Study to Gather Information About Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following a Recent Non Cardioembolic Ischemic Stroke Which Occurs When a Blood Clot Has Formed Somewhere in the Human Body (But Not in the Heart) Travelled to the Brain.

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 antiplatelet therapy in patients following a recent non cardioembolic ischemic stroke which occurs when a blood clot that has not formed in the heart travelled to the brain. 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 Efficacy and Safety of BAY2433334 in Patients Following an Acute Non-cardioembolic Ischemic Stroke

Conditions
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Acute Non-cardioembolic Ischemic Stroke

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: Participant must be 45 years of age and older at the time of signing the informed consent Non-cardioembolic ischemic stroke with persistent signs and symptoms of stroke lasting for ≥ 24 hours OR acute brain infarction documented by computed tomography (CT) or MRI AND with the intention to be treated with antiplatelet therapy during the study conduct Imaging of brain (CT or MRI) ruling out hemorrhagic stroke or another pathology that could explain symptoms (e.g. brain tumor, abscess, vascular malformation) Severity of index event nearest the time of randomization: Part A: minor stroke (defined as National Institutes of Health Stroke Scale (NIHSS) ≤ 7) can be enrolled Part B: participants with minor or moderate stroke and NIHSS ≤ 15 can be enrolled. Participants undergoing thrombolysis or endovascular therapy (mechanical thrombectomy) can be enrolled but at the earliest 24 hours after the intervention Randomization within 48 hours after the onset of symptoms of the index event (or after patients were last known to be without symptoms in case of wake-up stroke) Ability to conduct an MRI either before randomization or within 72 hours after randomization Exclusion Criteria: Prior ischemic stroke within last 30 days of index event History of atrial fibrillation or suspicion of cardioembolic source of stroke Dysphagia with inability to safely swallow study medication Contraindication to perform brain MRI Part A only: thrombolysis or endovascular therapy (mechanical thrombectomy) performed for index event Active bleeding; known bleeding disorder, history of major bleeding (intracranial, retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 months of randomization.

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: BAY2433334 high dose<br> | Drug: BAY2433334<br>* Tablet, taken orally once a day.<br>|
| Experimental: BAY2433334 medium dose<br> | Drug: BAY2433334<br>* Tablet, taken orally once a day.<br>|
| Experimental: BAY2433334 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 Symptomatic Ischemic Stroke or Covert Brain Infarcts Detected by Magnetic Resonance Imaging (MRI) | Ischemic stroke was defined as either of : 1) Rapid onset (or present on awakening) of a new focal neurological deficit with clinical (>24 hours symptoms/signs) or imaging evidence of infarction that was not attributable to a non-ischemic cause; 2) Acute worsening of an existing focal neurological deficit that was judged to be attributable to a new infarction or extension of the previous infarction in the same vascular territory, based on persisting symptoms/signs or imaging evidence of infarction and no evidence of a non-ischemic etiology. If imaging was inconclusive, persistent symptoms/signs must be significant (worsening of NIHSS score of 4 or more) and sustained (duration of ≥24 hours or until death). Covert brain infarcts were defined as incident infarcts detected by serial MRI in the absence of an adjudicated stroke consistent with the location of the infarct. MRI criteria for brain infarction were available in the MRI procedures manual. | From baseline up to 26 weeks | 
| Safety-Number of Participants With Composite of International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding and Clinically Relevant Non-major (CRNM) Bleeding | ISTH Major Bleeding criteria: 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, pericardial, retroperitoneal, intraarticular, or intramuscular with compartment syndrome), and/or 3. Clinically overt bleeding associated with a recent decrease in the hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value available before the event, and/or 4. Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. ISTH Clinically Relevant Non-Major Bleeding is considered any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of the following criteria 1. requiring medical intervention by a healthcare professional. 2. leading to hospitalization or increased level of care. 3. prompting a face to face (i.e. not just a telephone or electronic communication) evaluation. | From baseline up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy-Number of Participants With Composite of Symptomatic Ischemic Stroke and Covert Brain Infarcts Detected by MRI, Cardiovascular (CV) Death, Myocardial Infarction (MI) and Systemic Embolism. | 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. According to MI Universal Definition from 2018 the diagnosis of MI required the combination of: 1) Presence of acute myocardial injury, and 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. Systemic embolism was defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (this did not include thromboembolism of the pulmonary vasculature or venous thrombosis). | From baseline up to 26 weeks | 
| Efficacy-Number of Participants With Symptomatic Ischemic Stroke | Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. | From baseline up to 52 weeks | 
| Efficacy-Number of Participants With Covert Brain Infarcts Detected by MRI | Definition of covert brain infarcts can be referred to first Primary endpoint. | From baseline up to 26 weeks | 
| Efficacy-Number of Participants With Symptomatic Ischemic Stroke, CV Death, MI | Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. Definition of CV death and MI can be referred to first Second endpoint. | From baseline up to 52 weeks | 
| Efficacy-Number of Participants With Symptomatic Ischemic and Hemorrhagic Stroke | Definition of symptomatic ischemic can be referred to fourth secondary endpoint. Hemorrhagic stroke was defined as an acute, atraumatic extravasation of blood into the brain parenchyma, intraventricular or subarachnoid space with associated neurological symptoms. This did not include microbleeds or hemorrhagic transformation of an ischemic stroke. | From baseline up to 52 weeks | 
| Efficacy-Number of Participants With Disabling Stroke (mRS≥4) | Modified ranking score (mRS): 0-No symptoms at all; 1-No significant disability despite symptoms; despite symptoms, able to carry out all usual duties and activities; 2-Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance; 3-Moderate disability; requiring some help, but able to walk without assistance; 4-Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6-Death. | 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 ISTH Major Bleeding | Definition of ISTH major bleeding can be referred to second Primary endpoint. | From baseline up to 52 weeks | 
| Safety-Number of Participants With ISTH CRNM Bleeding | Definition of ISTH CRNM bleeding can be referred to second Primary endpoint. | From baseline up to 52 weeks | 
| Safety-Number of Participants With ISTH Minor Bleeding | All other overt bleeding episodes not meeting the above criteria for ISTH major or CRNM bleeding were classified as minor bleeding (e.g. bleeding from a minor wound that does not prompt a face-to-face evaluation for a physical examination or laboratory testing). | From baseline up to 52 weeks | 
| Safety-Number of Participants With Intracerebral Hemorrhage (Non-traumatic) | Non-traumatic intracerebral hemorrhage was defined as a hemorrhagic stroke on the recurrent stroke CRF page that is in addition classified as a bleeding with bleeding site intracranial (-subarachnoid, -intraparenchymal [excluding microbleeds], or -intraventricular) and spontaneous causality of bleeding, excluding all symptomatic and hemorrhagic transformation (defined by the PT hemorrhagic transformation). | From baseline up to 52 weeks |