Vericiguat Drug-drug Interaction Study With Isosorbite Mononitrate in Stable Coronary Artery Disease Patients

Study Overview
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Brief Summary
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This study is intended to investigate the pharmacodynamic drug-drug interaction as well as the safety and tolerability of isosorbite mononitrate and vericiguat in patients with stable coronary artery disease.

Official Title
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Multi-center, Randomized, Placebo-controlled, Double-blind Group Comparison Study to Investigate Safety, Tolerability and Blood Pressure of 2.5 mg, 5.0 mg and 10 mg Vericiguat Each Given Over 14 ± 3 Days Together With Isosorbite Mononitrate (ISMN) 60 mg Extended Release Formulation After a Pretreatment Phase (ISMN-starting Dose: 30 mg) in Stable Coronary Artery Disease (CAD) Patients With or Without Heart Failure Aged 30 to 80 Years - Vericiguat ISOsoRbite Mononitrate Interaction (VISOR) Study

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Vericiguat (BAY1021189)
* Drug: Placebo
* Drug: Isosorbide mononitrate (ISMN)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with stable CAD defined by coronary artery stenosis in any of the 3 main coronary vessels > 50% documented by coronary angiography within last 36 months or history of myocardial infarction Age: 30 to 80 years (inclusive) at the first screening examination Body mass index (BMI): above/equal 18.0 and below/equal 36.0 kg / m² Exclusion Criteria: Intervention e.g. revascularization by percutaneous coronary intervention (PCI) and/or coronary artery bypass graft (CABG) during the last 3 months Progressive angina with symptoms of worsening of angina within the < 3 months prior to the first screening examination History of recent (< 6 months prior to the first screening examination) myocardial infarction or unstable angina Symptomatic carotid stenosis, or transient ischemic attack or stroke within 3 months prior to the first screening examination or patients with stroke at more than 3 months prior to the first screening examination with significant residual neurologic involvement Insulin dependent diabetes mellitus Clinically relevant cardiac ischemia at screening Clinical significant persistent ischemia, which should be ruled out by clinical judgment of the investigator, based on medical history, available clinical data e.g. past angiograms or preexisting or current exercise testing with any imaging technique (e.g. dobutamine stress echocardiography, adenosine or dobutamine stress cardiac magnetic resonance imaging (CMR), scinthigraphy or exercise ECG) Atrial fibrillation, pacemaker, defibrillator, atrial ventricular (AV)-block II and III Systolic blood pressure below 110 or above 160 mmHg at first screening visit Diastolic blood pressure above 100 mmHg at first screening visit Heart rate below 50 or above 100 beats / min (taken from ECG measurement) at first screening visit Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m*2 at first screening visit

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vericiguat + isosorbite mononitrate<br>Subjects received Isosorbide mononitrate (ISMN) up-titration with 30 mg / 60 mg, about 7 days each,prior to start of vericiguat administration. Then subjects received 2.5 mg vericiguat for about 14 days, followed by 5 mg vericiguat for about 14 days, followed by 10 mg vericiguat for about 14 days together 60 mg ISMN od on each day of vericiguat administration, taken 1 hour prior to vericiguat (in-house days) or together with vericiguat (out-patient days). | Drug: Vericiguat (BAY1021189)<br>* 2.5 mg/tablet; 5 mg/tablet or 10 mg/tablet<br>Drug: Isosorbide mononitrate (ISMN)<br>* 30 mg/tablet or 60 mg/tablet<br>|
| Placebo Comparator: Placebo + isosorbite mononitrate<br>Subjects received Isosorbide mononitrate (ISMN) up-titration with 30 mg / 60 mg, about 7 days each, prior to start of placebo administration. Then subjects received placebo matching 2.5 mg vericiguat for about 14 days, followed by placebo matching 5 mg vericiguat for about 14 days, followed by placebo matching 10 mg vericiguat for about 14 days together 60 mg ISMN od on each day of placebo administration, taken 1 hour prior to placebo (in-house days) or together with placebo (out-patient days). | Drug: Placebo<br>* Matching placebo<br>Drug: Isosorbide mononitrate (ISMN)<br>* 30 mg/tablet or 60 mg/tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure | Regular measurements of blood pressure after a vericiguat administration on the first and on the last days of each dose step of vericiguat, and on the first days of ISMN up-titration. | Up to 8 weeks | 
| Heart rate | Regular measurements heart rate after a vericiguat administration on the first and on the last days of each dose step of vericiguat, and on the first days of ISMN up-titration. | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | Up to 9 weeks |