A Study to Learn How Safe Starting Vericiguat at a Dose of 5 Milligrams is in Participants With Chronic Heart Failure With Reduced Ejection Fraction

Chronic Heart Failure With Reduced Ejection Fraction Clinical Trial

Official title:

A Phase 2b Open-label Clinical Study to Evaluate the Tolerability and Safety of an Initiation Dose of 5 mg of Vericiguat in Participants With Chronic Heart Failure With Reduced Ejection Fraction

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06195930
• Other study ID #: 21683
• Secondary ID: 2023-507682-25-0
• Status: Recruiting
• Phase: Phase 2
• Start date: April 18, 2024
• Est. completion date: January 7, 2025

Study information

• Verified date: June 2024
• Source: Bayer
• Contact: Bayer Clinical Trials Contact
• Phone: (+)1-888-84 22937
• Email: clinical-trials-contact[@]bayer.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Researchers are looking for a better way to treat people who have chronic heart failure with reduced ejection fraction. Chronic heart failure with reduced ejection fraction (HFrEF) is a long-term condition that occurs when the heart is too weak to pump enough blood to the rest of the body. This results in a reduced supply of the oxygen that the body requires to function properly. The common symptoms of HFrEF include breathlessness, weakness, fatigue, and swelling in the ankles and legs. If left untreated, heart failure can lead to other serious health problems, including damage to other organs, which may result in hospital stays or even death.

Vericiguat is an approved drug for use in people with chronic HFrEF. It works by activating a protein called soluble guanylate cyclase, which helps dilating the blood vessels and in turn improves heart function.

Currently, treatment with vericiguat starts at a daily dose of 2.5 milligrams (mg), which increases to 5 mg after 2 weeks. The dose is then increased to the target dose of 10 mg after another 2 weeks.

In this study, researchers are trying to learn how well participants can tolerate and how safe it is to start vericiguat at a dose of 5 mg. Starting directly at the 5 mg dose is expected to help reach the target dose of 10 mg faster. Participants will take vericiguat 5 mg as a tablet by mouth once daily along with their regular heart medications.

At the start of the study, study doctors will check participants' medical history and perform full health check-ups to confirm if they can take part in the study. Throughout the study, study doctors will monitor participants' previous and current medications, their heart health, and their overall well-being. This will help researchers assess how safe the study drug is and if they experience adverse events. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events, irrespective of whether they think they are related to the study treatment.

Access to study treatment after the end of this study is not planned. Everyone, including study doctors and participants, will know what drug the participants receive during the study. Participants may be in the study for about 4 weeks.

Participants may not benefit from the treatment as the study is designed to assess safety and tolerability: the duration of the study is very short and participants will be taking a low dose of vericiguat without moving to the target dose of 10 mg during the study. However, the findings of this study may enable people with chronic HFrEF to safely skip one initial dosing step and reach the target dose of vericiguat faster.

Participants may experience medical problems such as low blood pressure, upset stomach, nausea, dizziness, and headache. Researchers will monitor and manage all these, and other, medical problems participants may have during the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: January 7, 2025
• Est. primary completion date: January 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has an Left ventricle ejection fraction (LVEF) of <45% assessed within 12 months before Visit 1 by local any imaging method, and no subsequent LVEF measurement > 45%. The most recent measurement must be used to determine eligibility.

• systolic blood pressure (SBP) = 100 mmHg at screening and Visit 1 (pre-treatment).

• No changes in guideline-directed medical therapy for heart failure (GDMT) dosing (including beta blockers, angiotensin-converting enzyme inhibitor/ angiotensin II receptor blocker (ACEI/ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRAs), hydralazine-nitrate combinations, sodium-glucose cotransporter 2 i(SGLT2) inhibitors, ivabradine, or oral diuretics):

• Within 4 weeks of screening for participants without a heart failure (HF) event =6 months prior to screening

• within 2 weeks of screening for participants with a HF event =6 months prior to screening

• planned during study participation

• No expected medical procedures to occur 2 weeks before screening or during study participation.

• Participants with ( group 1) OR without (group 2) recent worsening HF event Group 1:

History of chronic HF (NYHA class II symptomatic-IV) on GDMT with recent HFevent within 6 months of screening or outpatient IV / SC diuretic use within 3 months before screening.

