Overview

This randomized, double-blind, placebo-controlled phase III clinical trial aims to evaluate the efficacy and safety of intravenous recombinant human Prourokinase (rhPro-UK) in acute ischemic stroke patients with large vessel occlusion presenting 4.5-24 hours after last known well. The study will address two primary questions: 1) Whether rhPro-UK enhances pre-thrombectomy reperfusion rates and improves 90-day functional outcomes compared to placebo; 2) Whether rhPro-UK increases the risk of symptomatic intracranial hemorrhage and mortality.

Participants will be randomized to receive an intravenous bolus of rhPro-UK or matching placebo, with a total dose of 35mg (15mg administered as an intravenous push within 5 minutes, and the remaining 20mg continuously infused intravenously over 30 minutes). Key assessments include repeat neuroimaging (CT/CTA or MRI/MRA) at 24 hours post-treatment to evaluate reperfusion, NIH Stroke Scale score at day 5-7, and modified Rankin Scale score assessment at 90 days. Safety monitoring will focus on hemorrhagic transformation and mortality events throughout the study period.

Eligibility

Inclusion Criteria:

1. Age ≥18 years;
2. Acute ischemic stroke presenting within 4.5-24 hours of last known well;
3. No significant pre-stroke functional disability: for age \<80 years, pre-stroke modified Rankin scale (mRS) ≤2; for age ≥80 years, prestroke mRS ≤1;
4. Baseline NIHSS score ≥6;
5. Imaging criteria of BOTH:

1\. Occlusion on CTA/MRA in one of the following vessels: M1/M2 segment of middle cerebral artery, A1 segment of anterior cerebral artery, V4 segment of vertebral artery, basilar artery, or P1 segment of posterior cerebral artery. For A1, or P1 occlusions, vessel diameter must be ≥0.75 mm; 2. For anterior circulation occlusion: CTP/MRP demonstrating mismatch ratio ≥1.8, absolute mismatch volume ≥15 mL, and ischemic core volume \<70 mL; OR have a mismatch between the presence of an abnormal signal on MRI diffusion-weighted imaging and no visible signal change on FLAIR. For posterior circulation occlusion: pc-ASPECTS score ≥6.

6\. Plan to received endovascular thrombectomy; 7. The patient or their legal representative provides written informed consent.

Exclusion Criteria:

1. Intracranial hemorrhage confirmed by CT/MRI;
2. Onset accompanied by epileptic seizures, resulting in questionable stroke diagnosis and inability to obtain an accurate baseline NIHSS score;
3. Women who are pregnant or breastfeeding, or have a positive serum β-HCG test upon admission;
4. Already received intravenous thrombolytic after index stroke;
5. History of prior intracranial hemorrhage, including cerebral parenchymal hemorrhage, subarachnoid hemorrhage, and subdural/extradural hematoma;
6. Active bleeding or bleeding tendency, such as gastrointestinal bleeding, urinary tract bleeding, retinal hemorrhage, etc., or presence of coagulation dysfunction;
7. History of major recent surgery or trauma, such as intracranial or spinal surgery within the past 3 months, major surgery within the past 2 weeks, or severe head trauma within the past 3 weeks;
8. Baseline blood glucose \<2.8 mmol/L or \>22.2 mmol/L;
9. Received low molecular weight heparin within 24 hours, or oral anticoagulants with an International Normalized Ratio (INR) \>1.7, or thrombin inhibitors within 48 hours, among others;
10. Arterial tortuosity or other vascular anomalies precluding endovascular access to target vessel;
11. Pre-existing neurological/psychiatric disorders interfering with neurological assessment;
12. Space-occupying intracranial tumors (except for small meningiomas);
13. Intracranial aneurysm or arteriovenous malformation;
14. Terminal illness with life expectancy \<6 months;
15. Concurrent participation in other investigation clinical trials;
16. Presence of other conditions deemed by the investigator as unsuitable for participation in the study.