PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Stroke Clinical Trial

— PINNACLE  

Official title:

PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03507374
• Other study ID #: 00104839
• Status: Terminated
• Phase: Early Phase 1
• Start date: October 30, 2018
• Est. completion date: April 17, 2020

Study information

• Verified date: April 2020
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: April 17, 2020
• Est. primary completion date: April 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atherosclerosis
• Hemorrhage
• Intracranial Arteriosclerosis
• Intracranial Atherosclerosis
• Intraplaque Hemorrhage
• Stroke

Intervention

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

Locations

Country	Name	City	State
United States	University of Utah	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
University of Utah	Regeneron Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (39)

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* Note: There are 39 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mechanism of Alirocumab's effect	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.	Day 1 and Day 365
Other	Lab Assessment	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.	Baseline visit and Day 365
Other	Clinical Outcomes	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.	Baseline and Day 365
Primary	Vessel Wall MRI	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	Day 1 and Day 365
Secondary	Post-Contrast Plaque Enhancement	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.	Day 1