Carotid Artery Stenosis
Conditions
Keywords
carotid plaque morphology, carotid plaque composition, evolocumab
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.
Interventions
Auto-Injector, 140 mg every two weeks.
Matching Placebo for the active comparator (Evolocumab)
Sponsors
Imperial College London
Imperial College Healthcare NHS Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in lipid-rich necrotic core | 12 months | Change in lipid-rich necrotic core (LRNC) size at 12 months, compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LRNC regression | 12 months | Percentage of participants achieving LRNC regression at 12 months |
| LRNC volume | 24 months | Change in carotid plaque LRNC volume at other time-points, compared to baseline |
| LRNC percentage | 24 months | Change in carotid plaque LRNC percentage at other time-points, compared to baseline |
| Measures of other carotid plaque burden - Volume wall thickness | 24 months | Absolute and percentage change, compared to baseline, of volume wall thickness |
| Percentage of LRNC core | 12 months | Change in percentage lipid-rich necrotic core (LRNC) at 12 months, compared to baseline |
| Measures of other carotid plaque burden - Calcification | 24 months | Absolute and percentage change, compared to baseline, of plaque composition (calcification) |
| Measures of other carotid plaque burden - Fibrous tissue volume | 24 months | Absolute and percentage change, compared to baseline, of plaque composition (fibrous tissue volume) |
| Measures of other carotid plaque burden - New intra-plaque haemorrhage | 24 months | Absolute and percentage change, compared to baseline, of plaque composition (new intra-plaque haemorrhage) |
| Measures of other carotid plaque burden - Volume wall area | 24 months | Absolute and percentage change, compared to baseline, volume wall area |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Hospitalisation for heart failure | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Hospitalisation for heart failure |
| Exploratory outcomes 1: Change in biochemical parameters - total cholesterol | 24 months | Absolute and percentage change compared to baseline in total cholesterol. |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events -PAD-related end points: peripheral revascularization, | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: PAD-related end points: peripheral revascularization, |
| Exploratory outcomes 1: Change in biochemical parameters - LDL-C | 24 months | Absolute and percentage change compared to baseline in LDL-C. |
| Exploratory outcomes 1: Change in biochemical parameters - HDL-C | 24 months | Absolute and percentage change compared to baseline in high density lipoprotein-associated cholesterol (HDL-C). |
| Exploratory outcomes 1: Change in biochemical parameters - triglycerides | 24 months | Absolute and percentage change compared to baseline in triglycerides. |
| Exploratory outcomes 1: Change in biochemical parameters - lipoprotein (a) | 24 months | Absolute and percentage change compared to baseline in lipoprotein(a). |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Ischaemic and non-ischaemic stroke | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Ischaemic and non-ischaemic stroke |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - TIA | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Transient ischaemic attack |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Progression to carotid endarterectomy | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Progression to carotid endarterectomy |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - MI | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Myocardial infarction |
| Exploratory outcomes 2: Number of patients with Cardio & cerebrovascular events - Unstable angina | 24 months | Cardio- and cerebrovascular events \[be adjudicated by the Investigators\], including: Unstable angina |
Countries
United Kingdom
Outcome results
None listed