A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat (Atrial Fibrillation), and at Risk for Stroke

Study Overview
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Brief Summary
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Researchers are looking for a better way to treat people with atrial fibrillation and prevent stroke or systemic embolism (blood clots travelling through the blood stream to plug another vessel). Atrial fibrillation is a condition of having irregular and often rapid heartbeat. It can lead to the formation of blood clots in the heart which can travel through the blood stream to plug another vessel, and like this lead to serious and life-threatening conditions, such as a stroke. A stroke occurs because the brain tissue beyond the blockage no longer receives nutrients and oxygen so that brain cells die. As strokes arising from atrial fibrillation can involve extensive areas of the brain, it is important to prevent them. Blood clots are formed in a process known as coagulation. Medications are already available to prevent the formation of blood clots. When taken by mouth (orally), they are known as oral anticoagulants (OACs) including apixaban. OACs decrease the risk of the above-mentioned serious and life-threatening conditions. The main side effect of OACs is an increase of the risk of bleeding. The study treatment asundexian is a new type of anticoagulant currently under development to provide further treatment options. Asundexian aims to further improve the standard of care with regard to the risk of bleeding. The main purpose of this study is to collect more data about how well asundexian works to prevent stroke and systemic embolism and how safe it is compared to apixaban in people with atrial fibrillation and at high risk for stroke. To see how well the study treatment asundexian works researchers compare: how long asundexian works well and how long apixaban works well after the start of the treatment. Working well means that the treatments can prevent the following from happening: stroke and/or systemic embolism. The study will keep collecting data until a certain number of strokes or embolisms happen in the study. To see how safe asundexian is, the researchers will compare how often major bleedings occur after taking the study treatments asundexian and apixaban, respectively. Major bleedings are bleedings that have a serious or even life-threatening impact on a person's health. The study participants will be randomly (by chance) assigned to 1 of 2 treatment groups, A and B. Dependent on the treatment group, the participants will either take the study treatment asundexian by mouth once a day or apixaban by mouth twice a day for approximately 9 - 33 months. Each participant will be in the study for approximately 9 - 34 months. There will be visits to the study site every 3 to 6 months and up to 7 phone calls. Those participants who do not want or are unable to have visits to the study site may join the study remotely in selected locations. The location name contains the abbreviation - DCT in such cases. During the study, the study team will: take blood samples do physical examinations examine heart health using an electrocardiogram (ECG) check vital signs such as blood pressure and heart rate do pregnancy tests ask the participants questions 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 medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.

Official Title
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A Multicenter, International, Randomized, Active Comparator-controlled, Double-blind, Double-dummy, Parallel-group, 2-arm, Phase 3 Study to Compare the Efficacy and Safety of the Oral FXIa Inhibitor Asundexian (BAY 2433334) With Apixaban for the Prevention of Stroke or Systemic Embolism in Male and Female Participants Aged 18 Years and Older With Atrial Fibrillation at Risk for Stroke

Conditions
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Prevention of Stroke or Systemic Embolism, Atrial Fibrillation

Intervention / Treatment
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* Drug: Asundexian (BAY2433334)
* Drug: Apixaban
* Drug: Asundexian matching placebo
* Drug: Apixaban matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older (at legal age of consent according to local legislation) at the time of signing the informed consent Atrial fibrillation documented by ECG evidence with an indication for indefinite treatment with an oral anticoagulant CHA2DS2-VASc score ≥ 3 if male or ≥ 4 if female, OR CHA2DS2-VASc score of 2 if male or 3 if female and enrichment criteria. Exclusion Criteria: Mechanical heart valve prosthesis Moderate-to-severe mitral stenosis at the time of inclusion into the study Atrial fibrillation only due to reversible cause Requirement for chronic anticoagulation for a different indication than AF

Ages Eligible for Study
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Minimum Age: 18 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: Asundexian<br>Participants will receive asundexian and apixaban matching placebo. | Drug: Asundexian (BAY2433334)<br>* Once a day<br>Drug: Apixaban matching placebo<br>* Placebo to apixaban, twice a day<br>|
| Active Comparator: Apixaban<br>Participants will receive apixaban and asundexian matching placebo. | Drug: Apixaban<br>* 5 mg or 2.5 mg, twice a day, according to product label.<br>Drug: Asundexian matching placebo<br>* Placebo to asundexian, once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of composite of stroke or systemic embolism |  | Up to 34 months | 
| Time to first occurrence of ISTH major bleeding | ISTH = International Society on Thrombosis and Hemostasis | Up to 34 months | 
| Time to first occurrence of composite of stroke, systemic embolism, or ISTH major bleeding |  | Up to 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of composite of ischemic stroke or systemic embolism |  | Up to 34 months | 
| Time to first occurrence of all-cause mortality |  | Up to 34 months | 
| Time to first occurrence of ischemic stroke |  | Up to 34 months | 
| Time to first occurrence of CV death | CV = cardiovascular | Up to 34 months | 
| Time to first occurrence of composite of CV death, stroke, or myocardial infarction |  | Up to 34 months | 
| Time to first occurrence of composite of ISTH major or clinically relevant non-major bleeding |  | Up to 34 months | 
| Time to first occurrence of clinically relevant non-major bleeding |  | Up to 34 months | 
| Time to first occurrence of hemorrhagic stroke |  | Up to 34 months | 
| Time to first occurrence of intracranial hemorrhage |  | Up to 34 months | 
| Time to first occurrence of fatal bleeding |  | Up to 34 months | 
| Time to first occurrence of minor bleeding |  | Up to 34 months | 
| Time to first occurrence of composite of stroke, systemic embolism, ISTH major bleeding, or all-cause mortality |  | Up to 34 months | 
| Time to first occurrence of composite of disabling stroke (mRS ≥ 3), critical bleeding, or all-cause mortality | mRS = modified Rankin Scale | Up to 34 months |