<br>* Other names: MK-1242;|
| Placebo Comparator: Placebo<br>Participants receive 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 will be uptitrated to 5 mg and to 10 mg. | Drug: Placebo for vericiguat<br>* 2.5, 5.0, or 10.0 mg orally once daily<br>|

What is the study measuring?
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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 | 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| 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. | 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 | 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| 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. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| Percentage of Participants Who Experienced Symptomatic Hypotension | Study participants were monitored for symptomatic hypotension, an event of clinical interest, and results were reported. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) | 
| Percentage of Participants Who Experienced Syncope | Study participants were monitored for syncope, an event of clinical interest, and results were reported. | Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019) |