Cerebrolysin After Reperfusion in Extended-window EndoVascular Thrombectomy (CARE-EVT)

Cerebrolysin After Reperfusion in Extended-Window Endovascular Thrombectomy: A Multicenter Randomized Controlled Trial

Acute ischemic stroke caused by blockage of a large brain artery can lead to severe disability. Endovascular thrombectomy is a catheter-based procedure used to remove the blood clot and restore blood flow. It can benefit selected patients treated 6 to 24 hours after stroke onset, but some patients remain disabled even when the blocked artery is successfully reopened. Ongoing injury to brain tissue, small blood vessels, and the blood-brain barrier may contribute to this incomplete recovery.

This multicenter randomized clinical trial will evaluate whether Cerebrolysin, given after successful extended-window endovascular thrombectomy, can reduce brain tissue injury and support recovery. The study will enroll 100 adults aged 18 to 80 years at three stroke centers in Taiwan. Participants will be randomly assigned, after successful reperfusion has been confirmed, to receive either Cerebrolysin 30 mL or a matched normal saline placebo by intravenous infusion once daily for 10 consecutive days. The first infusion will begin within 36 hours of stroke onset. All participants will also receive standard stroke care and rehabilitation.

The primary outcome is final infarct volume measured by diffusion-weighted magnetic resonance imaging on Day 7 to Day 10. Other outcomes include functional recovery at 3 and 12 months, neurological improvement, symptomatic intracranial hemorrhage, cerebral edema, recurrent stroke, mortality, cognition, language, and mood. The study will also examine blood-brain barrier injury using computed tomography perfusion, dynamic contrast-enhanced magnetic resonance imaging, and serial plasma Claudin-5 measurements.

This study will determine whether Cerebrolysin shows evidence of reducing postreperfusion brain injury after successful thrombectomy and will help guide the design of a larger trial focused on clinical outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Cerebrolysin; Drug: Normal saline placebo

Detailed Description

This is an investigator-initiated, multicenter, randomized, placebo-controlled, participant- and outcome-assessor-blinded proof-of-concept trial conducted at three stroke centers within the Chang Gung Memorial Hospital system in Taiwan.

The study will enroll 100 participants aged 18 to 80 years with anterior-circulation acute ischemic stroke caused by internal carotid artery or M1/M2 middle cerebral artery occlusion. Eligible participants must undergo endovascular thrombectomy more than 6 hours and no more than 24 hours after stroke onset and must achieve successful reperfusion, defined as modified Thrombolysis in Cerebral Infarction grade 2b or 3, before randomization.

Participants will be randomized in a 1:1 ratio to receive Cerebrolysin 30 mL diluted in 70 mL normal saline or matched normal saline placebo. Study treatment will be administered intravenously over 60 minutes once daily for 10 consecutive days and will begin after randomization and within 36 hours of stroke onset. Both groups will receive standard post-thrombectomy stroke care, secondary prevention, and rehabilitation.

The primary outcome is final infarct volume measured on diffusion-weighted magnetic resonance imaging performed on Day 7 to Day 10. The key secondary clinical outcome is functional independence, defined as a modified Rankin Scale score of 0 to 2, at Month 3. Other outcomes include ordinal modified Rankin Scale, National Institutes of Health Stroke Scale, Barthel Index, symptomatic intracranial hemorrhage, asymptomatic hemorrhagic transformation, cerebral edema, recurrent stroke, all-cause mortality, vessel patency, cognition, language, and mood through Month 12.

Mechanistic assessments will evaluate blood-brain barrier injury. Computed tomography perfusion-derived blood-brain barrier permeability will be measured before thrombectomy and approximately 24 hours after reperfusion. Dynamic contrast-enhanced magnetic resonance imaging will assess subacute permeability on Day 7 to Day 10. Plasma Claudin-5, an exploratory marker of endothelial tight-junction injury, will be measured at groin puncture before reperfusion, 24 hours after reperfusion, and on Day 7.

The trial is designed to determine whether adjunctive Cerebrolysin reduces tissue-level injury and provides biological signals consistent with preservation of blood-brain barrier integrity after successful extended-window thrombectomy. The study is not powered to establish definitive clinical efficacy, and clinical and mechanistic secondary analyses will be considered exploratory.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Chien H Chang, MD; Phone Number: +886978009593; Email: cva9514@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 80 years.
• Acute anterior-circulation ischemic stroke caused by internal carotid artery or M1 or M2 middle cerebral artery occlusion confirmed by computed tomography angiography.
• Stroke onset-to-groin-puncture interval greater than 6 hours and no more than 24 hours.
• Prestroke modified Rankin Scale score of 0 to 2.
• Baseline National Institutes of Health Stroke Scale score of at least 6 with cortical signs.
• Alberta Stroke Program Early Computed Tomography Score greater than 3.
• Computed tomography perfusion target mismatch defined as ischemic core volume less than 70 mL, mismatch ratio at least 1.8, and mismatch volume at least 15 mL.
• Moderate-to-good collateral circulation, defined as filling of more than 50% of the middle cerebral artery territory on computed tomography angiography.
• Successful endovascular reperfusion, defined as modified Thrombolysis in Cerebral Infarction grade 2b or 3, confirmed before randomization.
• Study treatment can be initiated within 36 hours of stroke onset.
• Written informed consent obtained before randomization from the participant or a legally authorized representative.

