PCSK9 Inhibition in Patients with Symptomatic Intracranial Atherosclerosis

Principal Investigator: Adam  DeHavenon
Keywords: Stroke , Atherosclerosis , Syptomatic , Alirocumab , Stenosis , PRALUENT , Plaque , PCSK-9 , PINNACLE Department: Neurology
IRB Number: 00104839 Co Investigator:  
Specialty: Neurology, Neurology
Sub Specialties: Stroke , Vascular Neurology
Recruitment Status: Recruiting

Contact Information

Ka-Ho Wong
Ka-Ho.Wong@hsc.utah.edu
801.585.0541

Brief Summary

The purpose of this study will be to understand the mechanism by which PCSK9 inhibition reduces the rate of ischemic stroke seen in the pivotal studies that led to its FDA approval for ASCVD such as ischemic stroke. Those trials (FOURIER and ODYSSEY) enrolled almost 50,000 patients and showed that PCSK9 inhibition therapy is safe. However, the mechanism by which it reduces stroke isn unknown. We hypothesize that it reduces atherosclerotic plaque volume, which would be particularly beneficial for patients with intracranial atherosclerosis, who have the highest rate of recurrent stroke of any stroke mechanism. 

Single site, block randomized, placebo-controlled, double-blind, parallel design clinical trial of 40 adult patients with symptomatic intracranial atherosclerosis. The randomization is to the PCSK9 inhibitor alirocumab or placebo. In this research there are three objectives:

Objective 1: Determine if patients randomized to the PCSK9 inhibitor alirocumab have reduction in plaque volume of: 1) the stroke parent artery, and 2) additional intra- or extracranial cerebrovasculture arteries with atherosclerosis, particularly the carotid arteries and aortic arch

Objective 2: Determine if patients randomized to alirocumab have reduction in validated biomarkers of plaque vulnerability: 1) post-contrast plaque enhacement for intracranial atherosclerosis and 2) intraplaque hemorrhage for carotid atherosclerosis

Objective 3: Expore the mechanistic pathway for the effect of alirocumab in intra- and extracranial atherosclerosis, and if the rate of recurrent stroke is lower in patients randomized to alirocumab.

 

Inclusion Criteria

  • Adult patients, ≥ 18 years of age
  • Ischemic stroke (≤ 1 month from onset) in one major vascular territory on diffusion-weighted MRI
  • ICAD plaque of a “major intracranial artery,” causing >25% and <99% stenosis
    • Eligible arteries: vertebral (V4), basilar, PCA (P1, P2), MCA (M1, M2), terminal ICA, and ACA (A1)
  • Prescribed statin (American Heart Association guidelines would be atorvastatin 40 to 80 mg) 

Exclusion Criteria

  • Stroke mechanism other than ICAD, including history of atrial fibrillation, hypercoagulability, ipsilateral arterial dissection or carotid stenosis >50%, and rare causes of stroke such as vasculitis or CADASIL
  • Bihemispheric stroke or simultaneous stroke in the anterior and posterior circulation
  • Known to be statin intolerant
  • Positive pregnancy test
  • Gadolinium or PCSK9 inhibitor allergy
  • Acute or chronic kidney disease with eGFR<30 ml/min/1.73m2
  • Pacemaker or other MRI contraindications per American College of Radiology guidelines33
  • Inability to return for 1-year follow-up clinic visit and vwMRI