Published Online
on February 3, 2005

A more recent version of this article appeared on March 1, 2005

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Submitted on August 11, 2004
Revised on October 25, 2004
Accepted on November 10, 2004

A Pilot Dose-Escalation Safety Study of Tenecteplase in Acute Ischemic Stroke

E. Clarke Haley Jr MD^*; Patrick D. Lyden MD; Karen C. Johnston MD; Thomas M. Hemmen MD; the TNK in Stroke Investigators

From the Department of Neurology (E.C.H., K.C.J.), University of Virginia Health System, Charlottesville, Va; and the Department of Neuroscience (P.D.L., T.M.H.), University of California at San Diego.

^* To whom correspondence should be addressed. E-mail: ech{at}virginia.edu.

Background and Purpose--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.

Key words: ischemic stroke • tenecteplase • tissue plasminogen activator • thrombolytic therapy

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