Alirocumab for Stabilisation of Symptomatic Vulnerable Carotid Plaque

Official title

Alirocumab for Stabilisation of Symptomatic Vulnerable Carotid Plaque: A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial With High-Resolution Vessel-Wall MRI and Clinical Endpoints

Overview

CAROTID-STABILISE is a phase III, multicentre, randomised, double-blind, placebo-controlled trial evaluating whether alirocumab 150 mg subcutaneously every 2 weeks, added to high-intensity statin therapy, produces greater reduction in intraplaque haemorrhage (IPH) volume at 26 weeks compared with placebo in patients with recently symptomatic carotid stenosis of 50-69% harbouring IPH or lipid-rich necrotic core (LRNC) on high-resolution vessel-wall MRI. The study will enroll 280 participants across multiple centres with a 52-week extension for durability and clinical endpoints assessment.

Detailed description

BACKGROUND: Symptomatic carotid stenosis of 50-69% carries a 30-day recurrent-stroke risk of 5-8% and a 2-year risk of 15-20% on best medical therapy alone. A substantial proportion of patients are either surgically deferred or anatomically borderline where revascularisation benefit is debated. PCSK9 inhibitors have demonstrated carotid plaque regression, reduction in lipid-rich necrotic core, and reduction in arterial inflammation. However, no RCT has tested whether PCSK9 inhibition can reduce intraplaque haemorrhage or LRNC in symptomatic carotid plaque.

DESIGN: This is a phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group superiority trial with a 26-week primary endpoint assessment and a 52-week extension. Patients with recently symptomatic carotid stenosis (50-69%) with MRI-confirmed vulnerable plaque features (IPH or LRNC) will be randomised 1:1 to alirocumab 150 mg SC q2w or matched placebo, both on background high-intensity statin therapy.

PRIMARY ENDPOINT: Absolute change in IPH volume (mm³) from baseline to week 26, measured on MPRAGE sequences by a blinded central imaging core lab using semi-automated segmentation.

SECONDARY ENDPOINTS: Include percent change in LRNC volume, absolute change in minimum fibrous cap thickness, percent change in total plaque wall volume at weeks 26 and 52, composite of ipsilateral recurrent stroke or TIA through week 52, and proportion avoiding carotid revascularisation through week 52.

SAFETY: Monitored by an independent Data and Safety Monitoring Board (DSMB) with pre-specified interim analyses at 50% and 75% enrolment.

Interventions

• Drug Alirocumab
  Alirocumab 150 mg subcutaneous injection every 2 weeks via pre-filled pen for 52 weeks. First dose given at randomisation visit under supervision. Self-administered or caregiver-administered at home for subsequent doses. Alirocumab is a fully human monoclonal antibody that inhibits PCSK9, leading to significant LDL-C reduction beyond that achieved with statins alone.
• Drug Placebo
  Matched placebo subcutaneous injection every 2 weeks via pre-filled pen for 52 weeks. Visually identical to alirocumab injection. First dose given at randomisation visit under supervision. Self-administered or caregiver-administered at home for subsequent doses.
• Drug Atorvastatin
  Atorvastatin 80 mg oral tablet once daily as background high-intensity statin therapy for both arms. Rosuvastatin 40 mg daily may be substituted if patient is intolerant to atorvastatin. Administered throughout the entire study duration (52 weeks).

Primary outcome measures

• Absolute change in intraplaque haemorrhage (IPH) volume from baseline to week 26 [Time frame: Baseline to 26 weeks]

Secondary outcome measures (7)

• Percent change in lipid-rich necrotic core (LRNC) volume at week 26 [Time frame: Baseline to 26 weeks]
• Absolute change in minimum fibrous cap thickness at week 26 [Time frame: Baseline to 26 weeks]
• Percent change in total plaque wall volume at week 26 [Time frame: Baseline to 26 weeks]
• Percent change in intraplaque haemorrhage (IPH) volume at week 52 [Time frame: Baseline to 52 weeks]
• Percent change in lipid-rich necrotic core (LRNC) volume at week 52 [Time frame: Baseline to 52 weeks]
• Composite of ipsilateral recurrent ischaemic stroke or TIA through week 52 [Time frame: Randomisation to 52 weeks]
• Proportion of patients avoiding carotid revascularisation through week 52 [Time frame: Randomisation to 52 weeks]

Eligibility criteria

Inclusion criteria

• Age ≥ 40 and ≤ 80 years
• Recently symptomatic (TIA, amaurosis fugax, or non-disabling ischaemic stroke with mRS ≤ 2) referable to a carotid territory within 28 days of randomisation
• Ipsilateral extracranial internal carotid artery stenosis of 50-69% by NASCET criteria on CTA or DSA
• HR-VW-MRI evidence of IPH (MPRAGE hyperintensity ≥150% of adjacent sternocleidomastoid) OR LRNC ≥ 10% of plaque volume in the symptomatic plaque
• On a stable dose of high-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) for ≥ 4 weeks, or able and willing to initiate atorvastatin 80 mg daily at randomisation
• LDL-C ≥ 70 mg/dL (1.8 mmol/L) at screening
• Able to undergo 3T MRI (no contraindications)
• Provides written informed consent

Exclusion criteria

• Indication for urgent carotid revascularisation within 14 days per treating team
• Disabling stroke (mRS > 2) or NIHSS > 5 at randomisation
• Carotid stenosis ≥ 70% or occlusion
• Cardioembolic stroke source (atrial fibrillation, LV thrombus, endocarditis, PFO with high-risk features)
• Intracranial haemorrhage within 12 months or any history of symptomatic ICH
• eGFR < 30 mL/min/1.73 m²
• Active hepatobiliary disease or ALT/AST > 3x ULN
• Prior exposure to any PCSK9 inhibitor or inclisiran within 6 months
• Known hypersensitivity to alirocumab or excipients
• Pregnancy, breastfeeding, or unwillingness to use contraception in women of childbearing potential
• Life expectancy < 24 months
• Participation in another interventional trial within 30 days
• Inability to comply with follow-up or MRI schedule

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Egypt · 4 centers

• Alexandria University, Smouha University Comprehensive Stroke Center — Alexandria
• Ain Shams University — Cairo
• Cairo University — Cairo
• Neurology Department, Al-Azhar University — Cairo

Saudi Arabia · 3 centers

• King Khalid University — Abhā
• King Abdulaziz Medical City — Jeddah
• King Abdullah Medical City — Mecca

Turkey (Türkiye) · 2 centers

• Department of Neurology, Eskisehir Osmangazi University — Eskişehir
• Neurology Department, Dr. Lutfi Kirdar City Hospital — Istanbul

Jordan · 1 center

• Amman Specialized IR Center — Amman

Morocco · 1 center

• Centre Hospitalier Universitaire Ibn Sina de Rabat — Rabat

Pakistan · 1 center

• Aga Khan University — Karachi

Qatar · 1 center

• Weill Cornell Medicine-Qatar — Doha

Tunisia · 1 center

• Institut National de Neurologie — Tunis

Identifiers

NCT: NCT07586540 · MENASINO-CAROTID-2026-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