OR Group 2: History of chronic HF (NYHA class II symptomatic-IV) on GDMT without recent HF event within 6 months of screening or outpatient intravenous/ subcutaneous (IV / SC) diuretic use within 3 months before screening.

Exclusion Criteria:

• History of symptomatic hypotension 4 weeks before screening

• Primary valvular heart disease requiring surgical procedure or intervention or has undergone a vascular surgical procedure or intervention within 3months before visit 1

• Hypertrophic cardiomyopathy

• Acute myocarditis or Takotsubo cardiomyopathy

• Awaiting heart transplantation (United Network for Organ Sharing Class 1A /1B or equivalent) or has or anticipates receiving an implanted ventricular assist device, or has received a heart transplant.

• Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia.

• Acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI), undergone coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within 3months before Visit 1, or indication for coronary revascularization at the time of treatment assignment.

• Symptomatic carotid stenosis, transient ischemic attack (TIA), or stroke within 3 months before Visit 1.

• History of repaired or unrepaired simple congenital heart disease (e.g., atrial or ventricular septal defects, or patent ductus arteriosus) with ongoing hemodynamically significant residual lesions, or any history of complex congenital heart disease (e.g. tetralogy of Fallot, transposition of the great arteries, single ventricle disease) regardless of repair status.

• Active endocarditis or constrictive pericarditis.

• Hemodynamic instability or hypovolemia within 4 weeks of screening and during the screening period.

• Currently hospitalized.

• estimated glomerular filtration rate (eGFR) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation of <15 mL/min/1.73 m2 within 30 days before Visit 1 or on chronic dialysis. For participants with multiple eGFR results during screening, the most recent value will be used to determine eligibility.

• Severe hepatic insufficiency defined as albumin to bilirubin ratio (ALBI) Grade 3 or hepatic encephalopathy, or has hepatic laboratory abnormalities (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =3 ×upper limit of normal (ULN) or total bilirubin =2 × ULN). Exceptions for Gilbert's syndrome will be considered. Albumin, ALT, AST, and total bilirubin results within 30 days before Visit 1 may be used for assessment of laboratory abnormalities or the calculation of the ALBI score. For participants with multiple albumin and/or total bilirubin results during screening, the most recent value for each test will be used to calculate ALBI score.

• Malignancy or other noncardiac condition limiting life expectancy to <3years.

• Requires continuous home oxygen for severe pulmonary disease.

• Interstitial lung disease.

• Known allergy or hypersensitivity to vericiguat, any of its constituents, or any other soluble guanylate cyclase (sGC) stimulator.

• Amyloidosis or sarcoidosis.

• Concurrent or anticipated concomitant use of phosphodiesterase type 5 (PDE5) inhibitors such as vardenafil, tadalafil, and sildenafil during the study.

• Concurrent use of an sGC stimulator such as riociguat or vericiguat.

• Prior (within 2 weeks prior to screening) or anticipated concomitant administration of IV / SC diuretics or inotropes.

Related Conditions & MeSH terms

• Chronic Heart Failure With Reduced Ejection Fraction
• Heart Failure

Intervention

Drug:
• Vericiguat (BAY1021189) 5 mg
Vericiguat (BAY1021189) will be taken as 5 mg tablet 1x daily over at least 14 days up to 18 days (+ 4 days time window allowed)

