Background
This phase 1/2a, open-label, multicenter, dose-escalation, safety study describes
the first evaluation of plasmin as an intracranial thrombolytic treatment for acute
ischemic stroke in the middle cerebral artery. The rationale for intrathrombus administration
is that plasmin would bind fibrin inside the targeted clot, protecting it from circulating
inhibitors.
Methods
Plasmin was given in escalating doses within 9 hours of stroke onset, and treatment
efficacy was determined in 5 patient cohorts (N = 40): cohort 1 (20 mg, .5 mL/min),
cohort 2a (40 mg, .05 mL/min), cohort 2b (40 mg, .33 mL/min), cohort 3a (80 mg, .67 mL/min),
and cohort 3b (80 mg, .33 mL/min).
Results
Plasmin was generally safe at doses as high as 80 mg. No symptomatic intracranial
hemorrhage was observed, and the rate of asymptomatic intracranial hemorrhage (12.5%)
was consistent with that expected under supportive care. No relationship was observed
between the plasmin dose and the incidence or severity of bleeding events, any particular
serious adverse events, nor death. Changes in clinical chemistry, hematology, and
coagulation parameters following plasmin treatment were unremarkable and unrelated
to the dose. Plasmin administration resulted in successful reperfusion of the occluded
vessel in 25% of patients across all cohorts, with no relationship between successful
perfusion and total plasmin dose but a potential increase in reperfusion with slower
infusion rates.
Conclusions
Plasmin treatment of the occluded middle cerebral artery within 9 hours of stroke
onset was well tolerated and did notincrease adverse outcomes; however, successful
recanalization was achieved in only a limited number of patients.
Key Words
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Article info
Publication history
Published online: October 25, 2016
Accepted:
September 14,
2016
Received in revised form:
September 7,
2016
Received:
May 9,
2016
Footnotes
Grant support: This study was funded by Grifols, the sponsor of this clinical trial.
Conflict of interest: Kecia L. Courtney is an employee of Grifols, the sponsor of this study. Jeffrey L. Saver is an employee of the University of California and has served as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. Dr. Saver received stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical. Dr. Saver receives funding for services as a scientific consultant regarding trial design and conduct to Grifols, Medtronic, Stryker, Neuravi, BrainsGate, and Boehringer Ingelheim (prevention only). Dr. Saver serves as an unpaid consultant to Genentech, advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr. Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke.
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.022
Copyright
© 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
