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

Primary Purpose

Carotid Artery Stenosis

Status

Active

Phase

Phase 4

Locations

United Kingdom

Study Type

Interventional

Intervention

Evolocumab Auto-Injector [Repatha]

Placebo Auto-Injector

About this trial

This is an interventional treatment trial for Carotid Artery Stenosis focused on measuring carotid plaque morphology, carotid plaque composition, evolocumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Imperial College Healthcare NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Evolocumab

Arm Description

Matching Placebo.

Evolocumab Auto-Injector [Repatha]

Outcomes

Primary Outcome Measures

Change in lipid-rich necrotic core

Change in lipid-rich necrotic core (LRNC) size at 12 months, compared to baseline

Secondary Outcome Measures

Percentage of LRNC core

Change in percentage lipid-rich necrotic core (LRNC) at 12 months, compared to baseline

LRNC regression

Percentage of participants achieving LRNC regression at 12 months

LRNC volume

Change in carotid plaque LRNC volume at other time-points, compared to baseline

LRNC percentage

Change in carotid plaque LRNC percentage at other time-points, compared to baseline

Measures of other carotid plaque burden - Volume wall thickness

Absolute and percentage change, compared to baseline, of volume wall thickness

Measures of other carotid plaque burden - Volume wall area

Absolute and percentage change, compared to baseline, volume wall area

Measures of other carotid plaque burden - Calcification

Absolute and percentage change, compared to baseline, of plaque composition (calcification)

Measures of other carotid plaque burden - Fibrous tissue volume

Absolute and percentage change, compared to baseline, of plaque composition (fibrous tissue volume)

Measures of other carotid plaque burden - New intra-plaque haemorrhage

Absolute and percentage change, compared to baseline, of plaque composition (new intra-plaque haemorrhage)

Full Information

NCT ID

NCT03931161

First Posted

April 15, 2019

Last Updated

October 12, 2022

Sponsor

Imperial College Healthcare NHS Trust

Collaborators

Imperial College London

1. Study Identification

Unique Protocol Identification Number

NCT03931161

Brief Title

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

Acronym

EVOCAR-1

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 4, 2019 (Actual)

Primary Completion Date

May 6, 2023 (Anticipated)

Study Completion Date

May 6, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Imperial College Healthcare NHS Trust

Collaborators

Imperial College London

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Carotid Artery Stenosis

Keywords

carotid plaque morphology, carotid plaque composition, evolocumab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matching Placebo.

Arm Title

Evolocumab

Arm Type

Active Comparator

Arm Description

Evolocumab Auto-Injector [Repatha]

Intervention Type

Drug

Intervention Name(s)

Evolocumab Auto-Injector [Repatha]

Other Intervention Name(s)

Repatha

Intervention Description

Auto-Injector, 140 mg every two weeks.

Intervention Type

Drug

Intervention Name(s)

Placebo Auto-Injector

Other Intervention Name(s)

Placebo

Intervention Description

Matching Placebo for the active comparator (Evolocumab)

Primary Outcome Measure Information:

Title

Change in lipid-rich necrotic core

Description

Change in lipid-rich necrotic core (LRNC) size at 12 months, compared to baseline

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Percentage of LRNC core

Description

Change in percentage lipid-rich necrotic core (LRNC) at 12 months, compared to baseline

Time Frame

12 months

Title

LRNC regression

Description

Percentage of participants achieving LRNC regression at 12 months

Time Frame

12 months

Title

LRNC volume

Description

Change in carotid plaque LRNC volume at other time-points, compared to baseline

Time Frame

24 months

Title

LRNC percentage

Description

Change in carotid plaque LRNC percentage at other time-points, compared to baseline

Time Frame

24 months

Title

Measures of other carotid plaque burden - Volume wall thickness

Description

Absolute and percentage change, compared to baseline, of volume wall thickness

Time Frame

24 months

Title

Measures of other carotid plaque burden - Volume wall area

Description

Absolute and percentage change, compared to baseline, volume wall area

Time Frame

24 months

Title

Measures of other carotid plaque burden - Calcification

Description

Absolute and percentage change, compared to baseline, of plaque composition (calcification)

Time Frame

24 months

Title

Measures of other carotid plaque burden - Fibrous tissue volume

Description

Absolute and percentage change, compared to baseline, of plaque composition (fibrous tissue volume)

Time Frame

24 months

Title

Measures of other carotid plaque burden - New intra-plaque haemorrhage

Description

Absolute and percentage change, compared to baseline, of plaque composition (new intra-plaque haemorrhage)

Time Frame

24 months

Other Pre-specified Outcome Measures:

Title

Exploratory outcomes 1: Change in biochemical parameters - total cholesterol

Description

Absolute and percentage change compared to baseline in total cholesterol.

Time Frame

24 months

Title

Exploratory outcomes 1: Change in biochemical parameters - LDL-C

Description

Absolute and percentage change compared to baseline in LDL-C.

Time Frame

24 months

Title

Exploratory outcomes 1: Change in biochemical parameters - HDL-C

Description

Absolute and percentage change compared to baseline in high density lipoprotein-associated cholesterol (HDL-C).

Time Frame

24 months

Title

Exploratory outcomes 1: Change in biochemical parameters - triglycerides

Description

Absolute and percentage change compared to baseline in triglycerides.

Time Frame

24 months

Title

Exploratory outcomes 1: Change in biochemical parameters - lipoprotein (a)

Description

Absolute and percentage change compared to baseline in lipoprotein(a).

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Ischaemic and non-ischaemic stroke

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Ischaemic and non-ischaemic stroke

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - TIA

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Transient ischaemic attack

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Progression to carotid endarterectomy

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Progression to carotid endarterectomy

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - MI

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Myocardial infarction

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Unstable angina

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Unstable angina

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Hospitalisation for heart failure

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: Hospitalisation for heart failure

Time Frame

24 months

Title

Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events -PAD-related end points: peripheral revascularization,

Description

Cardio- and cerebrovascular events [be adjudicated by the Investigators], including: PAD-related end points: peripheral revascularization,

Time Frame

24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jaimini Cegla, BSc MSc MBBS MRCP FRCPath PhD

Organizational Affiliation

Imperial College London

Official's Role

Principal Investigator

Facility Information:

Facility Name

Imperial College Healthcare NHS Trust

City

London

ZIP/Postal Code

W12 0HS

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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