An Early Phase 1 interventional study of M5 and C1-inhibitor in Acute Ischemic Stroke, sponsored by TSI, LLC. Terminated at 1 site in Netherlands. Open to male participants aged 18 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-01-19.
Sponsored by TSI, LLC · Early Phase 1, Interventional, and Treatment
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:
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).
2,593 studies on the registry are indexed under Ischemic Stroke; 930 are open to participants now.
This study's enrollment of 8 is below the median of 120 across 1,752 interventional studies indexed under Ischemic Stroke.
Browse Ischemic Stroke studies →This is the only study on the registry with TSI, LLC as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
In the first study part subjects in cohorts of 4 will receive ascending doses of either M5 (3 subjects) or M5-placebo (1 subject) without C1-inhibitor.
Drug: M5
In the second study part subjects in cohorts of 5 will receive ascending doses of either M5 or M5-placebo, preceded by a single intravenous dose of C1-inhibitor or C1-inhibitor-placebo. Each subject will randomly be allocated to one of the following treatment arms within one cohort: * C1-inhibitor followed by M5 (3 subjects); * C1-inhibitor followed by M5-placebo (1 subject); * C1-inhibitor-placebo followed by M5-placebo (1 subject). Dose levels of both M5 and C1-inhibitor within each cohort will be chosen based on the available safety, pharmacokinetic and pharmacodynamic data of the preceding cohorts.
Drug: M5 · Drug: C1-inhibitor
single point mutant of serine protease prourokinase
a protease inhibitor belonging to the serpin superfamily.
Changes to vital signs, routine safety laboratory results, or ECG-findings
Time frame: -42d, -14h, -15', 15', 30', 45',60', 90', 10h, 24h, 48h, 7d
This study is terminated, as verified in Jan 2021. You cannot join it, but the record below documents what was studied.
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