Inclisiran for Prevention of Major Adverse Cardiovascular Events in High-Risk Primary Prevention Patients with Atherosclerotic Cardiovascular Disease

The primary objective is to demonstrate the superiority of inclisiran over placebo in reducing the risk of 4P-MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization. This endpoint is clinically relevant because it captures major adverse cardiovascular events in high-risk primary prevention patients. The secondary objectives are to demonstrate superiority of inclisiran over placebo in reducing the risk or rate of 3P-MACE and total 4P-MACE, as well as total 3P-MACE. Additional secondary objectives are to reduce the risk of cardiovascular death and all-cause mortality, and to evaluate the safety and tolerability of inclisiran compared with placebo.

The trial population comprised 9,000 participants with primary prevention of atherosclerotic cardiovascular disease. The study included men and women aged 40 to less than 80 years who were at increased risk for a first major adverse cardiovascular event and had no prior major ASCVD event. Selection was based on predefined cardiovascular risk features, including evidence of coronary artery disease on computed tomography or invasive coronary angiography, a coronary artery calcium score of at least 100 Agatston units, a high 10-year ASCVD risk, or an intermediate 10-year risk with at least two risk-enhancing factors. Participants receiving background lipid-lowering therapy were required to have a stable dose for at least 4 weeks before screening and to remain on that therapy throughout the study. Screening also required LDL-C of at least 70 mg/dL but less than 190 mg/dL. The sponsor did not provide additional information on general health status, lifestyle factors, diet, physical activity, or habits.

The study is a randomized, double-blind, placebo-controlled, multicenter clinical trial evaluating inclisiran for the prevention of major adverse cardiovascular events in high-risk primary prevention participants. The trial is planned to run from 2023-10-02 to 2029-04-16. After the screening visit, eligibility is assessed and written informed consent is obtained before any study procedures. Participants who meet the inclusion criteria are assigned to study treatment and followed according to the protocol for the full study period. Follow-up visits are performed to assess efficacy and safety outcomes, including major cardiovascular events, serious adverse events, and adverse events leading to treatment discontinuation. An end-of-study visit is conducted at the end of participation to complete final assessments. Expected participant involvement lasts for the duration of the trial, and early termination may occur if treatment is discontinued because of an adverse event or if other protocol-defined reasons lead to withdrawal from the study.

Inclisiran was administered as a solution for injection by subcutaneous route at a dose of 300 mg. The study was randomized and double-blind, and inclisiran was compared with placebo. Dosing frequency and the full administration schedule were not specified in the source data.

The comparator was a placebo to inclisiran, provided as a 0 mg/1.5 mL solution for injection in a pre-filled syringe. It was used as the non-experimental treatment under the same blinded study conditions. Information on additional dosing procedures or participant compliance monitoring was not specified in the source data.

Efficacy will be assessed by time to the first occurrence of 4P-MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization. Secondary efficacy assessments will include time to the first occurrence of 3P-MACE, times to the occurrences of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization, each assessed as first and recurrent events, times to the occurrences of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke, also assessed as first and recurrent events, time to cardiovascular death, and time to all-cause mortality.