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Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute
Vincent N S Thijs1, Andre Peeters, Milan Vosko
1Department of Neurology, University Hospitals Leuven, Leuven, Belgium. vincent.thijs@uz.kuleuven.ac.be
Background And Purpose:
Microplasmin is a recombinant truncated form of human plasmin. It has demonstrated efficacy in experimental animal models of stroke and tolerability in healthy volunteers. We tested the tolerability of microplasmin in patients with acute ischemic stroke.
Methods:
In a multicenter, double-blind, randomized, placebo-controlled Phase II trial, 40 patients with ischemic stroke were treated with either placebo or active drug between 3 and 12 hours after symptom onset in a dose-finding design. Ten patients received placebo, 6 patients received a total dose of 2 mg/kg, 12 patients received a total dose of 3 mg/kg, and 12 patients received a total dose of 4 mg/kg. We studied the pharmacodynamics of microplasmin and its effect on the clinical and hemodynamic parameters of the patients. MRI was used as a surrogate marker and matrix metalloproteinases serum concentrations were used as markers of neurovascular integrity. The study was underpowered to detect clinical efficacy.
Results:
Microplasmin induced reversible effects on markers of systemic thrombolysis and neutralized alpha(2)-antiplasmin by up to 80%. It was well tolerated with one of 30 treated patients developing a fatal symptomatic intracerebral hemorrhage. No significant effect on reperfusion rate or on clinical outcome was observed. Matrix metalloproteinase-2 levels were reduced in microplasmin-treated patients.
Conclusions:
Microplasmin was well tolerated and achieved neutralization of alpha(2)-antiplasmin. Further studies are warranted to determine whether microplasmin is an effective therapeutic agent for ischemic stroke.
Insights
Microplasmin was well tolerated in acute ischemic stroke patients, neutralizing alpha(2)-antiplasmin. Further studies are needed to confirm its efficacy as a therapeutic agent for stroke.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Medicine
Background:
- Microplasmin, a truncated recombinant human plasmin, shows promise in preclinical stroke models.
- Previous studies indicated good tolerability in healthy volunteers.
Purpose of the Study:
- To evaluate the tolerability and pharmacodynamics of microplasmin in acute ischemic stroke patients.
- To assess microplasmin's effects on clinical, hemodynamic, and neurovascular integrity markers.
Main Methods:
- A multicenter, double-blind, randomized, placebo-controlled Phase II trial involving 40 acute ischemic stroke patients.
- Patients received placebo or varying doses of microplasmin (2-4 mg/kg) 3-12 hours post-symptom onset.
- Pharmacodynamics, MRI, and serum matrix metalloproteinase levels were analyzed.
Main Results:
- Microplasmin demonstrated reversible systemic thrombolysis effects and neutralized alpha(2)-antiplasmin up to 80%.
- The drug was generally well tolerated, with one fatal intracerebral hemorrhage in 30 treated patients.
- No significant impact on reperfusion rates or clinical outcomes was observed; MMP-2 levels decreased.
Conclusions:
- Microplasmin is well-tolerated and effectively neutralizes alpha(2)-antiplasmin in acute ischemic stroke patients.
- While showing tolerability, its clinical efficacy for ischemic stroke requires further investigation.
