Evaluation of Inclisiran's Efficacy in Reducing Major Adverse Cardiovascular Events in Patients with Atherosclerotic Cardiovascular Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to demonstrate the superiority of **inclisiran** compared to placebo in reducing the risk of 3P-MACE, which is a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke, in participants with established atherosclerotic cardiovascular disease (ASCVD) and a low-density lipoprotein cholesterol (LDL-C) level of at least 1.8 mmol/L (70 mg/dL). This is clinically relevant as it addresses the need for effective interventions in reducing major adverse cardiovascular events in patients with ASCVD, a leading cause of morbidity and mortality.

Secondary objectives include:

• Demonstrating the superiority of inclisiran compared to placebo in reducing the risk of cardiovascular death.
• Demonstrating the superiority of inclisiran compared to placebo in reducing the risk of 4P-MACE, which includes cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization.
• Demonstrating the superiority of inclisiran compared to placebo in reducing the risk of major adverse limb events (MALE).
• Demonstrating the superiority of inclisiran compared to placebo in reducing the risk of all-cause death.
• Evaluating the safety and tolerability of inclisiran compared to placebo.

The clinical trial involves a total of **10,234** participants diagnosed with **atherosclerotic cardiovascular disease (ASCVD)**. The study population includes both male and female subjects aged 40 years and older. Participants were selected based on their established cardiovascular disease and a fasting LDL-C level of at least 1.8 mmol/L (70 mg/dL) at the screening visit. All participants are required to be on a stable and well-tolerated lipid-lowering regimen, which includes high-intensity statin therapy. The trial population comprises individuals with a history of myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease. The study does not specify particular lifestyle considerations such as diet or physical activity, but it includes a vulnerable population. The selection criteria ensure that participants have a consistent medical background relevant to the study's objective of evaluating the efficacy of inclisiran in reducing cardiovascular events.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **inclisiran** in reducing major adverse cardiovascular events in participants with established **atherosclerotic cardiovascular disease (ASCVD)**. The trial aims to demonstrate the superiority of inclisiran compared to placebo in reducing the risk of a composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke (3P-MACE). The study is expected to run from November 2021 to October 2027, with a total duration of approximately six years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥40 years), fasting LDL-C levels (≥1.8 mmol/L), and a stable lipid-lowering regimen that includes high-intensity statin therapy. Following the screening, participants will be randomized to receive either inclisiran or placebo. The trial includes regular follow-up visits to monitor safety and efficacy outcomes, with the primary endpoint being the time to the first occurrence of 3P-MACE. Secondary endpoints include time to cardiovascular death, 4P-MACE, major adverse limb events, all-cause death, and the number of participants with serious adverse events or adverse events leading to study treatment discontinuation.

The expected length of participant involvement is up to 72 months, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. Participants will be required to adhere to the study protocol, including the administration of the investigational product via **subcutaneous use** for inclisiran and **oral use** for statins such as **atorvastatin** and **rosuvastatin**. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment.

The clinical trial involves the administration of **Inclisiran**, a solution for injection, with the active substance being Inclisiran sodium. The pharmaceutical form is a pre-filled syringe, and the route of administration is subcutaneous use. The maximum daily dose is 300 mg, with a total maximum dose of 3900 mg over a treatment period of 72 weeks. The drug is of chemical origin and is used to assess its impact on major adverse cardiovascular events in participants with established cardiovascular disease.

**Rosuvastatin** is utilized as an auxiliary treatment in the trial. It is administered in tablet form, with the active substance being rosuvastatin. The route of administration is oral use. The maximum daily dose is 40 mg, with a total maximum dose of 87640 mg over a treatment period of 72 weeks. This medication is also of chemical origin.

**Atorvastatin** is another auxiliary treatment used in the study. It is provided in tablet form, with atorvastatin as the active substance. The administration route is oral use, with a maximum daily dose of 40 mg and a total maximum dose of 175200 mg over the 72-week treatment period. Atorvastatin is of chemical origin.

The trial also includes a **placebo** for Inclisiran, which is a 0 mg/1.5 mL solution for injection in a pre-filled syringe. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased results when comparing the effects of Inclisiran against a non-active substance.

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 a major adverse cardiovascular event (3P-MACE), which includes cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke. Secondary endpoints include the time to cardiovascular death, the time to the first occurrence of a 4P-MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or urgent coronary revascularization), the time to the first occurrence of Major Adverse Limb Events (MALE), time to all-cause death, and the number of participants with serious adverse events (SAEs) or adverse events (AEs) leading to study treatment discontinuation.

The trial is designed to demonstrate the superiority of **inclisiran** compared to placebo in reducing the risk of 3P-MACE in participants with established atherosclerotic cardiovascular disease (ASCVD) and a low-density lipoprotein cholesterol (LDL-C) level of at least 1.8 mmol/L (70 mg/dL). Participants must be on a stable and well-tolerated lipid-lowering regimen, including high-intensity statin therapy with either atorvastatin or rosuvastatin. The trial is a randomized, double-blind, placebo-controlled, multicenter study, with an estimated end date in October 2027.