A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke.
OBJECTIVE
Recombinant tissue-type plasminogen activator (rtPA) is the only approved treatment in acute ischemic stroke. However, intracerebral hemorrhage (ICH) occurs in 6.4% of patients treated with rtPA and limits its use. Tenecteplase (TNK) is a modified form of rtPA, with longer half-life and greater fibrin specificity. Patients after myocardial infarction had fewer systemic hemorrhages when treated with TNK compared with rtPA. This open-label, dose-escalation safety study was conducted to develop initial experience with TNK in the treatment of ischemic stroke.


METHODS
Eligible patients were treated with an intravenous bolus infusion of TNK within 3 hours of stroke onset. The dose escalation was conducted in tiers of 25 patients, starting at 0.1 mg/kg, to a planned maximum of 0.6 mg/kg. The primary endpoint was symptomatic intracranial hemorrhage within 36 hours of treatment. All patients were followed-up for 3 months.


RESULTS
Eighty-eight (88) patients were treated in 4 dosing tiers. In the first 3 tiers (0.1, 0.2, 0.4 mg/kg) of 25 patients each, no symptomatic and 2 (8%), 8 (32%), and 7 (28%) asymptomatic ICHs occurred. Enrollment into the fourth tier at 0.5 mg/kg was closed after 2 of 13 patients (15%) had symptomatic and 3 (23%) had asymptomatic ICHs. Overall, modified Rankin scores at 3 months were similar to those of historical controls treated with rtPA and not significantly different between treatment groups.


CONCLUSIONS
TNK doses of 0.1 to 0.4 mg/kg are safe in ischemic stroke. Future trials are needed to compare the effect of TNK on neurological outcome and safety as compared with rtPA.
Haley
E Clarke
EC
Department of Neurology, University of Virginia Health System, Charlottesville, Va, USA. ech@virginia.edu
Lyden
Patrick D
PD
Johnston
Karen C
KC
Hemmen
Thomas M
TM
D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D010865:Pilot Projects; D012449:Safety; D020521:Stroke / Q000188:drug therapy*; D000077785:Tenecteplase; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome
D005340:Fibrinogen; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase