Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke

Abstract

Background and Purpose-Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods-The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results-The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion-This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting apropitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke. (Stroke. 2010;41:707-711.)Key Words: acute ischemic stroke Ⅲ tenecteplase Ⅲ thrombolysis T o date, the only approved treatment for acute ischemic stroke is intravenous recombinant tissue plasminogen activator (alteplase, rtPA). Despite extensive efforts, implementation of this treatment has been limited, largely because of the narrow time limits within which treatment must be delivered, but also due to concerns regarding adverse bleeding risk. 1 Development of an alternative thrombolytic therapy that might be easier and safer to administer could lead to wider accept...

Intra-arterial Therapy for Acute Ischemic Stroke

“…Similarly tPA, although proven with IV infusion, may not be the ideal agent for IAT because of some neurotoxic effects resulting in higher rates of ICH [43]. There are multiple reports and small series, some prospective, of the use of other thrombolytics for IAT, including urokinase, reteplase, and tenecteplase, with promising but not definitive results [37,44]. The optimal dose of each thrombolytic is unknown.…”

Intravenous Thrombolytics for Ischemic Stroke

“…Authors concluded that TNK at doses of 0.1 to 0.4 mg/kg are safe in ischemic stroke, and a larger trial was designed. The next trial was funded by the National Institutes of Health and used a sophisticated design that allowed a seamless transition from phase II to III, provided a promising dose was found with adequate safety [63]. The trial began as a phase IIb randomized, double-blinded, and controlled trial that sought the optimal dose of tenecteplase: 0.1, 0.25, or 0.4 mg/kg.…”

Improving reperfusion therapy for acute ischaemic stroke

“…However, in a subsequent adaptive sequential design, phase 2B trial enrolling 112 patients, the 0.4 mg kg )1 dose was associated with a high rate of symptomatic haemorrhage and discarded. The trial was prematurely stopped before the 0.1 mg kg )1 or the 0.25 mg kg )1 could be distinguished as the most propitious dose to advance to a phase 3 trial, due to slow enrolment [55]. An on-going Australasian phase 2B study, Tenecteplase in Stroke (TIS) Trial, is comparing tenecteplase at 0.1 and 0.25 mg kg )1 dose tiers with IV tPA, using reperfusion at 24 h as a technical success endpoint.…”