Evaluation of Inclisiran in the Management of Primary Hypercholesterolaemia and Mixed Dyslipidaemia in High-Risk Atherosclerotic Cardiovascular Disease Patients

The primary objective of this study is to demonstrate that a decrease in **LDL-level** is achievable through the implementation of a complex, intensive lipid management program. This is clinically relevant as lowering LDL cholesterol is crucial in managing and reducing the risk of atherosclerotic cardiovascular disease, particularly in patients with primary hypercholesterolaemia, whether heterozygous familial or non-familial, or mixed dyslipidaemia.

Secondary objectives include assessing the efficacy of the program in reaching LDL-target levels and promoting plaque regression. These outcomes are significant as they further contribute to the reduction of cardiovascular events and improve overall cardiovascular health in high-risk patients.

The clinical trial focuses on individuals diagnosed with **primary hypercholesterolaemia** (heterozygous familial and non-familial) or mixed dyslipidaemia in atherosclerotic cardiovascular disease. The study population includes both male and female participants aged 18 years and older. Participants are required to agree to a maximum dose statin therapy, specifically Rosuvastatin at a minimum of 20 mg or Atorvastatin at a minimum of 40 mg. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include a fasting LDL-C local lab value of at least 1.8 mmol/L and evidence of atherosclerotic coronary disease, such as non-obstructive coronary plaques or a history of acute coronary syndrome with multi-vessel disease. Participants must provide written informed consent prior to any assessments. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed additional details regarding the selection process or specific lifestyle factors.

The clinical trial is designed to evaluate the efficacy of a **lipid-lowering** intervention in patients with **primary hypercholesterolaemia** (heterozygous familial and non-familial) or mixed dyslipidaemia in atherosclerotic cardiovascular disease. This is a Phase IV, randomized, double-blind, controlled trial with an estimated duration from May 2023 to July 2025. The primary objective is to demonstrate a decrease in LDL-levels through a comprehensive lipid management program. The trial will utilize **inclisiran**, administered as a 284 mg solution for injection in a pre-filled syringe via subcutaneous injection.

Participants will be involved in the study for a maximum treatment period of 21 days. The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age (≥18 years), agreement to maximum dose statin therapy, and specific LDL-C levels. Following the screening, participants will be randomized and receive the investigational product. Study visits will be scheduled to monitor the absolute and percent change in LDL-levels from the first to the last visit, as well as other secondary endpoints, including changes in coronary CT parameters and lifestyle factors.

Follow-up visits will occur at regular intervals to assess the primary and secondary endpoints, ensuring the safety and efficacy of the intervention. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall impact of the treatment. Participants may be withdrawn from the study if they experience adverse events, fail to comply with the protocol, or withdraw consent. The trial aims to provide valuable insights into the management of high-risk cardiovascular patients through intensive lipid management strategies.

The clinical trial involves the administration of **Leqvio**, a pharmaceutical product containing the active substance **inclisiran**. Leqvio is formulated as a **solution for injection** in a pre-filled syringe, with a concentration of 284 mg of inclisiran per syringe. The medication is administered via **subcutaneous injection**. The dosing regimen for this trial specifies a maximum daily dose of 284 mg, with a total treatment period not exceeding 21 days. Inclisiran, the active ingredient, is a **nucleic acid**-based compound, specifically designed to lower lipid levels in high-risk cardiovascular patients. The product is manufactured by Novartis Europharm Limited and is classified under the ATC code C10AX16.

In addition to the experimental treatment, participants may receive standard-of-care lipid-lowering therapies as part of their overall treatment regimen. These non-experimental treatments are not specified in detail within the trial documentation but are intended to complement the primary objective of achieving a decrease in LDL levels through a comprehensive lipid management program. Compliance with the dosing schedule and administration of Leqvio will be monitored throughout the trial to ensure adherence to the protocol and to evaluate the efficacy and safety of the treatment.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on lipid management in high-risk cardiovascular patients. The primary endpoints include the **absolute and percent change in LDL-level** from the first to the last visit, as well as the absolute and percent LDL-change from visit to visit. These measurements will provide a direct evaluation of the intervention's impact on LDL cholesterol levels, a critical factor in cardiovascular risk management.

Secondary endpoints will further explore the efficacy of the intervention by assessing changes in the percentage of patients reaching the LDL target of less than 1.4 mmol/L from the first to the last visit. Additionally, changes in coronary CT parameters, such as total plaque volume, low-attenuation plaque volume, Agatston score, plaque composition, and pericoronary and pericardial fat tissue, will be evaluated. Ultrasound endpoints will include changes in total plaque area, intima-media thickness, and plaque composition in femoral and carotid arteries. Other secondary measures will assess changes in BMI, lifestyle, diet, and health behavior, providing a comprehensive view of the intervention's impact on patient health.