Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack

Study Overview
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Brief Summary
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The purpose of this study is to try to find the best dose of the new drug BAY 2433334 to give to participants and to look at how well BAY 2433334 works on top of a dual antiplatelet therapy (acetylsalicylic acid +/- clopidogrel) in patients following a recent heart attack (myocardial infarction) that happens when a blood vessel in the heart suddenly becomes blocked. BAY 2433334, works by blocking a step of the blood clotting process in our body and thins the blood and is a so called oral FXIa inhibitor.

Official Title
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Multicenter, Randomized, Placebo Controlled, Double-blind, Parallel Group, Dose-finding Phase 2 Study to Evaluate the Efficacy and Safety of BAY 2433334 in Patients Following an Acute Myocardial Infarction

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Drug: BAY2433334
* Other: BAY2433334 matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be 45 years of age or older, at the time of signing the informed consent Acute myocardial infarction (excluding MI associated with PCI or CABG revascularization procedures) with: clinical symptoms of acute myocardial infarction AND elevated biomarkers of myocardial necrosis (creatine kinase-muscle and brain isoenzyme [CK-MB] or cardiac troponins) AND at least one of the following risk factors need to be fulfilled: Age ≥ 65 years Prior MI (before the index AMI event) Prior peripheral arterial disease Diabetes Mellitus Prior coronary artery bypass grafting (CABG) AND initial angiography and revascularization procedures, either PCI or CABG, as treatment for the index event performed before randomization. (Note: a planned, staged PCI procedure can be performed after randomization) Plan for dual antiplatelet therapy (ASA + P2Y12 inhibitor) after hospital discharge for the index AMI Randomization during hospitalization for the index AMI event and latest within 5 days of hospital admission Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent has to be signed before any study-specific procedure. Exclusion Criteria: Hemodynamically significant ventricular arrhythmias or cardiogenic shock at time of randomization Active bleeding; known bleeding disorder, history of major bleeding (intracranial, retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 months of randomization Planned use or requirement of full dose and long term anticoagulation therapy during study conduct.

Ages Eligible for Study
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Minimum Age: 45 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: BAY 2433334 high dose<br> | Drug: BAY2433334<br>* Tablet, taken orally once a day.<br>|
| Experimental: BAY 2433334 medium dose<br> | Drug: BAY2433334<br>* Tablet, taken orally once a day.<br>|
| Experimental: BAY 2433334 low dose<br> | Drug: BAY2433334<br>* Tablet, taken orally once a day.<br>|
| Placebo Comparator: BAY2433334 matching placebo<br> | Other: BAY2433334 matching placebo<br>* Tablet, taken orally once a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) | CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause | From baseline up to 52 weeks | 
| Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 | Type 2: any overt, actionable sign of hemorrhage that doesn't fit the criteria for type 3 or 5 but meets at least one of the following criteria: 1) requires nonsurgical, med intervention by a HCP, 2) leads to hospital or rise in level of care, or 3) prompt eval. Type 3a: 1) overt bleed + Hg drop of 3 to <5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation. | From baseline up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Number of Participants With CV Death | CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. | From baseline up to 52 weeks | 
| Efficacy - Number of Participants With MI | Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. According to MI Universal Definition from 2018 the diagnosis of MI requires combination of: 1. Presence of acute myocardial injury. 2. Evidence of acute myocardial ischemia derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging, or in case of post-mortem pathological findings irrespective of biomarker values. | From baseline up to 52 weeks | 
| Efficacy - Number of Participants With Stroke | Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. | From baseline up to 52 weeks | 
| Efficacy - Number of Participants With Stent Thrombosis | ST was defined incorporating diagnostic certainty as well as timing: Definite ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. Probable ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause | From baseline up to 52 weeks | 
| Efficacy - Number of Participants With All Cause Mortality |  | From baseline up to 52 weeks | 
| Safety - Number of Participants With All Bleeding | All bleeding events occurred from first intake of study intervention until 2 days after the last intake of study intervention | From baseline up to 52 weeks | 
| Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 | Type 3a: 1) overt bleed + Hg drop of 3 to <5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation. | From baseline up to 52 weeks | 
| Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 | Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional. For BARC bleeding definition 2,3 and 5, please refer to second primary endpoint. | From baseline up to 52 weeks |