A Phase 3, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Demonstrate the Efficacy and Safety of Milvexian, an Oral Factor XIa Inhibitor, for Stroke Prevention after an Acute Ischemic Stroke or High-Risk Transient Ischemic Attack

The primary objective of this study is to evaluate if **milvexian** reduces the risk of ischemic stroke compared with placebo. This is clinically relevant as ischemic stroke is a significant cause of morbidity and mortality, and effective prevention strategies are crucial for improving patient outcomes.

Secondary objectives include: - Evaluating if milvexian reduces the risk of cardiovascular disease (CVD), myocardial infarction (MI), or ischemic stroke compared with placebo. - Assessing if milvexian reduces the risk of ischemic stroke in the first 90 days compared with placebo. - Determining if milvexian reduces the risk of major adverse vascular events (MAVE), which include the composite of CVD, MI, ischemic stroke, major adverse limb events (MALE) such as major nontraumatic vascular limb amputation or acute limb ischemia, symptomatic pulmonary embolism (PE), or deep vein thrombosis (DVT) compared with placebo.

The clinical trial involves a total of **8619 participants** who are being studied to evaluate the efficacy of milvexian in reducing the risk of ischemic stroke compared to a placebo. The study population includes both **male and female subjects** aged 40 years and older, who have experienced an **Acute Ischemic Stroke** or a high-risk Transient Ischemic Attack. Participants were selected based on specific criteria, including a neurological deficit attributable to an acute brain infarction with an NIHSS score of 7 or less, or a high ABCD2 Score of 6 or more for TIA cases. The trial includes individuals who have undergone thrombolysis or thrombectomy, provided certain conditions are met, such as the exclusion of cerebral bleeding on post-treatment neuroimaging. Participants are required to be on current or planned antiplatelet treatment as per international or local guidelines, with specific limitations on ASA dosage. Female participants of childbearing potential must practice a highly effective method of contraception. The trial population is considered vulnerable, and the selection process ensures that participants meet the necessary health and treatment criteria to be included in the study.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, placebo-controlled study to evaluate the efficacy and safety of **Milvexian**, an oral Factor XIa inhibitor, for stroke prevention following an **acute ischemic stroke** or high-risk transient ischemic attack. The primary objective is to assess whether Milvexian reduces the risk of ischemic stroke compared to placebo. The trial is expected to run from July 2023 to November 2026, with participants involved for a maximum treatment period of 41 days.

Participants will be screened based on specific inclusion criteria, such as being 40 years or older and having experienced an ischemic stroke or transient ischemic attack with certain clinical characteristics. Randomization will occur within 48 hours of the onset of the event, or within 48 hours from the last known normal state if the stroke was evident upon awakening. The study will include a placebo group and will involve the administration of Milvexian, Clopidogrel, and Acetylsalicylic Acid, all in oral form.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by randomization and baseline assessments. Participants will then attend regular follow-up visits to monitor safety and efficacy outcomes, with the primary endpoint being the time to the first occurrence of ischemic stroke. Secondary endpoints include the time to the first occurrence of any component of the composite of cardiovascular death, myocardial infarction, or ischemic stroke, among others. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining safety assessments are completed.

Participant involvement is expected to last up to 41 days, with conditions for early termination including adverse events, withdrawal of consent, or protocol non-compliance. The trial will adhere to international and local guidelines for antiplatelet treatment, with specific dosing regimens for each medicinal product involved. The study aims to provide robust data on the potential benefits of Milvexian in reducing the risk of recurrent ischemic events in the specified patient population.

The clinical trial involves the administration of **Milvexian**, an oral Factor XIa inhibitor, under the product name JNJ-70033093. This investigational medication is provided in the form of a film-coated tablet. The active substance, **Milvexian**, is chemically derived and is administered orally. The maximum daily dose is 50 mg, with a total maximum dose of 62,300 mg over a treatment period of up to 41 days. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, a **Milvexian matching placebo** is utilized in the study. The placebo is designed to mimic the appearance and administration route of the active treatment, ensuring the double-blind nature of the trial. The placebo is administered orally, with the same frequency and schedule as the active treatment, to maintain consistency in the study protocol.

**Clopidogrel** is used as an auxiliary treatment in the trial. It is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose of Clopidogrel is 75 mg, with a total maximum dose of 1,875 mg over a treatment period of up to 21 days. This medication is included to provide standard-of-care therapy for participants, and its administration is carefully monitored to ensure adherence to the prescribed dosing regimen.

Another auxiliary treatment used in the study is **Acetylsalicylic Acid**, commonly known as aspirin. This medication is provided in tablet form and is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 123,000 mg over a treatment period of up to 41 days. The inclusion of Acetylsalicylic Acid serves as a standard-of-care therapy, and participant compliance with the dosing schedule is closely monitored to ensure accurate data collection and analysis.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the time to the first occurrence of an **ischemic stroke**. Secondary endpoints include the time to the first occurrence of any component of the composite of cardiovascular death (CVD), myocardial infarction (MI), or ischemic stroke; the time to the first occurrence of ischemic stroke within the first 90 days; and the time to the first occurrence of any component of major adverse vascular events (MAVE), which includes the composite of CVD, MI, ischemic stroke, major adverse limb events (MALE), symptomatic pulmonary embolism (PE), or deep vein thrombosis (DVT).