Urokinase for thrombolysis in patients with acute ischemic stroke: rationale and design of a phase I dose-escalation study

Background: Previous evidence supports the efficacy and safety of intravenous urokinase thrombolysis in acute ischemic stroke (AIS), with additional advantages in terms of cost-effectiveness. Existing studies suggest that treatment response may be dose-dependent; however, current dosing practices remain largely empirical and lack standardization based on high-quality evidence. Establishing a weight-based dosing regimen is, therefore, essential to maximize therapeutic benefit and minimize risks. Objective: To determine the maximum tolerated dose (MTD) of urokinase and to develop an optimized weight-adjusted dosing protocol for AIS. Methods: OUTSET is a prospective, single-center, phase I, dose-escalation clinical trial using a weight-based, rolling-six design in patients with AIS. Patients who meet the inclusion criteria will be assigned to one of four dose groups (15,000 IU/kg, 20,000 IU/kg, 25,000 IU/kg and 30,000 IU/kg). Urokinase will be administered intravenously, diluted in 100 mL of normal saline, over a period of 30 min. Outcomes: The primary endpoint is the identification of the MTD based on dose-limiting toxicity events, including symptomatic intracranial hemorrhage, major bleeding, and other significant adverse events. Discussion: This study offers a structured, weight-based approach to determining the MTD of intravenous urokinase for AIS using a rolling-six dose-escalation design. By addressing the current lack of standardized, body-weight-adjusted dosing protocols, the findings may enhance the clinical safety and efficacy of urokinase thrombolysis. The results are expected to inform future phase II/III trials and support the development of individualized thrombolytic strategies in routine stroke care. Clinical trial registration: ClinicalTrials.gov identifier: NCT07047326.