Cerebrolysin After Extended-Window Endovascular Thrombectomy

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.

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. Participant assent will also be sought whenever feasible.

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.

-------------------------------------------------------------------------------------------------------------------- Aphasia alone will not be considered evidence of incapacity. Supported communication methods will be used whenever feasible, and participants enrolled through representative consent will be re-consented if decision-making capacity is subsequently regained.