Intravenous Recombinant Human Prourokinase for Acute Medium Vessel Occlusion 4.5-24 Hours After Ischemic Stroke

Prior treatment

• Patients who have received reperfusion therapy, including intravenous thrombolysis, intra-arterial thrombolysis, or endovascular therapy (EVT), within 72 hours after the onset of the current stroke and before randomization..
• Active internal bleeding or a condition associated with a high risk of bleeding, including but not limited to gastrointestinal or urinary tract bleeding within the previous 21 days; major surgery, severe trauma, or biopsy of a major organ within the previous 21 days; arterial puncture at a noncompressible site within the previous 7 days; or any other condition considered by the investigator to confer a substantial bleeding risk.
• History of ischemic stroke, severe head trauma, or myocardial infarction within the previous 3 months.
• Intracranial or intraspinal surgery within the previous 3 months.
• Baseline head CT showing acute or previous intracranial hemorrhage, including intraparenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma, or epidural hematoma.
• Currently receiving hemodialysis or peritoneal dialysis.
• Current participation in another interventional clinical study that may affect the efficacy or safety evaluation of this study, or participation in another interventional clinical study within the previous 3 months.

Other illness

• Seizure at stroke onset when, in the investigator's judgment, the neurological deficit may be attributable to postictal Todd paralysis or another non-ischemic cause.
• Other severe neurological, psychiatric, or systemic disease that may substantially affect efficacy assessment, compliance, or completion of follow-up.
• Persistent severe hypertension that cannot be adequately controlled with medication, defined as systolic blood pressure ≥185 mmHg or diastolic blood pressure ≥110 mmHg before treatment and remaining uncontrolled after antihypertensive treatment.
• History of intracranial hemorrhage.
• Known intracranial tumor, cerebral arteriovenous malformation, giant intracranial aneurysm, or other intracranial lesion that may substantially increase the risk of intracranial hemorrhage.
• Any advanced terminal illness with an anticipated life expectancy of no more than 6 months.

Lab values

• Known history of severe hypersensitivity to recombinant human prourokinase, human albumin, mannitol, iodinated contrast media, or medications used for study-related examinations or treatment.
• Blood glucose \<2.8 mmol/L or \>22.2 mmol/L and, after appropriate treatment, the participant remains unsuitable for enrollment.
• Known coagulation abnormality or bleeding tendency, including but not limited to platelet count \<100 × 10\^9/L, international normalized ratio (INR) \>1.7, markedly prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) above the upper limit of normal and considered clinically significant, or markedly reduced fibrinogen level.
• Current or recent use of anticoagulant therapy associated with an increased thrombolysis-related bleeding risk, including use of a vitamin K antagonist with INR \>1.7; use of a direct thrombin inhibitor or factor Xa inhibitor within the previous 48 hours with abnormal relevant coagulation tests; or use of heparin within the previous 24 hours with APTT above the upper limit of normal.
• Severe renal impairment with estimated glomerular filtration rate \<30 mL/min or serum creatinine \>2.5 mg/dL.

Other

• Patients with a clear treatment plan established before randomization that includes intravenous thrombolysis.
• Planned EVT or intra-arterial thrombolysis.
• Rapidly improving clinical symptoms such that, in the investigator's judgment, the participant is not suitable for the study intervention.
• Baseline imaging showing a large cerebral infarction or marked early ischemic changes such that, in the investigator's judgment, intravenous thrombolytic treatment is inappropriate.
• Known severe adverse reaction to contrast media.
• Unable to undergo the required head CT, CTA, or CTP examinations, or imaging quality is insufficient to determine the responsible vessel occlusion and perfusion mismatch.
• Suspected aortic dissection.
• Pregnant or breastfeeding women, or women of childbearing potential with a positive pregnancy test.
• Inability, in the investigator's judgment, to complete the 90-day follow-up, poor expected compliance, or otherwise unsuitable for participation in the study.

• Age ≥18 years.
• Pre-stroke modified Rankin Scale (mRS) score of 0-1.
• Baseline National Institutes of Health Stroke Scale (NIHSS) score ≥6, or an NIHSS score of 4-5 with a disabling neurological deficit, including but not limited to hemianopia, aphasia, or impaired hand motor function.
• Time from last known well of 4.5 to 24 hours, including wake-up stroke or unwitnessed stroke. Symptom onset is defined as the last time the participant was known to be well.
• Primary medium vessel occlusion confirmed by computed tomography angiography (CTA), involving the M2, M3, or M4 segment of the middle cerebral artery (MCA); the A1, A2, A3, or A4 segment of the anterior cerebral artery (ACA); or the P1, P2, P3, or P4 segment of the posterior cerebral artery (PCA), and identified as the responsible vessel for the signs and symptoms of acute ischemic stroke.
• Perfusion mismatch on computed tomography perfusion (CTP), defined as an infarct core volume \<50 mL, a hypoperfused volume/infarct core volume ratio ≥1.2, and a hypoperfused volume minus infarct core volume ≥10 mL. The infarct core is defined as tissue with relative cerebral blood flow (rCBF) \<30%, and the hypoperfused region as tissue with Tmax \>6 seconds.
• Written informed consent provided by the participant or the participant's legally authorized representative.