title: Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious 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.
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA. ech@virginia.edu
authors.forename: E Clarke
authors.initials: EC
authors.lastname: Haley
authors.forename: John L P
authors.initials: JL
authors.lastname: Thompson
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Lyden
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hemmen
authors.forename: Devin L
authors.initials: DL
authors.lastname: Brown
authors.forename: Christopher
authors.initials: C
authors.lastname: Fanale
authors.forename: Richard
authors.initials: R
authors.lastname: Libman
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Kwiatkowski
authors.forename: Rafael H
authors.initials: RH
authors.lastname: Llinas
authors.forename: Steven R
authors.initials: SR
authors.lastname: Levine
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnston
authors.forename: Richard
authors.initials: R
authors.lastname: Buchsbaum
authors.forename: Gilberto
authors.initials: G
authors.lastname: Levy
authors.forename: Bruce
authors.initials: B
authors.lastname: Levin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy*; D000077785:Tenecteplase; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase