Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke.

Abstract

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.

• Authors: Vincent N S Thijs, Andre Peeters, Milan Vosko, Franz Aichner, Peter D Schellinger, Dietmar Schneider, Tobias Neumann-Haefelin, Joachim Röther, Antoni Davalos, Nils Wahlgren, Peter Verhamme
• Journal: Stroke (Stroke) Vol. 40 Issue 12 Pg. 3789-95 (Dec 2009) ISSN: 1524-4628 [Electronic] United States
• PMID: 19834019 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Fibrinolytic Agents
• Peptide Fragments
• Placebos
• microplasmin
• Fibrinolysin

Topics

• Acute Disease
• Aged
• Aged, 80 and over
• Brain Ischemia (drug therapy, pathology)
• Cerebral Revascularization (methods)
• Dose-Response Relationship, Drug
• Female
• Fibrinolysin (administration & dosage, adverse effects, pharmacokinetics)
• Fibrinolytic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Injections, Intravenous
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Peptide Fragments (administration & dosage, adverse effects, pharmacokinetics)
• Placebos
• Stroke (drug therapy, pathology)
• Treatment Outcome