A Phase 2/3 Randomized, Placebo-Controlled, Double-blind, Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Vericiguat in Pediatric Participants with Heart Failure due to Systemic Left Ventricular Systolic Dysfunction (VALOR)

The primary objective of this clinical study is to compare the **efficacy** of vericiguat versus placebo on the change in NT-proBNP from baseline to Week 16 in pediatric participants with heart failure due to systemic left ventricular systolic dysfunction. This objective is clinically relevant as NT-proBNP is a biomarker associated with heart failure severity, and its reduction could indicate improved cardiac function and patient outcomes. Additionally, during the extension period, the study aims to monitor the safety and tolerability of vericiguat, which is crucial for assessing the long-term use of the medication in this population.

Secondary objectives include: - Evaluating the efficacy of vericiguat compared with placebo on change in NT-proBNP from baseline to Week 52. - Assessing the efficacy of vericiguat in reducing the risk of the composite of cardiovascular death, heart failure hospitalization, or worsening of heart failure without hospitalization. - Evaluating the safety and tolerability of vericiguat compared with placebo. - Assessing the pharmacokinetics of vericiguat. - Evaluating change in NT-proBNP from baseline of the extension period to Week 16 of the extension period.

The clinical trial involves a total of **209 participants** diagnosed with **heart failure due to systemic left ventricular systolic dysfunction**. The study population includes both male and female subjects, ranging in age from over 28 days to under 18 years, with a minimum weight requirement of 3 kg. Participants were selected based on their symptomatic chronic heart failure resulting from systemic left ventricular systolic dysfunction, biventricular physiology, and a left ventricular ejection fraction of less than 45% assessed within three months prior to randomization. All participants are required to be on stable medical therapy for heart failure. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Female participants must not be pregnant or breastfeeding and must adhere to effective contraceptive methods if of childbearing potential. The trial aims to compare the efficacy of vericiguat versus placebo and monitor the safety and tolerability of vericiguat over an extended period.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and pharmacokinetics of **vericiguat** in pediatric participants with heart failure due to systemic left ventricular systolic dysfunction. The trial is structured into two periods: a base period and an extension period. The primary objective during the base period is to compare the efficacy of vericiguat versus placebo on the change in NT-proBNP from baseline to Week 16. The extension period focuses on monitoring the safety and tolerability of vericiguat. The trial is expected to conclude by April 2030, with recruitment having commenced in February 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as symptomatic chronic heart failure, biventricular physiology, and a left ventricular ejection fraction of less than 45%. Eligible participants will be randomized to receive either vericiguat or placebo. The base period will include regular follow-up visits to monitor changes in NT-proBNP and assess any adverse events. The extension period will continue to evaluate safety and efficacy, with a final end-of-study visit to conclude the participant's involvement.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including the occurrence of adverse events or withdrawal of consent. Participants must meet specific inclusion criteria, such as being between 28 days and 18 years of age, weighing at least 3 kg, and not being pregnant or breastfeeding. The study will ensure that participants are on stable medical therapy for heart failure and have completed the necessary baseline assessments. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results.

The clinical trial involves the administration of **Vericiguat**, a pharmaceutical product developed by Merck & Co. Inc. The active substance, vericiguat, is of chemical origin and is presented in various pharmaceutical forms, including tablets and oral suspension. The tablets are available in dosages of 2.5 mg, 5 mg, and 10 mg, while the oral suspension is formulated for pediatric use. The maximum daily dose of vericiguat is 10 mg, with a total maximum dose of 3505 mg over the treatment period. The treatment duration can extend up to 52 weeks, depending on the formulation. The route of administration for all forms is oral. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

A placebo is also utilized in this study, designed to match the vericiguat tablets and oral suspension in appearance but lacking the active ingredient. The placebo serves as a comparator to evaluate the efficacy and safety of vericiguat. Participants are randomly assigned to receive either the active treatment or the placebo, maintaining the double-blind nature of the trial. The placebo is administered following the same schedule and route as the active treatment to ensure consistency in the study design.

The efficacy of **Vericiguat** in the clinical trial will be assessed primarily by evaluating the change in n-terminal pro-brain natriuretic peptide (NT-proBNP) levels from baseline to Week 16. This parameter serves as a biomarker for heart failure severity and will be log-transformed for analysis. The primary endpoint for the base period is the change in NT-proBNP, while the extension period will focus on safety and tolerability, including the percentage of participants experiencing adverse events or discontinuing the study drug due to adverse events.

Secondary endpoints include the change in NT-proBNP from baseline to Week 52, time to first event of cardiovascular death, heart failure hospitalization, or worsening heart failure without hospitalization. Additional pharmacokinetic parameters such as the area under the curve (AUC0-24) of plasma vericiguat, half-life (t1/2), and oral clearance (CL/F) will also be measured. These assessments will be conducted at specified time points throughout the trial to ensure comprehensive evaluation of the drug's efficacy and safety profile.