IMPORTANCE: Trials have not demonstrated superiority of alteplase or tenecteplase vs standard care in patients with mild stroke and have raised safety concerns. Prourokinase is an alternative fibrinolytic that may have a favorable safety profile, and the benefit-risk profile of prourokinase in mild stroke is unknown. OBJECTIVE: To investigate the efficacy and safety of prourokinase in mild ischemic stroke within 4.5 hours of symptom onset. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, prospective, open-label, blinded-end point randomized clinical trial conducted from November 2022 through December 2023 with 3 months of follow-up. The trial was conducted at 89 hospitals in China. Patients with a baseline National Institutes of Health Stroke Scale score of 5 or less (scores range from 0-42, with higher scores indicating more severe neurological deficit) within 4.5 hours from the time the patient was last known to be well. Patients with intention to proceed to endovascular treatment were excluded. INTERVENTIONS: Eligible patients were randomly assigned in a 1:1 ratio to receive prourokinase, 35 mg (15-mg bolus + 20-mg infusion over 30 minutes) or standard care, including antiplatelet or anticoagulant therapy, at the discretion of local investigators. MAIN OUTCOMES AND MEASURES: The primary outcome was modified Rankin Scale score of 0 or 1 (range, 0-6, with higher scores indicating greater disability) at day 90. Safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: Of 3836 patients who underwent screening, 1446 (37.7%) were enrolled in the trial. Median (IQR) age was 65.9 (57.7-72.7) years, and 948 were male (65.5%). A total of 723 patients were assigned to prourokinase and 723 to standard care. The primary outcome occurred in 639 patients (88.5%) in the prourokinase group and 658 (91.0%) in the standard care group (relative risk, 0.97
95% CI, 0.94-1.01
2-sided P = .12). Symptomatic intracranial hemorrhage was 0.7% (5 of 723 patients) with prourokinase and 0% with standard care, and mortality at 90 days was 2.3% and 1.4%, respectively. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial demonstrate that prourokinase was not superior to standard care to improve the functional outcomes for patients with mild ischemic stroke within 4.5 hours after symptom onset but had a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05507645.