Clinical trial NCT03931161: Effect of Evolocumab on Carotid Plaque Composition in Asymptomatic Carotid Artery Stenosis (EVOCAR-1)
Official title: Effect of Evolocumab on Carotid Plaque Composition in Asymptomatic Carotid Artery Stenosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Carotid Artery Stenosis
Keywords: carotid plaque morphology
carotid plaque composition
evolocumab
Lead sponsor: Imperial College Healthcare NHS Trust
Sponsor class: OTHER
Collaborators: name: Imperial College London
First posted: 2019-04-30
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in lipid-rich necrotic core
timeFrame: 12 months
Secondary outcomes:
measure: Percentage of LRNC core
timeFrame: 12 months
measure: LRNC regression
timeFrame: 12 months
measure: LRNC volume
timeFrame: 24 months
measure: LRNC percentage
timeFrame: 24 months
measure: Measures of other carotid plaque burden - Volume wall thickness
timeFrame: 24 months
measure: Measures of other carotid plaque burden - Volume wall area
timeFrame: 24 months
measure: Measures of other carotid plaque burden - Calcification
timeFrame: 24 months
measure: Measures of other carotid plaque burden - Fibrous tissue volume
timeFrame: 24 months
measure: Measures of other carotid plaque burden - New intra-plaque haemorrhage
timeFrame: 24 months
Other outcomes:
measure: Exploratory outcomes 1: Change in biochemical parameters - total cholesterol
timeFrame: 24 months
measure: Exploratory outcomes 1: Change in biochemical parameters - LDL-C
timeFrame: 24 months
measure: Exploratory outcomes 1: Change in biochemical parameters - HDL-C
timeFrame: 24 months
measure: Exploratory outcomes 1: Change in biochemical parameters - triglycerides
timeFrame: 24 months
measure: Exploratory outcomes 1: Change in biochemical parameters - lipoprotein (a)
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Ischaemic and non-ischaemic stroke
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - TIA
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Progression to carotid endarterectomy
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - MI
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Unstable angina
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Hospitalisation for heart failure
timeFrame: 24 months
measure: Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events -PAD-related end points: peripheral revascularization,
timeFrame: 24 months
Locations:
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: Imperial College London
name: Jaimini Cegla, BSc MSc MBBS MRCP FRCPath PhD
role: PRINCIPAL_INVESTIGATOR
References: