A Phase 3, Randomized, Double-Blind, Double-Dummy, Parallel Group, Active-Controlled Study to Evaluate the Efficacy and Safety of Milvexian, an Oral Factor XIa Inhibitor, Versus Apixaban in Participants with Atrial Fibrillation

The primary objective of this study is to evaluate if **milvexian** is non-inferior to **apixaban** for the composite of stroke and non-CNS systemic embolism in participants with **atrial fibrillation**. This is clinically relevant as it aims to establish milvexian as a potential alternative to apixaban, which is a widely used anticoagulant, thereby potentially offering more options for stroke prevention in this patient population.

Secondary objectives include:

• Evaluating if milvexian is superior to apixaban in reducing the risk of the principal safety endpoint family, which includes ISTH major bleeding and the composite of ISTH major and CRNM bleeding.
• Assessing if milvexian is superior to apixaban for the composite of cardiovascular (CV) death, myocardial infarction (MI), stroke, and non-CNS systemic embolism.
• Determining if milvexian is superior to apixaban as assessed by CV death.
• Evaluating if milvexian is superior to apixaban as assessed by the composite of all-cause death, MI, stroke, and non-CNS systemic embolism.
• Assessing if milvexian is superior to apixaban as evaluated by the composite of CV death, MI, stroke, acute limb ischemia (ALI), and urgent hospitalization for vascular causes of ischemic nature, including thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

The clinical trial involves a total of **10,710** participants diagnosed with **Atrial Fibrillation**. The study population includes both male and female subjects, with an age range starting from 18 years and encompassing older adults, particularly those aged 65 years and above. Participants are medically stable and suitable for chronic antithrombotic treatment. The trial population was selected based on specific risk factors, including age, history of stroke, hypertension, diabetes mellitus, atherosclerotic vascular disease, and heart failure. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized**, **double-blind**, double-dummy, parallel group, active-controlled study to evaluate the efficacy and safety of **milvexian**, an oral Factor XIa inhibitor, versus **apixaban** in participants with **atrial fibrillation**. The primary objective is to determine if milvexian is non-inferior to apixaban for the composite endpoint of stroke and non-CNS systemic embolism. The trial is expected to last until May 2027, with recruitment starting in August 2023. Participants will be involved for a maximum treatment period of 48 weeks.

The study will include several visits, starting with a screening visit to assess eligibility based on criteria such as age, medical stability, and risk factors for atrial fibrillation. Eligible participants will be randomized to receive either milvexian or apixaban, with matching placebos used to maintain blinding. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The primary endpoint is the time to the first occurrence of the composite endpoint of stroke and non-CNS systemic embolism. Secondary endpoints include the time to the first occurrence of ISTH major bleeding and other composite cardiovascular events. The trial will ensure rigorous monitoring and data collection to achieve its objectives.

The clinical trial involves the administration of several treatments, including **Eliquis** (apixaban) and **Milvexian**. **Eliquis** is provided in two dosages: 5 mg and 2.5 mg film-coated tablets. The active substance in these tablets is **apixaban**, a chemical compound. The tablets are administered orally, with a maximum daily dose of 10 mg for the 5 mg tablets and 5 mg for the 2.5 mg tablets. The maximum treatment period for **Eliquis** is 48 weeks. The tablets will be supplied as over-encapsulated capsules to ensure blinding in the study.

**Milvexian**, identified by the sponsor product code JNJ-70033093, is another experimental medication used in this trial. It is provided as a film-coated tablet containing the active substance **milvexian**, a chemical compound. The administration route is oral, with a maximum daily dose of 200 mg and a total maximum dose of 292,000 mg over a 48-week period.

In addition to the experimental medications, the trial includes the use of placebos to maintain the double-blind design. The **Milvexian matching placebo** and **Apixaban matching placebo** are utilized, although specific details regarding their pharmaceutical form and administration are not provided.

Furthermore, **Ondexxya** (andexanet alfa) is included as an auxiliary treatment. It is provided as a 200 mg powder for solution for infusion, with the active substance being **andexanet alfa**, a protein-based compound. The administration route is intravenous, with a maximum daily and total dose of 1760 mg, intended for a single-day treatment period.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study is designed to evaluate the efficacy and safety of **Milvexian** compared to **Apixaban** in participants with atrial fibrillation, focusing on the composite outcome of stroke and non-CNS systemic embolism.

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 the composite endpoint of stroke and non-CNS systemic embolism. Secondary endpoints include the time to the first occurrence of ISTH major bleeding, the composite of ISTH major and CRNM bleeding, and the composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke, and non-CNS systemic embolism. Additional secondary endpoints involve the time to CV death, the composite endpoint of all-cause death, MI, stroke, and non-CNS systemic embolism, and the composite endpoint of CV death, MI, stroke, acute limb ischemia, and urgent hospitalization for vascular causes of ischemic nature.

The trial is designed as a Phase 3, randomized, double-blind, double-dummy, parallel group, active-controlled study. The main objective is to evaluate if **milvexian**, an oral Factor XIa inhibitor, is non-inferior to **apixaban** for the composite of stroke and non-CNS systemic embolism in participants with atrial fibrillation. The trial will involve the administration of the investigational product and comparator over a maximum treatment period of 48 weeks. The efficacy parameters will be collected and analyzed at specified time points throughout the study duration, ensuring a comprehensive assessment of the treatment's impact on the defined endpoints.