A first-in-human phase I trial of locally delivered human plasmin for hemodialysis graft occlusion

Abstract

Background: Hemodialysis (HD) grafts often fail because of stenosis at the venous anastomosis and thrombotic occlusion. Percutaneous management relies on thrombolysis with plasminogen activators, mechanical removal of thrombus, and angioplasty of the stenotic lesion.

Objectives: This report 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 angiography were treated with escalating dosages of plasmin (1, 2, 4, 8, 12, and 24 mg) infused over 30 min via criss-crossed pulse-spray catheters within the graft. The primary efficacy endpoint was > or =50% thrombolysis, as determined by comparison of pre-plasmin and 30-min post-plasmin fistulograms.

Results: Of 31 subjects who received study drug (safety population), one withdrew and 30 completed the trial (evaluable for efficacy). 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 >75% lysis.

Conclusions: This first phase I study of Plasmin (Human) TAL 05-00018, infused into thrombosed HD grafts, documents safety at dosages of 1-24 mg and an effective thrombolytic dosage of 24 mg. The results establish a foundation for further clinical study of catheter-based plasmin administration in thrombotic disorders.

Figure 1

Representative pre- and post-plasmin infusion fistulograms. Panel A shows contrast outlining a large filling defect (arrowheads) in the hemodialysis graft before regional plasmin infusion. Panel B is a digital subtraction study performed at 30 minutes after the initiation of plasmin (24 mg) infusion. Lysis was estimated as >75%, but residual thrombus remains along the wall (irregular contour). A stenotic lesion at the venous anastomosis underlies the thrombotic occlusion (arrow).

Figure 2

Plasma concentrations of α2-antiplasmin and fibrinogen. Panel A shows the mean % α-2 antiplasmin levels prior to (0 time) and at 30, 60 and 120 minutes after initiation of the plasmin infusions, and at the day 2-5 and day 30 followup visits. Panel B shows mean fibrinogen concentrations (mg/dL) at the same time points. All values represent mean +/- standard deviation of 5 determinations.

Figure 2

Plasma concentrations of α2-antiplasmin and fibrinogen. Panel A shows the mean % α-2 antiplasmin levels prior to (0 time) and at 30, 60 and 120 minutes after initiation of the plasmin infusions, and at the day 2-5 and day 30 followup visits. Panel B shows mean fibrinogen concentrations (mg/dL) at the same time points. All values represent mean +/- standard deviation of 5 determinations.

Figure 3

Antibody against plasmin and against streptokinase (SK). Panel A shows antibody levels against plasmin at baseline (pre-infusion, light rectangles) and at day 28 (dark rectangles), expressed as optical density ± SD. Panel B shows a similar analysis of antibody against SK, with values noted as micrograms/mL ± SD. There was no significant difference in any of the paired values and no trend towards antibody induction at escalating plasmin dosages.

Figure 3

Antibody against plasmin and against streptokinase (SK). Panel A shows antibody levels against plasmin at baseline (pre-infusion, light rectangles) and at day 28 (dark rectangles), expressed as optical density ± SD. Panel B shows a similar analysis of antibody against SK, with values noted as micrograms/mL ± SD. There was no significant difference in any of the paired values and no trend towards antibody induction at escalating plasmin dosages.