Clinical trial NCT06195930: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: HFrEF
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2024-01-08
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a multi-center, single arm, open label study of vericiguat initiation at 5 mg in HFrEF patients with EF \<45%. The total study duration is approximately 4 weeks, including a 2-week screening period and a 2-week treatment period .

Screening: Approximately 120 participants will be screened to achieve at least 100 participants who are assigned to study intervention and complete the treatment period of up to 2 weeks. Participants will undergo a screening visit to assess eligibility. Eligible participants must wait a mandatory 2 weeks before returning for Visit 1 in order to be clinically and hemodynamically stable.

Treatment: At Visit 1, participants will receive vericiguat 5 mg (on top of standard of care) with directions to take once daily for 2 weeks. Participants will return for a study visit (Visit 2) after 2 weeks of treatment.

Unscheduled visits may be utilized between Visits 1 and 2 at the discretion of the investigator for AE review and reporting.
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Evaluate the treatment tolerability defined as the number of participants completing the two-week 5 mg dose without discontinuation of study intervention
timeFrame: Day 1 to Day 14 (up to Day 18 if +4 days time window is used)
measure: 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
timeFrame: Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
Secondary outcomes:
measure: Any AE reported between Visit 1 and Visit 2.
timeFrame: Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
measure: Number of participants without AEs related to the study intervention between Visit 1 and Visit 2
timeFrame: Between Visit 1 (Day 1) and Visit 2 (Day 14 up to Day 18 if +4 days time window is used)
measure: Number of participants able to continuously take study intervention between Visit 1 and Visit 2 or to restart study intervention after any temporary interruption.
timeFrame: Day 14 up to Day 18 (if +4 days time window is used)
Other outcomes:
Locations:
city: Alexander City
country: United States
facility: Advanced Cardiovascular, LLC - Alexander City
state: Alabama
city: Richmond
country: United States
facility: Reid Physician Associates | Cardiology Department
state: Indiana
city: Baltimore
country: United States
facility: Ascension Saint Agnes Heart Care
state: Maryland
city: Saint Louis
country: United States
facility: St. Louis Heart & Vascular, PC
state: Missouri
city: New York
country: United States
facility: Chear Center LLC
state: New York
city: Buenos Aires
country: Argentina
facility: Centro de Investigacion y Prevencion Cardiovascular | Sede Recoleta
state: Ciudad Auton. De Buenos Aires
city: Caba
country: Argentina
facility: CEDIC Centro de Investigación Clínica | Buenos Aires, Argentina
state: Ciudad Auton. De Buenos Aires
city: Rosario
country: Argentina
facility: Consultorios Integrados Rosario | Instituto Medico de la Fundacion de Estudios Clinicos
state: Santa Fe
city: Corrientes
country: Argentina
facility: Instituto de Cardiologia de Corrientes Juana F. Cabral | Corrientes, Argentina
city: Santa Fe
country: Argentina
facility: Centro de Investigaciones Clinicas del Litoral | Santa Fe, Argentina
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Belgyógyaszati és Haematológiai Klinika, Kardiológia
city: Budapest
country: Hungary
facility: Eszak-Pesti Centrumkorhaz-Honvedkorhaz
city: Kaposvar
country: Hungary
facility: Somogy Varmegyei Kaposi Mor Oktato Korhaz
city: Pecs
country: Hungary
facility: Coromed Smo Kft
city: Szekesfehervar
country: Hungary
facility: Complex Rendelo Med Zrt.
city: Szekszard
country: Hungary
facility: Tolna Varmegyei Balassa Janos Korhaz
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
state: Lombardia
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
state: Lombardia
city: Milano
country: Italy
facility: IRCCS Centro Cardiologico Monzino
state: Lombardia
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: Lombardia
city: Chrzanow
country: Poland
facility: Malopolskie Centrum Sercowo-Naczyniowe PAKS
city: Katowice
country: Poland
facility: Vita Longa Sp. z o.o.
city: Krakow
country: Poland
facility: Centrum Medyczne Zdrowa
city: Lublin
country: Poland
facility: Clinical Best Solutions Sp. Z O.O. Sp.K.
city: Lublin
country: Poland
facility: NZOZ "Twoja Przychodnia" Sp. z o.o.
city: Piotrkow Trybunalski
country: Poland
facility: IRMED Osrodek Badan Klinicznych
city: Warszawa
country: Poland
facility: Clinical Best Solutions Sp. Z O.O. Sp.K.
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago de Compostela | Cardiology Department
state: A Coruña
city: Barcelona
country: Spain
facility: Hospital del Mar | Cardiology Department
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge | Bellvitge Biomedical Research Institute - Cardiology Department
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal | Cardiology - Research Unit
city: Madrid
country: Spain
facility: Hospital la Paz
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Lund
country: Sweden
facility: Capio Citykliniken - Hjartmottagning
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
Study officials:
References: