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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Carotid Artery Stenosis
• Intervention / Treatment: Drug: Placebo Auto-Injector; Drug: Evolocumab Auto-Injector [Repatha]

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 0HS
    • Imperial College Healthcare NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcomes 1: Change in biochemical parameters - total cholesterol	Absolute and percentage change compared to baseline in total cholesterol.	24 months
Exploratory outcomes 1: Change in biochemical parameters - LDL-C	Absolute and percentage change compared to baseline in LDL-C.	24 months
Exploratory outcomes 1: Change in biochemical parameters - HDL-C	Absolute and percentage change compared to baseline in high density lipoprotein-associated cholesterol (HDL-C).	24 months
Exploratory outcomes 1: Change in biochemical parameters - triglycerides	Absolute and percentage change compared to baseline in triglycerides.	24 months
Exploratory outcomes 1: Change in biochemical parameters - lipoprotein (a)	Absolute and percentage change compared to baseline in lipoprotein(a).	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Ischaemic and non-ischaemic stroke	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Ischaemic and non-ischaemic stroke	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - TIA	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Transient ischaemic attack	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Progression to carotid endarterectomy	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Progression to carotid endarterectomy	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - MI	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Myocardial infarction	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Unstable angina	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Unstable angina	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Hospitalisation for heart failure	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Hospitalisation for heart failure	24 months
Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events -PAD-related end points: peripheral revascularization,	Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: PAD-related end points: peripheral revascularization,	24 months

Collaborators and Investigators

• Sponsor: Imperial College Healthcare NHS Trust
• Collaborators: Imperial College London
• Investigators: Principal Investigator: Jaimini Cegla, BSc MSc MBBS MRCP FRCPath PhD, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2019
• Primary Completion (Anticipated): May 6, 2023
• Study Completion (Anticipated): May 6, 2024

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 24, 2019
• First Posted (Actual): April 30, 2019

Study Record Updates

• Last Update Posted (Actual): October 13, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: evolocumab; carotid plaque morphology; carotid plaque composition
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arterial Occlusive Diseases; Pathological Conditions, Anatomical; Carotid Artery Diseases; Carotid Stenosis; Constriction, Pathologic; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: EVOCAR-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No