A Double-Blind, Randomized, Placebo-Controlled Trial of Vericiguat in Patients with Heart Failure with Reduced Ejection Fraction (HFrEF) Using CardioMEMS™ HF System

The primary objective of the ARETHA trial is to investigate the effect of **vericiguat** in patients with **heart failure with reduced ejection fraction (HFrEF)**. This is clinically relevant as HFrEF is a condition characterized by the heart's inability to pump blood efficiently, leading to significant morbidity and mortality. Evaluating the efficacy of vericiguat could provide insights into potential therapeutic benefits for patients suffering from this condition.

Secondary objectives include evaluating the NT-proBNP reducing effect of vericiguat compared with placebo. NT-proBNP is a biomarker associated with heart failure severity, and its reduction could indicate improved cardiac function and patient outcomes.

The clinical trial focuses on patients diagnosed with **heart failure with reduced ejection fraction (HFrEF)**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a known chronic heart failure with a left ventricular ejection fraction of less than 45%, documented within the past 24 months. The trial does not involve a vulnerable population. Participants must have a CardioMEMS device implanted for clinical indication at least two weeks prior to the first visit and exhibit NYHA functional class II-IV symptoms. They should be on optimal and stable medical therapy for heart failure, with a systolic blood pressure of at least 100 mmHg and a diastolic pulmonary artery pressure greater than 15 mmHg on more than eight days in the last 14 days as recorded by the CardioMEMS system. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **vericiguat** in patients with heart failure with reduced ejection fraction (HFrEF). This is a randomized, double-blind, placebo-controlled trial, categorized as a phase IV clinical trial. The trial will involve the administration of Verquvo film-coated tablets in varying dosages (2.5 mg, 5 mg, and 10 mg) and a placebo, all administered orally. The primary objective is to assess the diastolic pulmonary artery pressure (dPAP) lowering effect of vericiguat compared to placebo, while the secondary objective is to evaluate the NT-proBNP reducing effect of vericiguat.

The trial is expected to commence recruitment on October 1, 2024, and conclude by January 30, 2026. Participants will be involved in the study for a maximum treatment period of up to 6 months, depending on the dosage group. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor the effects of the treatment, and an end-of-study visit to assess the overall outcomes. Participants must be 18 years or older, have a CardioMEMS device implanted for at least two weeks prior to the first visit, and meet specific criteria related to heart failure and blood pressure to be eligible for inclusion.

Participants may be withdrawn from the study if they experience adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial is classified as low-intervention due to the use of authorized medicinal products, ensuring a focus on safety and efficacy within the established treatment framework for heart failure. The trial's design and methodology are structured to provide robust data on the therapeutic potential of vericiguat in managing HFrEF, contributing valuable insights to the field of cardiology.

The clinical trial involves the administration of **Vericiguat**, an experimental medication, in the form of film-coated tablets. The trial includes three different dosages of Vericiguat: 2.5 mg, 5 mg, and 10 mg. Each dosage is provided as a film-coated tablet for oral administration. The 2.5 mg dosage is administered daily with a maximum treatment period of 6 weeks. The 5 mg dosage is also administered daily, with a maximum treatment period of 4 weeks. The 10 mg dosage is administered daily for a maximum treatment period of 2 weeks. The active substance in all Vericiguat tablets is chemically derived and is identified by the synonyms BAY 1021189 and MK-1242. The pharmaceutical form of these tablets is consistent across all dosages, ensuring uniformity in administration.

In addition to the experimental medication, a **placebo** is utilized as a comparator treatment in this double-blind, randomized, placebo-controlled trial. The placebo is provided in the form of a coated tablet, identical in appearance to the Vericiguat tablets, to maintain blinding. The placebo is administered orally, with a maximum daily dose of 10 mg and a maximum treatment period of 6 weeks. The placebo contains no active pharmaceutical ingredients and serves to evaluate the efficacy and safety of Vericiguat by comparison.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to investigate the effect of Vericiguat in patients with heart failure with reduced ejection fraction (HFrEF), utilizing the CardioMEMS™ HF System for patient monitoring. The study is conducted under the sponsorship of Bayer AG, with all substances being chemically derived and authorized for use within the European Union.

The efficacy of the clinical trial titled "ARETHA: cARdiomems vEriciguaT Heart fAilure" will be assessed through specific primary and secondary endpoints. The primary endpoint is to evaluate the diastolic pulmonary artery pressure (dPAP) lowering effect of **vericiguat** in comparison to placebo. The secondary endpoint involves assessing the NT-proBNP reducing effect of vericiguat compared with placebo. These endpoints will be measured using validated laboratory tests and patient-reported outcomes.

The trial will involve the administration of vericiguat in film-coated tablet form, with dosages of 2.5 mg, 5 mg, and 10 mg, as well as a placebo. The treatment period varies, with a maximum duration of 6 weeks for some dosages. The trial is designed as a double-blind, randomized, placebo-controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is categorized as a low-intervention clinical trial due to the use of authorized medicinal products, and it is classified as a phase IV clinical trial.