Phase IV Randomized, Double-Blind, Placebo-Controlled Study of Inclisiran with Lipid-Lowering Therapy in Hypercholesterolemia Patients

The primary objective of this study is to evaluate the **superiority** of inclisiran, when added to ongoing individually optimized lipid-lowering therapy (LLT), compared to placebo in achieving individual LDL-C targets in participants with **hypercholesterolemia**. This is measured by the proportion of participants reaching their LDL-C target levels (< 55 mg/dL or < 70 mg/dL) by day 90. Achieving these targets is clinically significant as it may reduce the risk of cardiovascular events associated with elevated LDL-C levels.

Secondary objectives include demonstrating the superiority of inclisiran over placebo in the context of ongoing LLT on several parameters:

• Reducing mean LDL-C levels over the double-blind study period.
• Muscle-related adverse events.
• Annualized number of days pain is experienced, assessed using a pain diary.
• Pain-related quality of life at day 360, evaluated using the Short-Form Brief Pain Inventory (SF-BPI).

The clinical trial focuses on **hypercholesterolemia** and involves a study population comprising both male and female participants aged 18 years and older. The trial includes individuals at very high risk, such as those with documented atherosclerotic cardiovascular disease, diabetes mellitus with target organ damage, or a pre-existing diagnosis of heterozygous familial hypercholesterolemia. High-risk participants are also included, characterized by markedly elevated single risk factors or moderate chronic kidney disease. Participants are required to have specific LDL-C levels and must be on a stable dose of statin for at least 30 days prior to screening. Fasting triglyceride levels must be below 400 mg/dL at both screening and baseline. The sponsor has not provided the total number of participants involved in the trial. The trial population was selected based on these criteria, ensuring a focus on individuals with significant cardiovascular risk factors. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy, safety, tolerability, and quality of life associated with ongoing individually optimized lipid-lowering therapy with or without **inclisiran** in participants diagnosed with **hypercholesterolemia**. This is a randomized, placebo-controlled, double-blind, multicenter phase IV study. The trial aims to demonstrate the superiority of inclisiran on top of ongoing lipid-lowering therapy compared to placebo in achieving individual LDL-C targets at day 90. The study is expected to conclude by March 2025, with recruitment having commenced in April 2022.

Participants will be involved in the study for a maximum treatment period of 360 days. The trial includes several key visits: an initial screening visit to confirm eligibility, baseline assessments, and multiple follow-up visits to monitor progress and safety. The end-of-study visit will assess the primary and secondary endpoints, including the proportion of participants achieving LDL-C targets and changes in LDL-C levels over the treatment period. Participants will be required to maintain a stable dose of a statin for at least 30 days prior to the screening and baseline visits.

Inclusion criteria specify that participants must be 18 years or older, with very high or high cardiovascular risk, and meet specific LDL-C level requirements. Exclusion criteria are not explicitly detailed in the provided data. Participants may be withdrawn from the study if they experience adverse events or fail to adhere to the study protocol. The trial involves the administration of **rosuvastatin** and inclisiran, with rosuvastatin being administered orally and inclisiran subcutaneously. The maximum daily dose for rosuvastatin is 40 mg, while inclisiran is administered at a maximum total dose of 900 mg over the study period.

The clinical trial involves the administration of **rosuvastatin**, a lipid-lowering medication, in the form of a **tablet**. The active substance, rosuvastatin, is of chemical origin. Participants will receive a maximum daily dose of 40 mg, with a total maximum dose of 14,400 mg over the course of the study. The treatment period is set for a maximum of 360 days. The route of administration is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule will be monitored throughout the trial.

In addition to rosuvastatin, the trial includes the administration of **inclisiran**, a nucleic acid-based medication, provided as a **solution for injection**. Inclisiran is administered subcutaneously using a pre-filled syringe. The maximum daily dose is 300 mg, with a total maximum dose of 900 mg over the study period. The treatment duration is also set for a maximum of 360 days. The inclisiran formulation is not intended for pediatric use, and participant adherence to the dosing regimen will be closely monitored.

A **placebo** is also utilized in this study, specifically designed to match the inclisiran sodium solution for injection. The placebo is administered in a pre-filled syringe, ensuring blinding in this randomized, placebo-controlled trial. The placebo does not contain any active substance and is used to assess the efficacy and safety of inclisiran in comparison to a non-active treatment.

The efficacy of the clinical trial will be assessed by evaluating the impact of **inclisiran** on achieving individual LDL-C targets in participants with hypercholesterolemia. The primary endpoint is the proportion of participants reaching their individual LDL-C target, defined as less than 55 mg/dL or less than 70 mg/dL, at day 90. This will be measured through laboratory tests to determine LDL-C levels.

Secondary endpoints include the relative change in LDL-C levels from baseline over the double-blind treatment period, the proportion of participants experiencing muscle-related adverse events as defined by the Standardized MedDRA Queries for rhabdomyolysis/myopathy from day 1 to day 360, and the proportion of participants experiencing self-reported pain. Additionally, changes from baseline in the SF-BPI pain severity and interference scores to day 360 will be evaluated, along with the proportion of participants with clinically relevant changes in these scores.

Data collection will occur at specified timepoints, including baseline, day 90, and day 360, using validated laboratory tests and patient-reported outcomes. The analysis will focus on comparing the efficacy of inclisiran in combination with ongoing lipid-lowering therapy against a placebo, with the aim of demonstrating the superiority of inclisiran in achieving LDL-C targets.