Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Asundexian for Ischemic Stroke Prevention in Adults Post-Acute Non-Cardioembolic Stroke or High-Risk TIA

The primary objective of this study is to assess the **efficacy** of the oral FXIa inhibitor asundexian in comparison to placebo, when used in conjunction with background antiplatelet therapy, in reducing the incidence of ischemic stroke in patients who have experienced an acute non-cardioembolic ischemic stroke or a high-risk transient ischemic attack (TIA). This is clinically relevant as it aims to provide a potential therapeutic option for preventing recurrent strokes in a high-risk population.

Secondary objectives include: - **Efficacy**: To evaluate whether asundexian is superior to placebo in reducing the occurrence of composite and individual efficacy endpoints. - **Safety**: To compare asundexian and placebo with respect to individual bleeding endpoints. - **Net clinical benefit**: To further compare the benefit and risk of asundexian and placebo concerning a composite of efficacy and safety endpoints.

The clinical trial involves a total of **6785 participants** who are being studied for the **prevention of ischemic stroke** in patients post-acute non-cardioembolic ischemic stroke or high-risk transient ischemic attack. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have experienced an acute non-cardioembolic stroke or high-risk transient ischemic attack. Participants were selected based on the presence of systemic or cerebrovascular atherosclerosis or an acute non-lacunar infarct. The trial includes a vulnerable population, indicating that special considerations are in place for their protection. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are representative of the target population for the intervention being tested.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of the oral FXIa inhibitor **asundexian** in preventing **ischemic stroke** in patients who have experienced an acute non-cardioembolic ischemic stroke or a high-risk transient ischemic attack (TIA). The trial is structured as a Phase 3, parallel-group, event-driven study. The estimated duration of the trial is from January 26, 2023, to October 10, 2025, with participant involvement expected to last up to 31 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), recent acute non-cardioembolic stroke or high-risk TIA, and the presence of systemic or cerebrovascular atherosclerosis or acute non-lacunar infarct. Following successful screening, participants will be randomized to receive either asundexian or a placebo, both administered as film-coated tablets for oral use. The primary endpoints include the time to the first occurrence of ischemic stroke and the time to the first occurrence of ISTH major bleeding. Secondary endpoints encompass a range of cardiovascular and bleeding events.

Throughout the trial, participants will attend follow-up visits to monitor the occurrence of any primary or secondary endpoints and to ensure safety. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's decision to withdraw consent. The trial aims to provide robust data on the potential benefits and risks of asundexian in this patient population.

The clinical trial involves the administration of the experimental medication **BAY 2433334**, which is an oral FXIa inhibitor known as **asundexian**. This investigational product is provided in the form of a **film-coated tablet**. The dosage regimen for BAY 2433334 is set at a maximum daily dose of 50 mg, with a total maximum dose of 47,500 mg over a treatment period of up to 31 days. The route of administration is oral, and the medication is classified as a small molecule. The active substance, asundexian, is of chemical origin and is developed by Bayer AG. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled trial. The placebo is designed to match the test product BAY 2433334 in appearance and is administered orally in a similar pharmaceutical form. The use of a placebo allows for the assessment of the efficacy and safety of asundexian in reducing ischemic stroke events in patients who have experienced an acute non-cardioembolic ischemic stroke or high-risk transient ischemic attack (TIA). The trial also evaluates the incidence of major bleeding events as defined by the International Society on Thrombosis and Hemostasis (ISTH) criteria. The placebo serves as a control to ensure that any observed effects can be attributed to the active investigational product.

Efficacy in this clinical trial will be assessed by evaluating the superiority of the oral FXIa inhibitor **asundexian** over placebo in reducing ischemic stroke in patients who have experienced an acute non-cardioembolic ischemic stroke or high-risk transient ischemic attack (TIA). The primary endpoints for efficacy evaluation include the time to the first occurrence of ischemic stroke and the time to the first occurrence of International Society on Thrombosis and Hemostasis (ISTH) major bleeding. Secondary endpoints encompass a range of outcomes such as the time to the first occurrence of all strokes (ischemic and hemorrhagic), cardiovascular death, myocardial infarction, disabling stroke, all-cause mortality, transient ischemic attack, and various bleeding events.

The trial is designed as a multicenter, randomized, placebo-controlled, double-blind, parallel-group, and event-driven Phase 3 study. Efficacy parameters will be collected and analyzed at specified time points, with a focus on the time to the first occurrence of the defined events. The study will utilize validated clinical criteria and scales to measure these outcomes, ensuring the reliability and accuracy of the data collected. The trial aims to provide comprehensive insights into the efficacy of asundexian in preventing ischemic events in the specified patient population.