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
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 280
- 试验地点
- 14
- 主要终点
- Absolute change in intraplaque haemorrhage (IPH) volume from baseline to week 26
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Alirocumab + High-Intensity Statin
Alirocumab 150 mg subcutaneous injection every 2 weeks via pre-filled pen, self-administered or caregiver-administered, from randomisation through week 52. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Placebo (Drug)
Placebo + High-Intensity Statin
Matched placebo subcutaneous injection every 2 weeks via pre-filled pen from randomisation through week 52, visually identical to alirocumab. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Placebo (Drug)
Alirocumab + High-Intensity Statin
Alirocumab 150 mg subcutaneous injection every 2 weeks via pre-filled pen, self-administered or caregiver-administered, from randomisation through week 52. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Alirocumab (Drug)
Alirocumab + High-Intensity Statin
Alirocumab 150 mg subcutaneous injection every 2 weeks via pre-filled pen, self-administered or caregiver-administered, from randomisation through week 52. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Atorvastatin (Drug)
Placebo + High-Intensity Statin
Matched placebo subcutaneous injection every 2 weeks via pre-filled pen from randomisation through week 52, visually identical to alirocumab. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Alirocumab (Drug)
Placebo + High-Intensity Statin
Matched placebo subcutaneous injection every 2 weeks via pre-filled pen from randomisation through week 52, visually identical to alirocumab. Plus atorvastatin 80 mg daily (or rosuvastatin 40 mg if intolerant) as background therapy.
干预措施: Atorvastatin (Drug)
结局指标
主要结局
Absolute change in intraplaque haemorrhage (IPH) volume from baseline to week 26
时间窗: Baseline to 26 weeks
Absolute change in intraplaque haemorrhage volume (mm³) from baseline to week 26, measured on MPRAGE sequences by a blinded central imaging core laboratory using semi-automated segmentation. IPH is defined as hyperintensity ≥150% of adjacent sternocleidomastoid muscle signal on 3T MRI.
次要结局
- Percent change in lipid-rich necrotic core (LRNC) volume at week 26(Baseline to 26 weeks)
- Absolute change in minimum fibrous cap thickness at week 26(Baseline to 26 weeks)
- Percent change in total plaque wall volume at week 26(Baseline to 26 weeks)
- Percent change in intraplaque haemorrhage (IPH) volume at week 52(Baseline to 52 weeks)
- Percent change in lipid-rich necrotic core (LRNC) volume at week 52(Baseline to 52 weeks)
- Composite of ipsilateral recurrent ischaemic stroke or TIA through week 52(Randomisation to 52 weeks)
- Proportion of patients avoiding carotid revascularisation through week 52(Randomisation to 52 weeks)
研究者
Ossama Mansour
Professor of Neurology, Alexandria University
Alexandria University