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

Acute Ischemic Stroke Clinical Trial

— TOPICAL-MRI  

Official title:

Trial of PCSK9 Inhibition in Patients With Acute Stroke and Symptomatic Intracranial Atherosclerosis - a Prospective, Randomized, Open-label, Blinded End-point Study With High-resolution MR Vessel Wall Imaging

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05001984
• Other study ID #: TOPICAL-MRI
• Secondary ID: MOST 110-2314-B-
• Status: Recruiting
• Phase: Phase 2
• Start date: August 1, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: September 2023
• Source: Chang Gung Memorial Hospital
• Contact: Yenchu Huang, MD
• Phone: +88653621000
• Email: yenchu.huang[@]msa.hinet.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate whether low-density lipoprotein (LDL-C) lowering with alirocumab results in greater change from baseline in intracranial atherosclerotic plaque at week 26 than control in adults with acute ischemic stroke from intracranial atherosclerosis taking lipid lowering therapy.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 31, 2024
• Est. primary completion date: August 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Atherosclerosis
• Intracranial Arteriosclerosis
• Intracranial Atherosclerosis
• Ischemic Stroke
• Stroke

Intervention

Drug:
• Alirocumab
Alirocumab 75mg subcutaneously every 2 weeks for a total of 26 weeks.

Locations

Country	Name	City	State
Taiwan	Yenchu Huang	Chiayi City

Sponsors (2)

Lead Sponsor	Collaborator
Chang Gung Memorial Hospital	Chang Gung University

Country where clinical trial is conducted

Taiwan, 

References & Publications (22)

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Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225. doi: 10.1056/NEJMoa1800410. Epub 2018 May 16. — View Citation

Kim D, Park JM, Kang K, Cho YJ, Hong KS, Lee KB, Park TH, Lee SJ, Kim JG, Han MK, Kim BJ, Lee J, Cha JK, Kim DH, Nah HW, Kim DE, Ryu WS, Kim JT, Choi KH, Choi JC, Lee BC, Yu KH, Oh MS, Kim WJ, Kwon JH, Shin DI, Sohn SI, Hong JH, Lee JS, Lee J, Gorelick PB, Bae HJ. Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke. Stroke. 2019 May;50(5):1184-1192. doi: 10.1161/STROKEAHA.119.024786. — View Citation

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* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The changes of intracranial atherosclerotic plaque: stenosis degree	The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as stenosis degree.; The degree of stenosis was calculated as: (1-lumen area of stenotic lesion/reference lumen area)×100%.	26 weeks
Primary	The changes of intracranial atherosclerotic plaque: percent atheroma volume	The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as percent atheroma volume (PAV).; The PAV was calculated using the following equation: PAV = S(EEM area - Lumen area) / SEEM area × 100, where EEM area is the cross-sectional area of the external elastic membrane and Lumen area is the cross-sectional area of the lumen.	26 weeks
Primary	The changes of intracranial atherosclerotic plaque: enhancement volume	The changes of intracranial atherosclerotic plaque in vessel-wall MRI before and after 6-month treatment, measured as enhancement volume.; The enhancement volume was measured as post-contrast plaque enhancement for intracranial arteries and intraplaque hemorrhage.	26 weeks
Secondary	Percentage of patients with major cardiovascular events	Defined as the composite of cardiovascular death, myocardial infarction, transient ischemic attack, ischemic stroke and hemorrhagic stroke.	26 weeks
Secondary	Percentage of patients with myocardial infarction	patients with myocardial infarction	26 weeks
Secondary	Percentage of patients with cardiovascular death	patients with cardiovascular death	26 weeks
Secondary	Percentage of patients with stroke	Include transient ischemic attack, ischemic and hemorrhagic stroke	26 weeks
Secondary	Percentage of patients with ischemic stroke or transient ischemic attack.	Percentage of patients with ischemic stroke or transient ischemic attack.	26 weeks
Secondary	Percentage of patients with new ischemic lesions	Defined as new ischemic lesions in the territory of ICAS between 2 MRIs	26 weeks
Secondary	Percentage of patients with favorable functional recovery	Defined as a mRS ?2 mRS. The Modified Rankin Scale (mRS) runs from 0-6, running from perfect health without symptoms(score 0) to death(score 6).	3 months
Secondary	Changes in serum biomarkers	Include liver function tests, HbA1c and lipid profiles.	26 weeks