PINNACLE: PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Sponsor

University of Utah (Other)

Overall Status

Terminated

CT.gov ID

NCT03507374

Collaborator

Regeneron Pharmaceuticals (Industry)

Enrollment

Location

Arms

17.6

Actual Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke Intracranial Atherosclerosis Intraplaque Hemorrhage	Drug: Alirocumab Drug: Placebo	Early Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Actual Study Start Date :

Oct 30, 2018

Actual Primary Completion Date :

Apr 17, 2020

Actual Study Completion Date :

Apr 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Comparator 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.	Drug: Placebo Placebo to be administered subcutaneously every 2 weeks identical to active drug (alirocumab)
Active Comparator: Active Comparator 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	Drug: Alirocumab Alirocumab is approved by the FDA as a secondary treatment for high cholesterol for adults whose cholesterol can not be controlled by diet and/or statin treatment. Additionally, Alirocumab works to inhibit the PCSK9 protein. Other Names: Praluent

Arm

Intervention/Treatment

Placebo Comparator: Placebo Comparator

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.

Drug: Placebo

Placebo to be administered subcutaneously every 2 weeks identical to active drug (alirocumab)

Active Comparator: Active Comparator

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

Drug: Alirocumab

Alirocumab is approved by the FDA as a secondary treatment for high cholesterol for adults whose cholesterol can not be controlled by diet and/or statin treatment. Additionally, Alirocumab works to inhibit the PCSK9 protein.

Other Names:

Praluent

Outcome Measures

Primary Outcome Measures

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

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.

Other Outcome Measures

Mechanism of Alirocumab's effect [Day 1 and Day 365]
To better understand the mechanism of alirocumab's effect on intra- and extracranial atherosclerosis, we will measure the endpoint of change in cholesterol markers [LDL-C, HDL-C, lipoprotein (a), apolipoprotein B, and triglyceride level]. The change in cholesterol markers will be correlated with the primary and secondary study endpoints on vwMRI. Cholesterol values will be measured at the baseline and comparison MRIs, which are 52 weeks apart. An additional exploratory outcome that we will measure is the composite endpoint of "recurrent stroke," which encompasses new symptomatic ischemic stroke, transient ischemic attack, or asymptomatic strokes that emerge between the study MRIs.
Lab Assessment [Baseline visit and Day 365]
At both study MRIs, the study coordinator will collect two blood samples. One sample will be tested with an i-STAT for beta hCG and creatinine levels prior to the MRI. The second sample which will be sent to ARUP Laboratories for testing of LDL-C, HDL-C, triglycerides, apolipoprotein B, and lipoprotein (a), biomarkers of cardiovascular disease risk.
Clinical Outcomes [Baseline and Day 365]
b) At both study visits (baseline vwMRI and follow-up vwMRI), a vascular neurologist blinded to treatment arm assignment will assess patients and their medical records for recurrent stroke. The neurologist will also have access to the "stroke characteristics" data from the neuroradiologist raters. The endpoint of recurrent stroke is defined both for the stroke parent artery and other arterial distributions in the cerebrovasculature.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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