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

The primary objective of this pivotal Phase 3 randomized, placebo-controlled clinical study is to evaluate the **efficacy** of vericiguat compared with placebo in reducing the risk of cardiovascular death or heart failure hospitalization in adults with chronic heart failure with reduced ejection fraction. This is clinically relevant as it addresses critical outcomes in a population with significant morbidity and mortality risks.

Secondary objectives include: - Evaluating the efficacy of vericiguat compared with placebo on reducing the risk of cardiovascular death. - Assessing the efficacy of vericiguat in reducing the risk of heart failure hospitalization. - Determining the efficacy of vericiguat in reducing the risk of all-cause mortality or heart failure hospitalization. - Evaluating the efficacy of vericiguat in reducing the risk of all-cause mortality. - Assessing the safety and tolerability of vericiguat compared with placebo.

The clinical trial involves a total of **4622 participants** diagnosed with **Chronic Heart Failure With Reduced Ejection Fraction**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a history of chronic heart failure classified as New York Heart Association (NYHA) Class II to IV, and they must be on guideline-directed medical therapy for heart failure. Additionally, participants were required to have a left ventricular ejection fraction of 40% or less, as assessed within the past year, and elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The trial also considers lifestyle factors such as the absence of heart failure hospitalization within the last six months or outpatient intravenous diuretic use within the last three months. Female participants are included if they are not pregnant or breastfeeding, and if they agree to follow contraceptive guidance if they are of childbearing potential. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the study's objective to assess the efficacy of vericiguat in reducing the risk of cardiovascular death or heart failure hospitalization.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of **vericiguat** in adults with **chronic heart failure with reduced ejection fraction**. The primary objective is to assess the impact of vericiguat on reducing the risk of cardiovascular death or heart failure hospitalization. The trial is expected to run from November 2021 to June 2025, with participants involved for a maximum treatment period of 25 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a history of chronic heart failure, left ventricular ejection fraction of 40% or less, and elevated N-terminal pro-brain natriuretic peptide levels. Following randomization, participants will receive either vericiguat or a placebo, administered orally in tablet form. The study includes regular follow-up visits to monitor safety and efficacy outcomes, with the primary endpoint being the time to the first occurrence of a composite endpoint of cardiovascular death or heart failure hospitalization. Secondary endpoints include time to first occurrence of cardiovascular death, heart failure hospitalization, and all-cause mortality, among others.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of vericiguat in the target population.

The clinical trial involves the administration of **Vericiguat**, a pharmaceutical product in tablet form, with a chemical origin. Vericiguat is identified by the sponsor product code MK-1242 and is manufactured by Merck & Co. Inc. The active substance in Vericiguat is vericiguat, also known by its synonyms BAY 1021189 and MK-1242. The maximum daily dose of Vericiguat is 10 mg, with a total maximum dose of 7425 mg over a treatment period of up to 25 weeks. The route of administration is oral, and the product is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** control group. The placebo is designed to match the Vericiguat tablets in appearance and is available in two forms: a tablet corresponding to the 2.5 mg and 5 mg doses of Vericiguat, and a tablet corresponding to the 10 mg dose. The placebo tablets are administered orally, and like Vericiguat, they are not formulated for pediatric use. The placebo serves as a comparator treatment to evaluate the efficacy and safety of Vericiguat in reducing the risk of cardiovascular death or heart failure hospitalization in adults with chronic heart failure with reduced ejection fraction.

The efficacy of **Vericiguat** in the clinical trial will be assessed by evaluating its impact on reducing the risk of cardiovascular death or heart failure hospitalization in adults with chronic heart failure with reduced ejection fraction. The primary endpoint for efficacy evaluation is the time to the first occurrence of the composite endpoint of cardiovascular death or heart failure hospitalization. Secondary endpoints include the time to the first occurrence of cardiovascular death, time to the first occurrence of heart failure hospitalization, time to total heart failure hospitalizations (including first and recurrent events), time to the first occurrence of the composite endpoint of all-cause mortality or heart failure hospitalization, and time to all-cause mortality.

Data collection for these endpoints will be conducted throughout the trial duration, with specific timepoints for assessment not explicitly detailed. The trial is designed as a pivotal Phase 3 randomized, placebo-controlled study, ensuring rigorous evaluation of the efficacy of Vericiguat compared to placebo. The study will also monitor the percentage of participants who experience one or more selected nonserious adverse events, serious adverse events, and events of clinical interest, providing a comprehensive assessment of both efficacy and safety.