CARotid plaqUe StabilizatiOn and Regression With Evolocumab.

Study Overview
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Brief Summary
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The CARUSO trial aims at investigating the efficacy of evolocumab in promoting carotid plaque morphological stabilization and regression as compared to traditional lipid lowering therapy (LLT). Primary end-point of the study is the superiority of evolocumab on top of ongoing LLT versus ongoing LLT in carotid plaque morphological stabilization and regression at 6 and 12 months, respectively. Secondary end-points are: LDL-Cholesterol (LDL-C) absolute and percentage changes in the two groups at 12 month follow-up, and adverse cerebrovascular and cardiac events at 12 and 24 months

Detailed Description
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Optimal lipid-lowering therapy (LLT) is a mainstay for the therapeutic management of atherosclerotic vascular disease. Cardiac and cerebrovascular adverse events and progression of atherosclerosis are, indeed, reduced in proportion to the achieved LDL cholesterol (LDL-C) levels.In addition, regression of atherosclerotic plaques with optimal LLT has been observed. However, optimal LLT with statin and ezetimibe, might be limited by the onset of adverse effects (i.e. disabling myalgias, diarrhea) with are usually dose -dependent, and the maximum tolerated statin dose might be insufficient to reach the recommended LDL-C goals. The advent of proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) has allowed the achievement of very low LDL-C levels, and the fulfillment of the recommended LDL-C targets. However, while the experience with PCSK9i in patients with coronary artery disease has been wide, and coronary plaque regression has been documented, little is known regarding carotid plaque regression following therapy with PCSK9i. Only a few case reports have been published, and no observational study has been carried out so far. Furthermore, morphological carotid plaque stabilization has a prognostic role, and the possibility of its early achievement with PCSK9i may be relevant, especially in the context of percutaneous or surgical carotid interventions.

Official Title
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CARotid plaqUe StabilizatiOn and Regression With Evolocumab: the CARUSO Study

Conditions
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Carotid Artery Disease

Intervention / Treatment
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* Drug: Evolocumab
* Other: lipid-lowering therapy (LLT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: asymptomatic patients with uni- or bilateral carotid artery stenosis ≥50% and LDL-C values ≥100 mg/dL despite ongoing lipid lowering therapy Exclusion Criteria: age <18 or ≥81 years old known intolerance to evolocumab ongoing or previous treatment with PCSK9i prior stroke or transient ischemic attack total carotid occlusion major active infection or major hematologic, renal, hepatic, or endocrine dysfunction malignancy with life expectancy below 24 months failure to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized controlled study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Evolocumab<br>Subcutaneous evolocumab 140 mg will be administered every 2 weeks on top of optimal lipid-lowering therapy | Drug: Evolocumab<br>* Evolocumab 140 mg s.c. every two weeks on top of optimal lipid lowering therapy<br>* Other names: Repatha;Other: lipid-lowering therapy (LLT)<br>* lipid-lowering therapy (LLT)<br>|
| Placebo Comparator: Standard<br>No further treatment besides optimal lipid-lowering therapy will be administered | Other: lipid-lowering therapy (LLT)<br>* lipid-lowering therapy (LLT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphological carotid plaque stabilization | Morphological stabilization of the carotid plaque evaluated with Carotid duplex ultra-sonography | Six months | 
| Carotid plaque regression | Carotid plaque regression evaluated with Carotid duplex ultra-sonography and defined as reduction of the entity of the stenosis and/or peak systolic velocity by at least 5%, as compared to baseline. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of LDL-C | Absolute changes of LDL-C | 12 months | 
| Major adverse cerebrovascular events | All-cause mortality, cardiovascular mortality, stroke, myocardial infarction, any coronary or peripheral revascularization | 12 and 24 months |