Plasmin (Human) Administration in Acute Middle Cerebral Artery Ischemic Stroke: Phase 1/2a, Open-Label, Dose-Escalation, Safety Study.

Background: This phase 1/2a, open-label, multicenter, dose-escalation, safety study describes the first evaluation of plasmin as an intracranial thrombolytic treatment for acute ischemic stroke in the middle cerebral artery. The rationale for intrathrombus administration is that plasmin would bind fibrin inside the targeted clot, protecting it from circulating inhibitors.

Methods: Plasmin was given in escalating doses within 9 hours of stroke onset, and treatment efficacy was determined in 5 patient cohorts (N = 40): cohort 1 (20 mg, .5 mL/min), cohort 2a (40 mg, .05 mL/min), cohort 2b (40 mg, .33 mL/min), cohort 3a (80 mg, .67 mL/min), and cohort 3b (80 mg, .33 mL/min).

Results: Plasmin was generally safe at doses as high as 80 mg. No symptomatic intracranial hemorrhage was observed, and the rate of asymptomatic intracranial hemorrhage (12.5%) was consistent with that expected under supportive care. No relationship was observed between the plasmin dose and the incidence or severity of bleeding events, any particular serious adverse events, nor death. Changes in clinical chemistry, hematology, and coagulation parameters following plasmin treatment were unremarkable and unrelated to the dose. Plasmin administration resulted in successful reperfusion of the occluded vessel in 25% of patients across all cohorts, with no relationship between successful perfusion and total plasmin dose but a potential increase in reperfusion with slower infusion rates.

Conclusions: Plasmin treatment of the occluded middle cerebral artery within 9 hours of stroke onset was well tolerated and did notincrease adverse outcomes; however, successful recanalization was achieved in only a limited number of patients.