A Phase 3, Randomized, Double-Blind, Placebo-controlled, Event-driven Study to Demonstrate the Efficacy and Safety of Milvexian, an Oral Factor XIa Inhibitor, After a Recent Acute Coronary Syndrome

The primary objective of this study is to demonstrate that **milvexian** is superior to placebo, in addition to standard-of-care, in reducing the risk of Major Adverse Cardiovascular Events (MACE), which is a composite of cardiovascular (CV) death, myocardial infarction (MI), and ischemic stroke. This is clinically relevant as it addresses the need for effective interventions to prevent recurrent cardiovascular events in patients with Acute Coronary Syndrome (ACS), a condition associated with high morbidity and mortality.

Secondary objectives include: - Demonstrating that milvexian is superior to placebo, in addition to standard-of-care, in reducing the risk of Major Adverse Vascular Events (MAVE), which includes CV death, MI, ischemic stroke, major adverse limb events (MALE), and symptomatic venous thromboembolism (VTE). - Determining whether milvexian reduces the risk of the composite of all-cause mortality (ACM), MI, and ischemic stroke compared to placebo. - Assessing whether milvexian reduces the risk of CV death compared to placebo. - Evaluating whether milvexian reduces the risk of ACM compared to placebo.

The clinical trial involves a total of **9128 participants** diagnosed with **Acute Coronary Syndrome** (ACS). The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having an index event consistent with spontaneous cardiac ischemia and a diagnosis of ACS within seven days prior to randomization. The trial population also includes individuals with at least two additional risk factors such as being aged 65 or older, having diabetes mellitus, or a history of myocardial infarction, among others. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, and all female participants of childbearing potential were required to have a negative pregnancy test at screening. The trial aims to evaluate the efficacy of milvexian in reducing the risk of major adverse cardiovascular events (MACE) compared to a placebo, in addition to standard care.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, event-driven study to evaluate the efficacy and safety of **milvexian**, an oral Factor XIa inhibitor, in patients with **acute coronary syndrome**. The trial aims to demonstrate that milvexian is superior to placebo, in addition to standard-of-care, in reducing the risk of major adverse cardiovascular events (MACE), which include cardiovascular death, myocardial infarction (MI), and ischemic stroke. The study is expected to run until November 30, 2026, with recruitment having commenced on August 10, 2023.

Participants will be involved in the study for a maximum treatment period of 48 weeks. The trial includes several key visits: an initial screening visit to confirm eligibility based on specific inclusion criteria, such as having an index event of acute coronary syndrome within 7 days prior to randomization and possessing at least two additional risk factors. Follow-up visits will be scheduled to monitor the participants' health status and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The primary endpoint of the study is the time to the first occurrence of MACE, while secondary endpoints include the time to the first occurrence of major adverse vascular events (MAVE), all-cause mortality (ACM), MI, ischemic stroke, and cardiovascular death. The trial will utilize a combination of **ticagrelor**, **acetylsalicylic acid**, **prasugrel**, and **clopidogrel** as auxiliary treatments, with milvexian and its matching placebo being the primary investigational products. All medications will be administered orally in the form of film-coated tablets.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Milvexian**, also known by its sponsor product code JNJ-70033093. Milvexian is a chemical product formulated as a film-coated tablet. It is administered orally, although the specific dosage and frequency are not provided in the data. The maximum treatment period for Milvexian is 48 weeks. Participant compliance with the administration of Milvexian will be monitored throughout the trial.

In addition to Milvexian, the trial includes the use of a **Milvexian Matching Placebo**. This placebo is intended to mimic the appearance and administration route of the active drug, ensuring the study remains double-blind. The placebo is not associated with any active substance and is used to compare the efficacy and safety of Milvexian against a non-active control.

Several **non-experimental treatments** are also utilized in the study, serving as standard-of-care therapies. These include **Ticagrelor**, **Acetylsalicylic Acid**, **Prasugrel**, and **Clopidogrel**. Each of these medications is a chemical product available in film-coated tablet form and administered orally. Ticagrelor is administered at a maximum daily dose of 180 mg, with a total maximum dose of 262,800 mg over the treatment period. Acetylsalicylic Acid is given at a maximum daily dose of 100 mg, with a total maximum dose of 146,000 mg. Prasugrel is administered at a maximum daily dose of 10 mg, with a total maximum dose of 14,600 mg. Clopidogrel is provided in two different dosages: one with a maximum daily dose of 75 mg and a total maximum dose of 109,500 mg, and another with a single maximum dose of 300 mg. The maximum treatment period for these non-experimental treatments is also 48 weeks.

All medications, including the experimental and non-experimental treatments, are administered orally. The trial is designed to ensure participant compliance through regular monitoring and adherence checks. The study aims to evaluate the efficacy and safety of Milvexian in reducing the risk of major adverse cardiovascular events (MACE) in patients who have recently experienced an acute coronary syndrome, in comparison to the placebo and in addition to standard-of-care therapies.

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 **MACE** (Major Adverse Cardiovascular Events), which includes the composite of cardiovascular death, myocardial infarction (MI), and ischemic stroke. Secondary endpoints include the time to the first occurrence of MAVE (Major Adverse Vascular Events), time to the first occurrence of all-cause mortality (ACM), MI, and ischemic stroke, time to cardiovascular death, and time to ACM.

The trial is designed to demonstrate the efficacy of Milvexian, an oral Factor XIa inhibitor, in reducing the risk of MACE in patients who have experienced a recent acute coronary syndrome. The study is randomized, double-blind, placebo-controlled, and event-driven. Efficacy assessments will be conducted throughout the trial duration, with specific timepoints for measuring the occurrence of the defined endpoints. The data collected will be analyzed to determine the superiority of Milvexian over placebo in addition to standard-of-care treatment.