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

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.

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.