Evaluation of Inclisiran in Reducing Major Adverse Cardiovascular Events in High-Risk Primary Prevention of Atherosclerotic Cardiovascular Disease

The primary objective of this study is to demonstrate the **superiority** of inclisiran compared to placebo in reducing the risk of 4P-MACE, which is a composite measure including cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, and urgent coronary revascularization. This objective is clinically relevant as it addresses the prevention of major adverse cardiovascular events in high-risk primary prevention patients, potentially reducing morbidity and mortality associated with atherosclerotic cardiovascular disease (ASCVD).

Secondary objectives include:

• Demonstrating the superiority of inclisiran over placebo in reducing the risk of 3P-MACE, which includes CV death, non-fatal MI, and non-fatal ischemic stroke.
• Demonstrating the superiority of inclisiran in reducing the rate of total 4P-MACE and 3P-MACE.
• Evaluating the reduction in risk of CV death and all-cause mortality with inclisiran compared to placebo.
• Assessing the safety and tolerability of inclisiran in comparison to placebo.

The clinical trial involves a total of **9000 participants** who are being studied for the **primary prevention of atherosclerotic cardiovascular disease (ASCVD)**. The study population includes both male and female subjects aged between 40 and 79 years. Participants are selected based on their increased risk for a first major adverse cardiovascular event (MACE), with no prior major ASCVD event. This includes individuals with evidence of atherosclerotic coronary artery disease, a coronary artery calcium score of at least 100 Agatston units, or a high 10-year ASCVD risk. Participants are required to have a low-density lipoprotein cholesterol (LDL-C) level of at least 70 mg/dL but less than 190 mg/dL at the screening visit. Those on a background lipid-lowering therapy must have a stable dose for at least four weeks prior to screening and be willing to continue this therapy throughout the study. The trial includes a vulnerable population, and the selection process ensures that participants meet specific health criteria to assess the efficacy of inclisiran compared to placebo in reducing the risk of 4P-MACE.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** multicenter study aimed at evaluating the effect of **inclisiran** on preventing major adverse cardiovascular events in high-risk primary prevention patients. The trial targets individuals at increased risk for a first major adverse cardiovascular event (MACE) and aims to demonstrate the superiority of inclisiran compared to placebo in reducing the risk of a composite endpoint known as 4P-MACE, which includes cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization. The trial is expected to run until April 2029, with recruitment starting in October 2023.

Participants will be involved in the study for a maximum treatment period of 75 weeks. The study will include several key visits: an initial **screening visit** to confirm eligibility based on criteria such as age, risk factors, and lipid levels; regular follow-up visits to monitor health status and treatment effects; and an end-of-study visit to assess final outcomes. The primary endpoint is the time to the first occurrence of 4P-MACE, while secondary endpoints include time to the first occurrence of 3P-MACE, times to occurrences of individual cardiovascular events, and overall mortality rates.

Inclusion criteria require participants to be between 40 and 80 years of age, with no prior major atherosclerotic cardiovascular disease (ASCVD) events but at increased risk for a first MACE. Participants must have stable lipid-lowering therapy if applicable and meet specific LDL-C levels at screening. Conditions for early termination from the study include the occurrence of serious adverse events (SAEs) or adverse events (AEs) leading to study treatment discontinuation. The trial will utilize a pre-filled syringe for subcutaneous administration of inclisiran or placebo, with a maximum daily dose of 300 mg and a total dose not exceeding 4200 mg over the study period.

The clinical trial involves the administration of **Inclisiran**, an experimental medication, which is a **solution for injection**. Inclisiran is a nucleic acid-based therapeutic agent, specifically designed for **subcutaneous use**. The pharmaceutical form is a pre-filled syringe, although it does not possess a CE mark. The maximum daily dose of Inclisiran is 300 mg, with a total maximum dose of 4200 mg over the course of the study. The treatment period is set for a maximum of 75 days. Inclisiran sodium is the active substance, and the drug is of chemical origin. The clinical dossier indicates that there are alternative packaging sites for clinical trial supplies, and the drug substance has a retest period of 36 months, with a similar shelf life for the drug product.

The study also includes a **placebo** comparator, which is a 0 mg/1.5 mL solution for injection in a pre-filled syringe, designed to match the administration form of Inclisiran. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo does not contain any active substance and serves as a control to evaluate the efficacy and safety of Inclisiran in reducing the risk of major adverse cardiovascular events in high-risk primary prevention patients.

The efficacy of **inclisiran** in preventing major adverse cardiovascular events (MACE) will be assessed in a randomized, double-blind, placebo-controlled multicenter study. The primary endpoint for evaluating efficacy is the time to the first occurrence of 4P-MACE, which includes a composite of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, and urgent coronary revascularization. Secondary endpoints include the time to the first occurrence of 3P-MACE, times to occurrences of cardiovascular death, nonfatal MI, non-fatal ischemic stroke, and urgent coronary revascularization (both first and recurrent), time to cardiovascular death, time to all-cause mortality, and the number of participants with serious adverse events (SAEs) and adverse events (AEs) leading to study treatment discontinuation.

The study will involve the administration of **inclisiran** as a solution for injection, with a maximum treatment period of 75 days. Efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, which is estimated to conclude by April 16, 2029. The trial aims to demonstrate the superiority of **inclisiran** compared to placebo in reducing the risk of MACE in high-risk primary prevention patients. The study will utilize a pre-filled syringe for the administration of the investigational product, ensuring consistent and accurate dosing.