Phase 3 Study on Abelacimab Efficacy and Safety in High-Risk Atrial Fibrillation Patients Unsuitable for Oral Anticoagulation

The primary objective of this study is to assess whether **abelacimab** is superior to placebo in reducing the risk of ischemic stroke or systemic embolism (SE) in patients with **Atrial Fibrillation** (AF) who have been deemed unsuitable for oral anticoagulation therapy. This is clinically relevant as it addresses a critical need for effective stroke prevention in a high-risk population that cannot tolerate standard anticoagulation treatments.

Secondary objectives include evaluating abelacimab versus placebo with regard to:

• The composite of ischemic stroke, SE, myocardial infarction (MI), venous thromboembolism (VTE), or acute limb ischemia.
• Net clinical outcome defined as the composite of ischemic stroke, SE, or Bleeding Academic Research Consortium (BARC) type 3c/5 bleeding.
• Both cardiovascular mortality and all-cause mortality.
• Net clinical outcome defined as the composite of ischemic stroke, SE, MI, VTE, acute limb ischemia, or International Society on Thrombosis and Haemostasis (ISTH) major bleeding.
• The risk of bleeding in patients with AF who have been deemed unsuitable for oral anticoagulation therapy.

The clinical trial involves a total of **1000 participants** diagnosed with **Atrial Fibrillation**. The study population includes both male and female subjects, aged between **65 and 74 years** with a CHA2DS2VASc score of 4 or higher, or aged 75 years and older with a CHA2DS2VASc score of 3 or higher. Participants were selected based on their unsuitability for oral anticoagulation therapy, as determined by their responsible physician, due to the risks outweighing the benefits or personal unwillingness to take such medication. Additionally, individuals with severe renal insufficiency, a history of significant bleeding, or those requiring daily use of antiplatelet agents were considered. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to evaluate the efficacy of abelacimab in reducing the risk of ischemic stroke or systemic embolism in this specific patient group.

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of **abelacimab** in high-risk patients with **atrial fibrillation** who are deemed unsuitable for oral anticoagulation. The primary objective is to assess whether abelacimab is superior to placebo in reducing the risk of ischemic stroke or systemic embolism (SE) in this patient population. The trial is expected to run from May 1, 2023, to May 28, 2025, with a maximum treatment period of 48 weeks for each participant.

Participants will be randomly assigned to receive either abelacimab 150 mg/ml solution for infusion or a matching placebo. The study drug will be administered via subcutaneous use. The primary efficacy endpoint is the time to the first occurrence of confirmed ischemic stroke or SE, while the primary safety endpoint is the time to the first occurrence of adjudicated BARC type 3c/5 bleeding. Secondary efficacy endpoints include composite outcomes such as ischemic stroke, SE, myocardial infarction (MI), venous thromboembolism (VTE), acute limb ischemia, cardiovascular mortality, and all-cause mortality.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, CHA2DS2VASc score, and unsuitability for oral anticoagulation. Follow-up visits will be scheduled throughout the treatment period to monitor safety and efficacy outcomes. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent.

Inclusion criteria require participants to have a documented diagnosis of atrial fibrillation or atrial flutter, be aged 65-74 with a CHA2DS2VASc score of ≥4, or aged ≥75 with a CHA2DS2VASc score of ≥3. Participants must also be judged unsuitable for oral anticoagulation or left atrial appendage closure by their physician. The trial aims to provide valuable insights into the potential benefits of abelacimab for patients with limited treatment options due to the risks associated with standard anticoagulation therapies.

The clinical trial involves the administration of **Abelacimab**, a concentrate for solution for infusion, with a concentration of 150 mg/mL. Abelacimab is a protein-based therapeutic agent developed by Anthos Therapeutics Inc. The medication is administered via **subcutaneous use**. The dosing regimen for Abelacimab involves a maximum daily dose of 150 mg, with a total maximum dose of 7200 mg over a treatment period of up to 48 weeks. The trial aims to evaluate the efficacy and safety of Abelacimab in high-risk patients with atrial fibrillation who are unsuitable for oral anticoagulation therapy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

The study also includes a **placebo** group, which receives a 0 mg/mL solution for infusion/injection that matches the appearance of Abelacimab. The placebo is designed to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as Abelacimab, providing a control for evaluating the true efficacy of the experimental medication. The use of a placebo allows for a rigorous assessment of Abelacimab's potential benefits in reducing the risk of ischemic stroke or systemic embolism in the target patient population.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary efficacy endpoint is defined as the time to the first occurrence of confirmed **ischemic stroke** or systemic embolism (SE). This endpoint will be measured to determine the effectiveness of abelacimab compared to placebo in reducing these events in patients with atrial fibrillation (AF) who are unsuitable for oral anticoagulation therapy.

Secondary efficacy endpoints include a composite of ischemic stroke, SE, myocardial infarction (MI), venous thromboembolism (VTE), or acute limb ischemia. Additional secondary endpoints involve a composite of ischemic stroke, SE, or BARC type 3c/5 bleeding, as well as cardiovascular mortality and all-cause mortality. These endpoints will be analyzed to provide a comprehensive assessment of the treatment's impact on various cardiovascular outcomes.

The trial is designed as a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The efficacy parameters will be collected and analyzed at specified time points throughout the study duration, which is estimated to conclude by May 28, 2025. The data collected will be used to determine the superiority of abelacimab over placebo in the specified patient population.