Phase 3 Randomized Study Comparing Asundexian and Apixaban for Stroke Prevention in Atrial Fibrillation Patients at Risk

The primary objective of this study is to demonstrate that **asundexian** is superior, or at least non-inferior, to **apixaban** in the prevention of stroke and systemic embolism in participants with **atrial fibrillation** at risk for stroke. Additionally, the study aims to establish the superiority of asundexian over apixaban in terms of major bleeding as assessed by the International Society on Thrombosis and Hemostasis (ISTH) criteria, as well as in terms of overall benefit and risk. This is clinically relevant as it addresses the need for effective and safer anticoagulant options for patients with atrial fibrillation, a condition associated with a high risk of stroke.

Secondary objectives include:

• Comparing the effects of asundexian and apixaban with respect to composite and individual efficacy endpoints.
• Comparing asundexian and apixaban with respect to composite and individual bleeding endpoints.
• Comparing the benefit and risk of asundexian and apixaban with respect to a composite of efficacy and safety endpoints.

The clinical trial involves a total of **7882 participants** who are being studied for the **prevention of stroke or systemic embolism in atrial fibrillation**. The study population includes both male and female subjects, aged **18 years or older**, with documented atrial fibrillation requiring indefinite treatment with an oral anticoagulant. Participants were selected based on specific criteria, including a CHA2DS2-VASc score of **>=3 if male or >=4 if female**, or a score of 2 if male or 3 if female with additional enrichment criteria. The trial includes a vulnerable population, indicating that special considerations are in place for their participation. The selection process ensures a diverse representation of individuals at risk for stroke, with no specific lifestyle considerations such as diet or physical activity mentioned. The trial aims to assess the efficacy and safety of asundexian compared to apixaban in this population.

The clinical trial is designed as a **randomized**, double-blind, double-dummy, parallel-group, Phase 3 study to evaluate the efficacy and safety of the oral FXIa inhibitor **asundexian** (BAY 2433334) compared to **apixaban** for the prevention of stroke or systemic embolism in participants with **atrial fibrillation** at risk for stroke. The trial involves two arms, with participants receiving either the test product or the comparator, along with their respective placebos, to maintain blinding. The study is expected to run from December 2022 to August 2025, with participant involvement lasting up to 33 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older) and documented atrial fibrillation with an indication for indefinite oral anticoagulant treatment. The CHA2DS2-VASc score will also be assessed to determine stroke risk. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including the time to first occurrence of composite endpoints such as stroke, systemic embolism, or major bleeding as defined by the International Society on Thrombosis and Hemostasis (ISTH). The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The primary endpoints focus on the time to first occurrence of stroke or systemic embolism, ISTH major bleeding, and a composite of these events. Secondary endpoints include time to first occurrence of ischemic stroke, all-cause mortality, cardiovascular death, and various bleeding events. The trial aims to demonstrate the superiority or at least non-inferiority of asundexian compared to apixaban in terms of both efficacy and safety.

The clinical trial involves the administration of **BAY 2433334**, a film-coated tablet containing the active substance **asundexian**. This investigational medication is provided by Bayer AG and is administered orally. The maximum daily dose is 50 mg, with a total maximum dose of 50,000 mg over a treatment period of 33 days. The pharmaceutical form is a film-coated tablet, and the medication is classified as a chemical substance. Participant compliance with the dosing schedule is monitored throughout the trial.

**Eliquis 5 mg film-coated tablets** are used as a comparator in the study. The active substance in these tablets is **apixaban**, provided by Bristol-Myers Squibb/Pfizer EEIG. The tablets are administered orally, with a maximum daily dose of 10 mg and a total maximum dose of 10,000 mg over 33 days. The tablets are repackaged and relabeled for the trial, and participant adherence to the dosing regimen is closely monitored.

Additionally, **Eliquis 2.5 mg film-coated tablets** are included as another comparator. These tablets also contain **apixaban** and are provided by Bristol-Myers Squibb/Pfizer EEIG. The administration route is oral, with a maximum daily dose of 5 mg and a total maximum dose of 5,000 mg over the same treatment period of 33 days. The tablets are similarly repackaged and relabeled, and compliance is tracked throughout the study.

The trial also includes a **placebo** for the comparator product Apixaban 5 mg. This placebo is used to maintain the double-blind nature of the study. The pharmaceutical form and administration details are not specified, but it is implied that the placebo is administered in a manner consistent with the active comparator to ensure blinding.

Another **placebo** is used for the test product BAY 2433334. This placebo is similarly employed to preserve the study's double-blind design. As with the other placebo, specific details regarding the pharmaceutical form and administration are not provided, but it is assumed to be consistent with the active test product.

Lastly, a **placebo** for the comparator product Apixaban 2.5 mg is included. This placebo serves the same purpose as the others, ensuring that the study remains double-blind. The administration details are not explicitly stated, but it is expected to mimic the active comparator's administration to maintain blinding.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the time to the first occurrence of a composite of stroke or systemic embolism, the time to the first occurrence of **International Society on Thrombosis and Hemostasis (ISTH)** major bleeding, and the time to the first occurrence of a composite of stroke, systemic embolism, or ISTH major bleeding. These endpoints are designed to evaluate the effectiveness of the oral FXIa inhibitor asundexian (BAY 2433334) compared to apixaban in preventing stroke or systemic embolism in participants with atrial fibrillation at risk for stroke.

Secondary endpoints will further assess the efficacy by measuring the time to the first occurrence of various events, including ischemic stroke, all-cause mortality, cardiovascular death, and a composite of cardiovascular death, stroke, or myocardial infarction. Additional secondary endpoints include the time to the first occurrence of clinically relevant non-major bleeding, hemorrhagic stroke, intracranial hemorrhage, fatal bleeding, minor bleeding, and a composite of stroke, systemic embolism, ISTH major bleeding, or all-cause mortality. The trial will also evaluate the time to the first occurrence of a composite of disabling stroke, critical bleeding, or all-cause mortality. These endpoints will be measured and analyzed to determine the comparative benefit and risk of asundexian versus apixaban in the specified patient population.