Phase 1 study of human plasma-derived plasmin (TAL-05-00018) in hemodialysis graft occlusion.

INTRODUCTION: Hemodialysis grafts often fail because of stenosis at the venous anastomosis resulting in thrombosis. Percutaneous intervention involves thrombolysis with plasminogen activators, mechanical removal of thrombus, and angioplasty of the stenotic lesions.
OBJECTIVES: This article describes a phase I trial using plasmin (human) TAL 05-00018, a direct-acting fibrinolytic agent, to evaluate safety and, secondarily, to establish effective thrombolytic dosing. PATIENTS/
METHODS: Six cohorts of five patients with acute HD graft occlusion documented by fistulagrams were treated with increasing dosages of plasmin (1, 2, 4, 8, 12, and 24 mg) infused within the graft over 30 min via two criss-crossed pulse-spray catheters. The primary efficacy endpoint was at least 50% thrombolysis, as determined by fistulography.
RESULTS: There was no significant change in plasma alpha-2 antiplasmin or fibrinogen concentration, major bleeding did not occur, and there were no deaths. Serious adverse events in four patients were not related to the study drug. There was a dose-response relationship for the primary efficacy endpoint, all five subjects receiving 24 mg achieving more than 75% lysis.
CONCLUSION: This first phase I study of plasmin (human) TAL 05-00018, infused into thrombosed HD grafts, documents safety at all doses and an effective thrombolytic dosage of 24 mg indicating that further investigation into locally delivered plasmin is warranted.