Locations

Country	Name	City	State
Argentina	Centro de Investigación y Prevención Cardiovascular	Buenos Aires	Ciudad Auton. De Buenos Aires
Argentina	Centro de Investigaciones Clínicas	Caba	Ciudad Auton. De Buenos Aires
Argentina	Inst. de Cardiología de Corrientes Juana Francisca Cabral	Corrientes
Argentina	Instituto Médico de la Fundación Estudios Clinicos	Rosario	Santa Fe
Argentina	Centro de Investigaciones Clinicas del Litoral	Santa Fe
Hungary	Eszak-Pesti Centrumkorhaz-Honvedkorhaz	Budapest
Hungary	Semmelweis Egyetem Belgyógyaszati és Haematológiai Klinika, Kardiológia	Budapest
Hungary	Somogy Varmegyei Kaposi Mor Oktato Korhaz	Kaposvar
Hungary	Coromed Smo Kft	Pecs
Hungary	Complex Rendelo Med Zrt.	Szekesfehervar
Hungary	Tolna Varmegyei Balassa Janos Korhaz	Szekszard
Italy	ASST Papa Giovanni XXIII	Bergamo	Lombardia
Italy	ASST Spedali Civili di Brescia	Brescia	Lombardia
Italy	IRCCS Centro Cardiologico Monzino	Milano	Lombardia
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia	Lombardia
Italy	Universita degli Studi di Roma "La Sapienza" - Umberto I Policlinico di Roma	Rome
Italy	Molinette Hospital University of Torino	Torino	Piemonte
Poland	Malopolskie Centrum Sercowo-Naczyniowe PAKS	Chrzanow
Poland	Vita Longa Sp. z o.o.	Katowice
Poland	Centrum Medyczne Zdrowa	Krakow
Poland	NZOZ "Twoja Przychodnia" Sp. z o.o.	Lublin
Poland	IRMED Osrodek Badan Klinicznych	Piotrkow Trybunalski
Poland	Clinical Best Solutions Sp. Z O.O. Sp.K.	Warszawa
Spain	Hospital del Mar | Cardiology Department	Barcelona
Spain	Hospital Universitari de Bellvitge | Bellvitge Biomedical Research Institute - Cardiology Department	Barcelona
Spain	Hospital la Paz	Madrid
Spain	Hospital Ramon y Cajal | Cardiology - Research Unit	Madrid
Spain	Hospital Clinico Universitario de Santiago de Compostela | Cardiology Department	Santiago de Compostela	A Coruña
Spain	Hospital Clínico Universitario de Valencia	Valencia
Sweden	Capio Citykliniken - Hjartmottagning	Lund
Sweden	Danderyds Sjukhus	Stockholm
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
United States	Advanced Cardiovascular, LLC - Alexander City	Alexander City	Alabama
United States	Ascension Saint Agnes Heart Care	Baltimore	Maryland
United States	Chear Center LLC	Bronx	New York
United States	Reid Physician Associates | Cardiology Department	Richmond	Indiana
United States	St. Louis Heart & Vascular, PC	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Hungary,  Italy,  Poland,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the treatment tolerability defined as the number of participants completing the two-week 5 mg dose without discontinuation of study intervention	In the 2-week treatment period, participants will take 5 mg of vericiguat once daily. In this outcome measure the treatment tolerability, defined as the completion of the two-week once daily 5 mg dose without discontinuation of study intervention is to be evaluated.	Day 1 to Day 14 (up to Day 18 if +4 days time window is used)
Primary	Evaluate the treatment tolerability defined as the number of participants completing the two-week 5 mg dose without moderate to severe hypotension between Visit 1 and Visit 2	In the 2-week treatment period, participants will take 5 mg of vericiguat once daily. In this outcome measure the treatment tolerability, defined as the completion of the two-week once daily 5 mg dose without moderate to severe symptomatic hypotension between Visit 1 and Visit 2 is to be evaluated. Symptomatic hypotension is an Adverse event of special interest as assessed by the investigator. Moderate and Severe are defined as follows: • Moderate: A type of adverse event that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant.; • Severe: A type of adverse event that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention.	Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
Secondary	Any AE reported between Visit 1 and Visit 2.	Any AE reported between Visit 1 and 2 to describe safety events of initiation of 5 mg dose	Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
Secondary	Number of participants without AEs related to the study intervention between Visit 1 and Visit 2	Absence of AEs related to study intervention between Visit 1 and Visit 2 to describe safety events of initiation of 5 mg dose	Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
Secondary	Number of participants able to continuously take study intervention between Visit 1 and Visit 2 or to restart study intervention after any temporary interruption.	To further evaluate the tolerability of 5 mg as a starting dose of vericiguat. The study intervention may be temporarily interrupted and then resumed unless the interruption was caused by symptomatic moderate to severe hypotension. In this case, resumption is not permitted.	Day 14 up to Day 18 (if +4 days time window is used)

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