title: European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND.
abstract: OBJECTIVE
  Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.
  
  
  METHODS
  ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4-26 and pre-stroke modified Rankin Scale (mRS) 0-1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo.
  
  
  RESULTS
  The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0-1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0-1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.
authors.affiliation: Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany Hemasse.Amiri@med.uni-heidelberg.de.
authors.forename: Hemasse
authors.initials: H
authors.lastname: Amiri
authors.affiliation: Department of Statistics, Boehringer Ingelheim, Bieberach, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Bluhmki
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Eschenfelder
authors.affiliation: Florey Neuroscience Institutes, University of Melbourne, Parkville, Australia.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Donnan
authors.affiliation: Department of Neurology, Roger Salengro Hospital, Lille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Leys
authors.affiliation: Department of Neurology, Hospital Vall d'Hebron-Barcelona, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Molina
authors.affiliation: Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ringleb
authors.affiliation: Department of Neurology, Johannes-Wesling-Medical-Centre Minden, Minden, Germany.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Schellinger
authors.affiliation: Department of Neurology, University of Erlangen-Nuernberg, Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwab
authors.affiliation: Emergency Department Stroke Unit, La Sapienza University Hospital, Rome, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
authors.affiliation: Department of Neurology, Karolinska University Hospital-Solna, Solna, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wahlgren
authors.affiliation: Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
mesh_terms: D061605:Administration, Intravenous; D002985:Clinical Protocols / Q000592:standards*; D004311:Double-Blind Method; D006801:Humans; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D020521:Stroke / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D010959:Tissue Plasminogen Activator
keywords: acute stroke therapy; clinical trial; ischemic stroke; magnetic resonance imaging; recombinant tissue plasminogen activator; thrombolytic therapy