PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Early Phase 1

Terminated

• Conditions: Stroke; Intracranial Atherosclerosis; Intraplaque Hemorrhage
• Interventions: Drug: Placebo; Drug: Alirocumab

• Registration Number: NCT03507374
• Lead Sponsor: University of Utah

Brief Summary

This will be a randomized double blind placebo-controlled pilot study using a repeated measures design in which participants with acute ischemic stroke and intracranial atherosclerotic disease are randomized to either drug or placebo.

Detailed Description

The purpose of this study will be a dataset that lays the foundation for a randomized controlled trial of PCSK9 inhibition in intracranial atherosclerotic disease (ICAD) patients, designed to show a reduction in the primary endpoint of ischemic stroke recurrence. Such a trial would provide evidence for the utility of alirocumab to prevent recurrent stroke in ICAD. While we are proposing future studies to reduce recurrent ICAD stroke risk, it should be noted that, in the long term, our research may lead to effective primary ICAD stroke risk reduction through PCSK9 inhibition in patients at high risk of stroke identified through asymptomatic stenosis, post-contrast plaque enhancement (PPE) or intraplaque hemorrhage (IPH) on vwMRI.

Study Timeline

• Study First Submitted: 2018-04-13
• Study First Submitted QC: 2018-04-13
• Study First Posted: 2018-04-25
• Study Start: 2018-10-30
• Status Verified: 2020-04
• Primary Completion: 2020-04-17
• Study Completion: 2020-04-17
• Last Update Submitted: 2020-04-18
• Last Update Posted: 2020-04-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 20

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)
• Able to tolerate high-dose statin (atorvastatin 40-80 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
• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Comparator	Placebo	After review of eligibility criteria, 20 patients will be randomized to the placebo arm of the study where patient will administer one subcutaneous injection of placebo every two weeks for a total of 52 weeks. Additionally, per standard-of-care, patient will also be treated with atorvastatin 40-80 mg.
Active Comparator	Alirocumab	After review of eligibility criteria, 20 patients will be randomized to receive the investigational treatment of alirocumab 150mg which will be administered subcutaneously with a single-dose pre-filled pen syringe every 2 weeks for a total of 52 weeks. Additionally, per standard-of-care, patient will also be treated with atorvastatin 40-80 mg

Primary Outcome Measures

Name	Time	Method
Vessel Wall MRI	Day 1 and Day 365	Our primary outcome measures will be to assess the Vessel Wall MRI on Day 365 and compare it to day 1.The primary endpoint is nominal change in the composite percent atheroma volume (PAV) of the stroke parent artery and additional intra- or extracranial cerebrovasculature arteries with atherosclerosis (≥ 25% stenosis) from baseline to week 52. We will use measure PAV on vessel wall MRI (vwMRI), which evaluates all arteries from the aortic arch to the distal intracranial vasculature in a single scan. The primary endpoint will be analyzed for both: 1) the composite PAV of the stroke parent artery and any additional intra- or extracranial arteries that have at least 25% stenosis, and 2) separately for the PAV of the stroke parent artery. The PAV measurements will be performed using the validated MRI-PlaqueView software. Stenosis of the stroke parent artery and all additional arteries included in the composite PAV will be measured using standard methodology and also be evaluated as

Secondary Outcome Measures

Name	Time	Method
Post-Contrast Plaque Enhancement	Day 1	Secondary endpoint 1 is post-contrast plaque enhancement for intracranial arteries and intraplaque hemorrhage for the carotid artery, which are determined by two experienced neuroradiologist raters. If there is disagreement, then a third rater serves as a tie-breaker. The signal intensity characteristics of both endpoints have been standardized in prior literature.

Trial Locations

Locations (1)

University of Utah; 🇺🇸 Salt Lake City, Utah, United States