Exclusion Criteria:

• Life expectancy less than 6 months or a serious medical, neurological, or psychiatric condition likely to interfere with study treatment, follow-up, or outcome assessment.
• Current pregnancy or breastfeeding.
• Known iodinated contrast allergy that precludes required endovascular or imaging procedures.
• Acute or chronic renal failure with creatinine clearance less than 30 mL/min.
• Known hypersensitivity or contraindication to Cerebrolysin.
• Aspartate aminotransferase or alanine aminotransferase greater than 2 times the upper limit of normal, or total bilirubin greater than 2 mg/dL.
• Blood glucose less than 50 mg/dL or greater than 400 mg/dL.
• Platelet count less than 50,000/mm3 or international normalized ratio greater than 3.
• Seizure at stroke onset that prevents reliable neurological assessment.
• Pre-existing intracranial hemorrhage or multiple vascular occlusions on baseline neuroimaging.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cerebrolysin After Successful Extended-Window Thrombectomy; Participants will receive Cerebrolysin 30 mL diluted in 70 mL normal saline, administered intravenously over 60 minutes once daily for 10 consecutive days. The first infusion will begin after successful endovascular reperfusion and randomization and within 36 hours of stroke onset. All participants will also receive standard post-thrombectomy stroke care, secondary prevention, and rehabilitation.	Drug: Cerebrolysin; Cerebrolysin 30 mL diluted in 70 mL normal saline will be administered intravenously over 60 minutes once daily for 10 consecutive days. Treatment will begin after successful endovascular reperfusion and randomization and within 36 hours of stroke onset.
Placebo Comparator: Matched Placebo After Successful Extended-Window Thrombectomy; Participants will receive 100 mL normal saline placebo, administered intravenously over 60 minutes once daily for 10 consecutive days according to the same schedule as the experimental arm. The first infusion will begin after successful endovascular reperfusion and randomization and within 36 hours of stroke onset. All participants will also receive standard post-thrombectomy stroke care, secondary prevention, and rehabilitation.	Drug: Normal saline placebo; Normal saline 100 mL will be administered intravenously over 60 minutes once daily for 10 consecutive days according to the same schedule as Cerebrolysin. Infusion bags, drip chambers, and visible tubing will be covered to maintain masking.; Other Names: cerebrolysin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Final Infarct Volume on Diffusion-Weighted MRI	Final infarct volume will be quantified on Day 7-10 diffusion-weighted magnetic resonance imaging using standardized semiautomated lesion segmentation with manual correction when required. Imaging readers will be blinded to treatment allocation. Participants who are unable to undergo MRI will remain in the intention-to-treat population, and missing primary-outcome data will be addressed using prespecified imputation and sensitivity analyses.	Day 7 to Day 10 after stroke onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Independence Defined as Modified Rankin Scale Score 0-2	The proportion of participants achieving functional independence, defined as a modified Rankin Scale score of 0 to 2, will be assessed using a validated structured interview.	Month 3 and Month 12 after stroke onset
Symptomatic Intracranial Hemorrhage	Symptomatic intracranial hemorrhage will be defined according to the ECASS III criteria.	Within 7 days after stroke onset
Change in Computed Tomography Perfusion-Derived Blood-Brain Barrier Permeability	Blood-brain barrier permeability surface area product will be measured using the Patlak model before thrombectomy and approximately 24 hours after reperfusion. The change from baseline will be compared between treatment groups.	Pre-EVT and 24 ± 6 hours after reperfusion
Plasma Claudin-5 Concentration-Time Profile	Plasma Claudin-5 concentrations will be measured as an exploratory marker of endothelial tight-junction injury.	At groin puncture before reperfusion, 24 ± 6 hours after reperfusion, and Day 7 ± 1
Montreal Cognitive Assessment Score	Global cognitive function will be assessed using the Montreal Cognitive Assessment, with lower scores indicating greater cognitive impairment.	Months 3, 6, and 12
Recurrent Stroke	The occurrence of recurrent ischemic or hemorrhagic stroke will be recorded through clinical follow-up and review of available medical records.	Through Month 12

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Collaborators: EVER Pharma France SAS

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: March 25, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): April 1, 2024

Study Record Updates

• Last Update Posted (Actual): August 11, 2026
• Last Update Submitted That Met QC Criteria: August 9, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Cerebrolysin; Neuroprotection; Large Vessel Occlusion; Endovascular Thrombectomy; Blood-Brain Barrier; Computed Tomography Perfusion; Extended Time Window; Claudin-5
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; Physiological Effects of Drugs; Neuroprotective Agents; Protective Agents; Nootropic Agents; cerebrolysin
• Other Study ID Numbers: 202302239A3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual participant data may be shared after publication of the primary trial results upon reasonable request. Data sharing will require approval by the investigators, applicable ethical and regulatory review, protection of participant confidentiality, institutional approval, and execution of a data-use agreement. The trial protocol and statistical analysis plan will be made available with the primary trial publication. Statistical code may also be shared upon reasonable request, subject to institutional approval.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No