Effect of Evolocumab on Carotid Plaque Composition in Asymptomatic Carotid Artery Stenosis (EVOCAR-1)

Study Overview
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Brief Summary
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This is a phase IV, randomised, placebo-controlled, double-blind, parallel group study to determine the effect of Evolocumab treatment on carotid plaque morphology and composition in asymptomatic patients with >50% carotid artery stenosis.

Detailed Description
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In this study patients will be randomised in a 1:1 ratio to receive Evolocumab 140 mg every two weeks or matching placebo, to be administered for 12 months. After 12 months of treatment, patients will remain in follow-up for a further 12 months. High resolution magnetic resonance imaging (MRI) will be used to serially monitor the impact of Evolocumab on carotid plaque morphology and composition in patients with significant carotid stenosis who do not meet clinical criteria for carotid endarterectomy. This approach will reveal if clinically beneficial plaque regression occurs, without requiring the large patient cohorts or long follow-up needed for cardiovascular outcome trials. Results from this study will establish whether treatment with Evolocumab is likely to be beneficial to patients with asymptomatic carotid stenosis.

Official Title
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Effect of Evolocumab on Carotid Plaque Composition in Asymptomatic Carotid Artery Stenosis

Conditions
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Carotid Artery Stenosis

Intervention / Treatment
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* Drug: Evolocumab Auto-Injector [Repatha]
* Drug: Placebo Auto-Injector


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Sufficient English language ability to adequately understand the study Able to give informed consent Significant carotid artery plaque with 50-70% stenosis on ultrasound or MRI performed prior to screening Significant asymptomatic carotid artery plaque with >70% stenosis on ultrasound or MRI performed prior to screening, but carotid endarterectomy or carotid artery stenting has been deemed unsuitable by multidisciplinary team during routine clinical care Lipid-rich necrotic core (LRNC) on baseline MRI scan Adequate image quality for MRI analysis. LDL-C ≥2.6 mmol/L (100 mg/dL) On stable dose of maximally-tolerated lipid-lowering therapy in accordance with UK national clinical guidelines (NICE CG18120) for ≥2 months prior to screening. Acceptable non-statin lipid-lowering medications include ezetimibe or a fibrate. Exclusion Criteria: Any medical condition which, in the opinion of the investigators, would present an unacceptable risk to the participant if they were to take part in the trial, or prevent them from following the trial protocol Current or previous treatment with a PCSK9 inhibitor Eligible for PCSK9 inhibitor treatment under current NICE guidelines Contra-indication to or inability to use Evolocumab treatment, including: Sensitivity to Evolocumab or any associated excipients Unable to tolerate or perform self-administration of Evolocumab by auto-injector Lack of suitable refrigerated storage Contra-indication to or inability to tolerate MRI Estimated glomerular filtration rate (eGFR) ≤45 mL/min/1.73 m2 prior to MRI scan Pregnancy or breast-feeding Women of childbearing potential who are unwilling or unable to use a highly effective method of contraception

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching Placebo. | Drug: Placebo Auto-Injector<br>* Matching Placebo for the active comparator (Evolocumab)<br>* Other names: Placebo;|
| Active Comparator: Evolocumab<br>Evolocumab Auto-Injector [Repatha] | Drug: Evolocumab Auto-Injector [Repatha]<br>* Auto-Injector, 140 mg every two weeks.<br>* Other names: Repatha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lipid-rich necrotic core | Change in lipid-rich necrotic core (LRNC) size at 12 months, compared to baseline | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of LRNC core | Change in percentage lipid-rich necrotic core (LRNC) at 12 months, compared to baseline | 12 months | 
| LRNC regression | Percentage of participants achieving LRNC regression at 12 months | 12 months | 
| LRNC volume | Change in carotid plaque LRNC volume at other time-points, compared to baseline | 24 months | 
| LRNC percentage | Change in carotid plaque LRNC percentage at other time-points, compared to baseline | 24 months | 
| Measures of other carotid plaque burden - Volume wall thickness | Absolute and percentage change, compared to baseline, of volume wall thickness | 24 months | 
| Measures of other carotid plaque burden - Volume wall area | Absolute and percentage change, compared to baseline, volume wall area | 24 months | 
| Measures of other carotid plaque burden - Calcification | Absolute and percentage change, compared to baseline, of plaque composition (calcification) | 24 months | 
| Measures of other carotid plaque burden - Fibrous tissue volume | Absolute and percentage change, compared to baseline, of plaque composition (fibrous tissue volume) | 24 months | 
| Measures of other carotid plaque burden - New intra-plaque haemorrhage | Absolute and percentage change, compared to baseline, of plaque composition (new intra-plaque haemorrhage) | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carotid plaque morphology, carotid plaque composition, evolocumab