Comparative Efficacy of Inclisiran Sodium Versus Bempedoic Acid in LDL-C Reduction in Atherosclerotic Cardiovascular Disease Patients

The primary objective of this study is to demonstrate the **superiority** of Inclisiran compared to bempedoic acid (BPA) in combination with standard of care, which includes a maximally tolerated high-intensity (HI) statin dose with or without Ezetimibe, in reducing relative low-density lipoprotein cholesterol (**LDL-C**) levels at Day 150. This is clinically relevant as achieving superior LDL-C reduction is crucial in managing **hypercholesterolemia** and reducing the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease.

Secondary objectives include:

• Demonstrating the superiority of Inclisiran compared to BPA in patients on maximally tolerated HI statin dose without Ezetimibe in relative reduction of LDL-C levels at Day 150.
• Demonstrating the superiority of Inclisiran compared to BPA in patients on maximally tolerated HI statin dose with Ezetimibe in reducing relative LDL-C levels at Day 150.
• Exploring the effect of Inclisiran compared to BPA on the individual responsiveness of participants.
• Assessing the efficacy of Inclisiran compared to BPA in reducing LDL-C (absolute reduction).
• Assessing the efficacy of Inclisiran compared to BPA in reducing LDL-C [time-adjusted percent change] starting Day 30 and up to Day 150.
• Assessing the efficacy of Inclisiran compared to BPA in reducing LDL-C [time-adjusted percent change] between Day 90 and Day 150.
• Assessing adherence to lipid-lowering therapy over time in participants receiving Inclisiran compared to BPA on top of maximally tolerated HI statins (+/- Ezetimibe) using the Morisky 8-Item Medication Adherence Scale (MMAS-8).
• Assessing the effect of Inclisiran compared to BPA regarding treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM v. II).
• Assessing the effect of Inclisiran compared to BPA regarding pain-related quality of life using the Short Form Brief Pain Inventory (SF-BPI).

The clinical trial focuses on participants diagnosed with **hypercholesterolemia**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their cardiovascular risk profile, requiring them to be on a stable and well-tolerated lipid-lowering regimen, which includes a high-intensity statin therapy. The trial population includes individuals categorized as very high or high cardiovascular risk, with conditions such as documented atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus with target organ damage, or a pre-existing diagnosis of heterozygous familial hypercholesterolemia. Lifestyle considerations such as diet and physical activity are not explicitly detailed. The trial includes a vulnerable population, indicating a careful selection process to ensure the safety and efficacy of the intervention. Key inclusion criteria involve specific lipid and cardiovascular risk factors, but the overall health status of participants is not detailed beyond these parameters.

The clinical trial is designed as a **randomized**, multicenter, open-label study aimed at comparing the effectiveness of **Inclisiran Sodium** to **Bempedoic Acid** in lowering LDL cholesterol (LDL-C) levels in participants diagnosed with **hypercholesterolemia**. The trial will involve participants who are on a stable lipid-lowering regimen, including a high-intensity statin therapy, and are categorized as having very high or high cardiovascular risk. The primary objective is to demonstrate the superiority of Inclisiran in reducing LDL-C levels at Day 150 compared to Bempedoic Acid, in combination with standard care. The trial is expected to commence recruitment on May 20, 2024, and conclude by September 30, 2025, with a total participant involvement duration of 150 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as fasting LDL-C levels and cardiovascular risk factors. Following randomization, participants will attend follow-up visits at specified intervals to monitor LDL-C levels and assess individual responsiveness to treatment. The end-of-study visit will occur at Day 150, where the primary and secondary endpoints, including percent change from baseline in LDL-C levels, will be evaluated. Participants are expected to adhere to the study protocol throughout the trial duration, with conditions such as non-compliance or adverse events potentially leading to early termination from the study.

The trial will utilize a controlled design, with participants receiving either Inclisiran Sodium via subcutaneous injection or Bempedoic Acid orally, alongside their existing statin regimen. The study will ensure rigorous data collection and analysis to assess the efficacy and safety of the interventions. The trial's findings are anticipated to contribute valuable insights into the management of hypercholesterolemia, particularly in individuals at elevated cardiovascular risk.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their effectiveness in lowering LDL cholesterol levels in participants with atherosclerotic cardiovascular disease. **Inclisiran Sodium** is administered as a solution for injection in a pre-filled syringe. The maximum daily dose is 284 mg, with a total maximum dose of 568 mg over the treatment period. The administration route is subcutaneous, and the treatment period is up to 150 days. The product is labeled for clinical trial use.

**Bempedoic Acid** is provided in the form of film-coated tablets. The maximum daily dose is 180 mg, with a total maximum dose of 27,000 mg over the treatment period. The administration route is oral, and the treatment period is up to 150 days. The product is also labeled for clinical trial use.

**Rosuvastatin** is administered as film-coated tablets with a maximum daily dose of 40 mg and a total maximum dose of 6,000 mg over the treatment period. The administration route is oral, and the treatment period is up to 150 days. This product is a marketed product and not specifically labeled for clinical trial use.

**Atorvastatin** is provided in the form of film-coated tablets. The maximum daily dose is 80 mg, with a total maximum dose of 12,000 mg over the treatment period. The administration route is oral, and the treatment period is up to 150 days. This product is a marketed product and not specifically labeled for clinical trial use.

**Ezetimibe** is administered as tablets with a maximum daily dose of 10 mg and a total maximum dose of 1,500 mg over the treatment period. The administration route is oral, and the treatment period is up to 150 days. This product is a marketed product and not specifically labeled for clinical trial use.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to demonstrate the superiority of Inclisiran in combination with standard-of-care therapy, which may include maximally tolerated high-intensity statin doses with or without Ezetimibe, in reducing LDL cholesterol levels.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the reduction of low-density lipoprotein cholesterol (LDL-C) levels in participants with atherosclerotic cardiovascular disease. The primary endpoint is the percent change from baseline in LDL-C levels at Day 150. Secondary endpoints include the individual responsiveness of participants, defined through on-treatment LDL-C levels of less than 55 mg/dL for very high-risk subjects and less than 70 mg/dL for high-risk subjects at Day 150, as well as the absolute change from baseline in LDL-C at Day 150. Additional secondary endpoints involve the percent change from baseline in LDL-C levels between Day 30 up to Day 150 and between Day 90 and Day 150.

Other secondary endpoints include mean changes from baseline in the Morisky Medication Adherence Scale (MMAS-8), Treatment Satisfaction Questionnaire for Medication (TSQM), and Short Form Brief Pain Inventory (SF-BPI) over time. The proportion of participants with a clinically significant change from baseline, defined as a minimum clinically important difference (MCID) of 2 points in SF-BPI at Day 150, will also be evaluated. These efficacy parameters will be measured and collected at specified timepoints, with the primary focus on Day 150, using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.