Clinical trial NCT05532046: A Study to Learn How Safe Study Drug BAY2413555 is, How it Affects the Body, and How it Moves Into, Through, and Out of the Body Over 4 Weeks of Use in Participants With Heart Failure and Implanted Cardiac Defibrillator or Cardiac Resynchronization Devices (ICD/CRT)
Official title: A Phase 1b Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Titration Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 4 Weeks Treatment With BAY 2413555 in Participants With Heart Failure and Implanted Cardiac Defibrillator or Cardiac Resynchronization Devices
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Chronic Heart Failure
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2022-09-08
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Researchers are looking for a better way to treat people who have chronic heart failure. Chronic heart failure is a medical condition with shortness of breath, tiredness and ankle swelling in which the heart does not pump blood as well as it should.

BAY2413555 is a new compound which is under development for the treatment of heart failure. Heart failure is a serious disease in which the heart pumps less well. BAY2413555 is expected to protect the heart and improve cardiac function.

The main purpose of this study is to learn how safe BAY2413555 is compared to placebo in participants with chronic heart failure and implanted cardiac defibrillator, or cardiac resynchronization devices (ICD/CRT). A placebo is a treatment that looks like a medicine, but does not have any medicine in it. ICD/CRT are machines placed in the body that use an electric shock/impulse to reset the heart or get it beating correctly. To study the safety, the researchers will record all medical problems the participants may have during the study after starting the study treatment. Medical problems that happen after the participants have started their treatment are also known as "treatment emergent adverse events" (TEAEs). The TEAEs will be compared between participants who received BAY2413555 and those who received placebo.

The second purpose of this study is to learn whether BAY2413555 effects electrical signals inside the heart compared to placebo.

The study has two parts, A and B. Each part will last for two weeks. In part A, the participants will be assigned by chance to either take BAY2413555 as a tablet by mouth once per day or a placebo. Participants from part A who do not need to stop the study based on predefined criteria continue in part B. They will be assigned by chance to receive either the same dose of BAY2413555 as in part A or a higher dose. Participants who have taken placebo in part A will as well be assigned in part B.

Each participant will be in the study for approximately 90 days (including the screening period and follow-up period). In the study, participants will take study medication for 28 days. 8 visits to the study site and 1 telephone contact visit are planned. During the study, the study team will:

* do physical examinations
* check vital signs
* examine heart health using ECG
* check the participants' ICD/CRT information
* take exercise testing
* take blood and urine samples
* ask the participants questions about how they are feeling about their quality of life
* ask the participants questions about how they are feeling and what adverse events they are having. An adverse event is any problem that happens during the trial. Doctors keep track of all adverse events that happen in trials, even if they do not think the adverse events might be related to the study treatments or a study procedure. Participants will be closely monitored during the entire study duration and site personnel will take action to mitigate any negative effect, if any, as appropriate.

About 30 days after the participants take their last treatment, the study doctors and their team will check the participants' health.


Eligibility criteria: Inclusion Criteria:

* Providing signed informed consent
* Diagnosis of heart failure lasting for at least 3 months, New York Heart Association (NYHA) functional class I-III prior to Visit 1
* Left ventricular ejection fraction (LVEF) ≤ 45% as documented by any imaging modality within the past 12 months prior to Visit 1
* Treatment with Guideline-Directed Medical Therapy Including with mandatory betablocker treatment with either Metoprolol, Carvedilol, Bisoprolol or Nebivolol on stable, highest individually tolerated dose for at least 2 weeks prior to Visit 1
* Implanted cardiac defibrillator (ICD) with pacemaker backup function OR cardiac resynchronization device (CRT)

  * first implantation at least 3 months prior to Visit 1

Exclusion Criteria:

* Permanent atrial fibrillation or other than Sinus rhythm at Visit 1
* History of higher degree atrioventricular (AV) block (Mobitz type II or third-degree AV block) within 4 weeks prior to Visit 1
* Indication for or planned procedure:

  * Planned cardiac surgery, carotid angioplasty or surgery, transcatheter aortic valve implantation (TAVI) or mitral valve clipping within 3 months starting from the Screening Visit
  * Percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or implantation of a cardiac resynchronization therapy defibrillator device indicated at Screening or planned within 3 months starting from the Screening Visit
  * Valvular Disease Repair indicated at Screening or planned within 3 months starting from the Screening Visit.
* Occurrence of any of the following within 4 weeks prior to Visit 1:

  * Myocardial infarction
  * Stroke or transient ischemic attack (TIA)
  * coronary artery bypass graft (CABG)
  * percutaneous coronary intervention (PCI)
  * Carotid angioplasty
  * Ablation therapy of atrial fibrillation or other rhythm abnormalities
* Heart rate (HR) \> 100 bpm at Screening Visit
* Restrictive, infiltrative or hypertrophic cardiomyopathy, constrictive pericarditis, acute myocarditis within 3 months prior to Visit 1
* Malignancy of the hematological system within 5 years prior to the Screening Visit
* Listed for heart transplantation and/or anticipated implantation of a ventricular assist device at the Screening Visit
* Hepatic insufficiency classified as Child-Pugh B or C at the Screening Visit
* Estimated (according to the investigator's judgement) inability to perform exercise testing
* Any of the following from the blood sample taken at the Screening Visit

  * Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m\^2 (calculated according to the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation)
  * Hemoglobin \< 11 g/dL
  * White blood cell (WBC) \< 3000/mm\^3
  * Thrombocytes \< 100 000/mm\^3
* Currently receiving or planned to receive dialysis or ultrafiltration
* Chronic obstructive pulmonary disease (COPD) Stage 3 or 4 (GOLD criteria), requiring treatment, or symptomatic asthma requiring current treatment
* Prior or concomitant therapy with cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors or inducers.

Relevant substances need to be discontinued

* at least 2 weeks before randomization for CYP3A4 inducers
* at least 5 half-lives before randomization for CYP3A4 inhibitors Restarting of these therapies is possible 28 days after last intake of study intervention. This criterion also applies to other inhibitors of CYP3A4, e.g., grapefruit.

Prior and concomitant therapy with amiodarone is allowed.

* Concomitant treatment with acetylcholine esterase inhibitors within 4 weeks prior to Visit 1
* Use of other investigational drugs. Previous (within 4 weeks, or 5 half-lives of the investigational drug, whichever is longer, prior to Visit 1) or concomitant participation in another clinical study with investigational medicinal product(s) or device(s)
* Life expectancy \< 6 months at the Screening Visit

Primary outcomes:
measure: Number of participants with treatment-emergent adverse events (TEAEs)
timeFrame: Up to 56 days
Secondary outcomes:
measure: Number of participants with higher degree atrioventricular (AV) blocks, symptomatic pauses/bradycardia
timeFrame: Up to 28 days
measure: Changes from baseline in resting heart rate (HR) after 2 and 4 weeks of dosing with BAY2413555
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Accel Research Sites - Atlanta Clinical Research Center
state: Georgia
city: Silver Spring
country: United States
facility: White Oak Medical Center
state: Maryland
city: Camp Hill
country: United States
facility: Capital Area Research, LLC
state: Pennsylvania
city: Hellerup
country: Denmark
facility: Capital Region | Gentofte Hospital - Cardiology Research
city: Odense C
country: Denmark
facility: Odense Universitetshospital, Hjertemedicinsk Amb.
city: Roskilde
country: Denmark
facility: Zealand University Hospital | Roskilde - Cardiology Department
city: Dresden
country: Germany
facility: Pratia | Klinische Forschung Dresden
state: Sachsen
city: Ashkelon
country: Israel
facility: Barzilai Ashkelon University Medical Center | Cardiology Department
city: Haifa
country: Israel
facility: Rambam Health Care Campus | Internal Medicine - Cardiology Department
city: Zefat
country: Israel
facility: Ziv Medical Center | Cardiology Department
city: Milano
country: Italy
facility: Humanitas Research Hospital | Cardio Center - Clinical, Interventional Cardiology and Coronary Care
state: Lombardia
city: Pisa
country: Italy
facility: Fondazione Toscana Gabriele Monasterio | Heart Hospital Gaetano Pasquinucci - Cardiology Department
state: Toscana
city: Babio - Beade
country: Spain
facility: Hospital Alvaro Cunqueiro | Cardiology Department
state: Pontevedra
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: Córdoba
country: Spain
facility: Junta de Andalucía | University Hospital Reina Sofia - Cardiology Department
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria | Cardiology Department
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
Study officials:
References: