Research Into the Effect of a Clot-dissolving Agent and Its Inhibitor

Acute Ischemic Stroke Clinical Trial

Official title: Phase 1 Trial of Mutant proUK, M5, and Its Inhibitor, C1-inhibitor

Status Terminated

Clinical Trial Summary

Single-chain urokinase-type plasminogen activator (pro-urokinase) is a highly effective thrombolytic drug. At pharmacologic concentrations however, pro-urokinase is converted to urokinase - a non specific thrombolytic, limiting its therapeutic use. Mutant pro-urokinase (M5) is more stable and its conversion to urokinase is inhibited by C1-inhibitor.

The primary objectives of the study are:

• To assess the overall safety and tolerability related to systemic plasminogen activation of single doses of M5 over a wide dose range (study part I).

• To assess the effect of single doses of C1-inhibitor on the overall safety and tolerability of single doses of M5 and its effect on M5-induced coagulation changes (study part II).

Clinical Trial Description

Mutant proUK, M5, was specifically designed to improve the plasma stability of single-chain proUK by reducing its intrinsic catalytic activity and allowing it to retain its proenzyme form until it encounters a thrombus. As an additional consequence of the mutation, its two-chain enzymatic form (tcM5) is sensitive to inhibition by C1-inhibitor (C1INH) a relatively abundant plasma inhibitor.

While it has a negligible effect on urokinase (UK), C1INH inhibits tcM5 irreversibly, preventing non-specific plasminogen activation, responsible for bleeding complications. The effect of endogenous C1INH can be augmented by the addition of exogenous C1INH. In vitro studies in rats and dogs indicated that adding C1INH to plasma prior to clot lysis by M5 prevented bleeding, fibrinogenolysis and plasminogen depletion but did not affect the rate of fibrinolysis. In a recent pilot rat stroke study, at similarly effective doses, M5, preceded by C1INH adjunctive therapy, was equivalent to tPA alone but caused significantly less ICH, was much more effective than tPA preceded by adjunctive C1INH, and was the only group with a significant functional improvement at 24h.

Dose restrictions which limit efficacy of tPA-based thrombolysis are expected to be circumvented by M5 preceded by adjunctive C1INH. C1INH is a commercially available plasma derived product with a well-established safety and efficacy profile and is currently indicated and available for routine prophylaxis of hereditary angioedema (HAE). ;

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Stroke

• NCT number: NCT01694381
• Study type: Interventional
• Source: TSI, LLC
• Status: Terminated
• Phase: Early Phase 1
• Start date: September 2012
• Completion date: October 2012