A Phase 3 Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-0616 in Reducing Major Adverse Cardiovascular Events in Participants at High Cardiovascular Risk

The primary objective of this Phase 3 randomized, placebo-controlled clinical study is to evaluate the efficacy of **enlicitide** decanoate compared with placebo in increasing the time to the first event of coronary heart disease (CHD) death-based major adverse cardiovascular events (MACE)-plus. This composite endpoint includes coronary heart disease death, myocardial infarction (MI), ischemic stroke (both fatal and nonfatal), acute limb ischemia or major amputation, and urgent arterial revascularization (coronary, cerebrovascular, or peripheral). The clinical relevance of this objective lies in its potential to reduce the incidence of significant cardiovascular events in participants at high cardiovascular risk, thereby improving patient outcomes in atherosclerotic cardiovascular disease (ASCVD).

Secondary objectives include:

• Evaluating the efficacy of enlicitide compared with placebo in increasing the time to the first event of 3-point MACE.
• Assessing the efficacy in increasing the time to the first event of cardiovascular (CV) death-based MACE plus.
• Determining the efficacy in increasing the time to the first event of either coronary heart disease death or myocardial infarction (MI).
• Evaluating the efficacy in increasing the time to cardiovascular death.
• Assessing the efficacy in increasing the time to all-cause death.
• Evaluating the efficacy in increasing the time to the first event of each of the individual components of the primary endpoint: coronary heart disease death, MI, ischemic stroke, acute limb ischemia or major amputation, and urgent arterial revascularization.
• Assessing the effect of enlicitide compared with placebo on percent change from baseline in low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), and lipoprotein (a) at Week 52.
• Evaluating the safety and tolerability of enlicitide compared with placebo.

The clinical trial involves a total of **10,505 participants** diagnosed with **Atherosclerotic Cardiovascular Disease (ASCVD)**. The study population includes both male and female subjects, with an age range starting from 18 years and extending to older adults. Participants were selected based on their history of major ASCVD events or their high risk for a first major ASCVD event, as defined by specific age and health criteria. All participants are required to have fasted lipid values within certain thresholds and must be on a stable dose of moderate- or high-intensity statin therapy, with or without additional lipid-lowering treatments, for at least 30 days prior to the screening. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to evaluate the efficacy of enlicitide decanoate in increasing the time to the first event of coronary heart disease death-based major adverse cardiovascular events.

The clinical trial is a **Phase 3 randomized, placebo-controlled** study designed to evaluate the efficacy and safety of **MK-0616** in reducing major adverse cardiovascular events in participants at high cardiovascular risk. The trial involves the administration of **enlicitide chloride** in the form of a film-coated tablet, with a maximum daily dose of 20 mg and a total dose amount of 43,800 mg over a treatment period of 72 weeks. The study is structured to include a placebo group for comparison, ensuring a robust assessment of the investigational product's effects.

The trial is expected to commence recruitment on June 5, 2024, and conclude by November 1, 2029. Participants will be involved in the study for the duration of the treatment period, with regular study visits scheduled to monitor their health and the study's progress. The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as a history of atherosclerotic cardiovascular disease (ASCVD) or high risk for a first major ASCVD event. Follow-up visits will occur at predetermined intervals to assess primary and secondary endpoints, including coronary heart disease death-based major adverse cardiovascular events (MACE) plus, and other cardiovascular outcomes.

The end-of-study visit will mark the completion of the participant's involvement, where final assessments will be conducted to evaluate the overall impact of the treatment. Participants may be withdrawn from the study early if they experience adverse events that necessitate discontinuation or if they no longer meet the study's inclusion criteria. The trial's design ensures that data collected will provide valuable insights into the potential benefits and risks associated with the use of **MK-0616** in a high-risk cardiovascular population.

The clinical trial involves the administration of **MK-0616**, an experimental medication formulated as a **film-coated tablet**. The active substance in MK-0616 is **enlicitide chloride**, a chemical compound developed by Merck & Co. Inc. The medication is administered **orally** with a maximum daily dose of **20 mg**. The total maximum dose over the treatment period is **43,800 mg**, with the treatment duration extending up to **72 weeks**. The trial aims to evaluate the efficacy of MK-0616 in reducing major adverse cardiovascular events in participants at high cardiovascular risk.

In addition to the experimental medication, the study includes a **placebo** group. The placebo is designed to match the MK-0616 tablet in appearance but does not contain the active substance. The placebo serves as a comparator to assess the efficacy of MK-0616. Participants in the placebo group will receive the placebo tablet orally, following the same administration schedule as the experimental group. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

The efficacy of the investigational product, **enlicitide chloride**, will be assessed in a Phase 3 randomized, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the time to the first event of coronary heart disease (CHD) death-based major adverse cardiovascular events (MACE)-plus. This composite endpoint includes coronary heart disease death, myocardial infarction (MI), ischemic stroke (fatal and nonfatal), acute limb ischemia or major amputation, and urgent arterial revascularization.

Secondary endpoints include 3-point MACE, cardiovascular death-based MACE plus, coronary heart disease death or MI, cardiovascular death, all-cause death, and time to first event of MI, ischemic stroke, acute limb ischemia or major amputation, and urgent arterial revascularization. Additionally, the trial will measure percent changes from baseline in low-density lipoprotein cholesterol (LDL-C), Apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and Lipoprotein (a). The number of participants experiencing adverse events (AEs) and those discontinuing the study intervention due to AEs will also be recorded.