Trial of PCSK9 Inhibition in Patients With Acute Stroke and Symptomatic Intracranial Atherosclerosis

Study Overview
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Brief Summary
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This study will evaluate whether low-density lipoprotein (LDL-C) lowering with alirocumab results in greater change from baseline in intracranial atherosclerotic plaque at week 26 than control in adults with acute ischemic stroke from intracranial atherosclerosis taking lipid lowering therapy.

Detailed Description
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In this trial, we will conduct a prospective, randomized, open-label, blinded end-point study using high-resolution MRI in patients with acute ischemic stroke from intracranial atherosclerosis to evaluate the efficacy and safety of alirocumab. We hypothesis that additional alirocumab treatment on a background of statin therapy could result in greater stabilization of intracranial plaque and regression of arterial stenosis.

Official Title
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Trial of PCSK9 Inhibition in Patients With Acute Stroke and Symptomatic Intracranial Atherosclerosis - a Prospective, Randomized, Open-label, Blinded End-point Study With High-resolution MR Vessel Wall Imaging

Conditions
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Intracranial Atherosclerosis, Acute Ischemic Stroke, ICAS - Intracranial Atherosclerosis

Intervention / Treatment
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* Drug: Alirocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) score of 1-15 Ischemic lesions on diffuse-weighted imaging located in the territory of symptomatic intracranial atherosclerosis (ICAS). Symptomatic ICAS (above 30%) at the M1 or M2 of the middle cerebral artery, basilar artery or at the intracranial portion of the internal carotid artery or vertebral artery. Serum LDL-C ≥70 mg/dL for subjects on lipid-lowering therapies (such as a statin and/or ezetimibe) or LDL-C ≥100 mg/dL for subjects without lipid-lowering therapies. Ability to randomize within 7 days of time last known free of new ischemic symptoms. Ability to receive alirocumab or statin treatment within 7 days of stroke onset. Head CT or MRI ruling out hemorrhage or other pathology, such as vascular malformation, tumor, or abscess, that could explain symptoms or contraindicate therapy. Pre-stroke modified Rankin Scale (mRS)≦2 Exclusion Criteria: Age <20 years. Judged by clinical physician. After endovascular intervention or endarterectomy for the symptomatic ICAS. Patients with more than 50% stenosis of extra-cranial arteries the relevant arteries on magnetic resonance angiography (MRA), including extra-cranial carotid artery or vertebral arteries. Patients with high risk of cardioembolic source, such as atrial fibrillation, acute myocardial infarction, severe heart failure or valvular heart disease. Other determined stroke etiology, such as vasculitis, shock, antiphospholipid antibody syndrome, arterial dissection, CADASIL and etc. Qualifying ischemic event induced by angiography or surgery. Severe non-cardiovascular comorbidity with life expectancy <6 months. Contraindication or allergy to alirocumab or Gadolinium Severe renal (serum creatinine >2 mg/dL) or calculated glomerular filtration rate <30 mL/min/ 1.73 m2 by estimated glomerular filtration rate (eGFR) using Cockcroft Gault methodology. Hepatic insufficiency (INR>1.2; ALT>40 U/L or any resultant complication, such as variceal bleeding, encephalopathy, or jaundice) Hemostatic disorder or systemic bleeding in the past 3 months Current thrombocytopenia (platelet count <100 x109/L) or leukopenia (<2 x109/L) Anemia（<10 mg/dL） History of drug-induced hematologic or hepatic abnormalities History of malignancy that required surgery, radiation therapy or systemic therapy. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use effective contraception. Other neurological conditions that would complicate assessment of outcomes during follow-up.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, open-label, blinded end-point study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>In addition to high-intensity statin and antiplatelet treatment, patients will receive treatment of alirocumab 75mg subcutaneously every 2 weeks for a total of 26 weeks | Drug: Alirocumab<br>* Alirocumab 75mg subcutaneously every 2 weeks for a total of 26 weeks.<br>* Other names: Praluent;|
| No Intervention: Control group<br>Patient will have high-intensity statin and antiplatelet treatment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes of intracranial atherosclerotic plaque: stenosis degree | The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as stenosis degree. The degree of stenosis was calculated as: (1-lumen area of stenotic lesion/reference lumen area)×100%. | 26 weeks | 
| The changes of intracranial atherosclerotic plaque: percent atheroma volume | The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as percent atheroma volume (PAV). The PAV was calculated using the following equation: PAV = Σ(EEM area - Lumen area) / ΣEEM area × 100, where EEM area is the cross-sectional area of the external elastic membrane and Lumen area is the cross-sectional area of the lumen. | 26 weeks | 
| The changes of intracranial atherosclerotic plaque: enhancement volume | The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as enhancement volume. The enhancement volume was measured as post-contrast plaque enhancement for intracranial arteries and intraplaque hemorrhage. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with major cardiovascular events | Defined as the composite of cardiovascular death, myocardial infarction, transient ischemic attack, ischemic stroke and hemorrhagic stroke. | 26 weeks | 
| Percentage of patients with myocardial infarction | patients with myocardial infarction | 26 weeks | 
| Percentage of patients with cardiovascular death | patients with cardiovascular death | 26 weeks | 
| Percentage of patients with stroke | Include transient ischemic attack, ischemic and hemorrhagic stroke | 26 weeks | 
| Percentage of patients with ischemic stroke or transient ischemic attack. | Percentage of patients with ischemic stroke or transient ischemic attack. | 26 weeks | 
| Percentage of patients with new ischemic lesions | Defined as new ischemic lesions in the territory of ICAS between 2 MRIs | 26 weeks | 
| Percentage of patients with favorable functional recovery | Defined as a mRS ≦2 mRS. The Modified Rankin Scale (mRS) runs from 0-6, running from perfect health without symptoms(score 0) to death(score 6). | 3 months | 
| Changes in serum biomarkers | Include liver function tests, HbA1c and lipid profiles. | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intracranial Atherosclerosis, Acute Ischemic Stroke, PCSK9 inhibitor