Evaluation of Evolocumab in Carotid Plaque Stabilization and Regression in Patients with Carotid Stenosis: A Randomized Controlled Trial

The primary objective of the CARUSO study is to evaluate the **superiority** of **evolocumab** in addition to ongoing lipid-lowering therapy (LLT) compared to LLT alone in patients with **carotid stenosis**. This will be assessed through: a) morphological stabilization of the carotid plaque at 6 months, defined as regression of ulcerations and "soft" components, achieving a regular plaque morphology with a prevalence of fibrous atheroma (type III and IV), evaluated using Doppler ultrasound (DUS), magnetic resonance imaging (MRI), or computed tomography (CT); b) regression of the carotid plaque at 12 months, defined as a reduction in the extent of stenosis and peak systolic velocity (PSV) by at least 5% compared to baseline values. The clinical relevance of this objective lies in potentially reducing the risk of cerebrovascular events by stabilizing and regressing carotid plaques, which are significant contributors to stroke risk.

The secondary objective is to evaluate the absolute and percentage change in low-density lipoprotein cholesterol (LDL-C) values in the two groups at 12 months follow-up. This objective is clinically significant as it may provide insights into the lipid-modifying effects of evolocumab, which could further inform its role in managing cardiovascular risk in patients with carotid stenosis.

The clinical trial focuses on evaluating the efficacy of evolocumab in patients with **carotid stenosis**. The study population includes both male and female participants, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are generally in good health, excluding those classified as a vulnerable population. The trial targets asymptomatic individuals with carotid stenosis of at least 50% and LDL-C levels of 100 mg/dL or higher, despite maximal lipid-lowering therapy. Lifestyle factors such as diet and physical activity are not specified. The total number of participants is not provided, as the sponsor has not disclosed this information. Selection criteria emphasize the inclusion of individuals with specific clinical characteristics, ensuring a focused study population.

The clinical trial is designed to evaluate the **superiority** of **evolocumab** in addition to ongoing lipid-lowering therapy (LLT) compared to LLT alone in patients with **carotid stenosis**. This study is a randomized, double-blind, controlled trial with an estimated duration from March 2021 to March 2025. The trial aims to assess the morphological stabilization and regression of carotid plaque over a period of 12 months. Participants will be randomly assigned to receive either evolocumab or a placebo, in addition to their current LLT regimen. The primary endpoints include the morphological stabilization of the carotid plaque at 6 months and the regression of the plaque at 12 months, as measured by imaging techniques such as Doppler ultrasound (DUS), magnetic resonance imaging (MRI), or computed tomography (CT).

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as asymptomatic carotid stenosis of at least 50% and LDL-C levels of 100 mg/dL or higher despite maximal LLT. Following randomization, participants will attend regular follow-up visits to monitor their progress and assess the primary and secondary endpoints. The end-of-study visit will occur at the 12-month mark, where final assessments will be conducted to evaluate the outcomes of the intervention. The expected length of participant involvement is approximately 12 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent.

Participants will receive the investigational product, Repatha 140 mg solution for injection, administered either intravenously or subcutaneously, with a maximum daily dose of 140 mg. The trial is not categorized as low intervention and is conducted under the sponsorship of Amgen Europe B.V. The study is not intended for pediatric populations, and the investigational product is not classified as an orphan drug. The trial's primary objective is to demonstrate the added benefit of evolocumab in achieving the desired clinical outcomes in the target population.

The clinical trial involves the administration of **Repatha**, a pharmaceutical product containing the active substance **evolocumab**. Repatha is formulated as a **solution for injection** in a pre-filled syringe, with a concentration of 140 mg per syringe. The administration routes for this medication are either **intravenous (IV)** or **subcutaneous (SC)**. The dosing regimen specifies a maximum daily dose of 140 mg, with a total treatment period not exceeding 112 days. The product is manufactured by Amgen Europe B.V. and is classified under the ATC code C10AX13. Evolocumab, the active substance, is a protein of non-human origin, specifically categorized as "Protein - Other".

In addition to the experimental treatment with Repatha, participants will continue their ongoing lipid-lowering therapy (LLT) as part of the study protocol. This standard-of-care therapy serves as a comparator to evaluate the efficacy of evolocumab in achieving the trial's primary objectives. The trial aims to assess the superiority of evolocumab in conjunction with LLT compared to LLT alone, focusing on the morphological stabilization and regression of carotid plaque over specified timeframes. Compliance with the dosing schedule and administration route will be monitored throughout the study to ensure adherence to the protocol.

The efficacy of **evolocumab** in the clinical trial will be assessed by evaluating its superiority in addition to ongoing lipid-lowering therapy (LLT) compared to LLT alone. The primary endpoints for efficacy evaluation include the morphological stabilization of the carotid plaque at 6 months and the regression of the carotid plaque at 12 months. Morphological stabilization is defined as the regression of ulcerations and "soft" components, achieving a regular plaque morphology with a prevalence of fibrous atheroma (type III and IV). This will be evaluated using Doppler Ultrasound (DUS), Magnetic Resonance Imaging (MRI), or Computed Tomography (CT). Regression of the carotid plaque is defined as a reduction in the extent of stenosis and peak systolic velocity (PSV) by at least 5% compared to baseline values.