Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke.
OBJECTIVE
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.
Thijs
Vincent N S
VN
Department of Neurology, University Hospitals Leuven, Leuven, Belgium. vincent.thijs@uz.kuleuven.ac.be
Peeters
Andre
A
Vosko
Milan
M
Aichner
Franz
F
Schellinger
Peter D
PD
Schneider
Dietmar
D
Neumann-Haefelin
Tobias
T
Röther
Joachim
J
Davalos
Antoni
A
Wahlgren
Nils
N
Verhamme
Peter
P
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002548:Cerebral Revascularization / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005341:Fibrinolysin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010919:Placebos; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D010919:Placebos; C054561:microplasmin; D005341:Fibrinolysin