title: Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial.
abstract: OBJECTIVE
  Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients.
  
  
  METHODS
  G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging).
  
  
  RESULTS
  G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1.
  
  
  CONCLUSIONS
  G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00927836.
authors: From the Department of Neurology, University of Münster, Münster, Germany (E.B.R.); Department of Neurology, University of Leuven, Leuven, Belgium (V.T.); Vesalius Research Center, VIB, Leuven, Belgium (V.T.); Department of Clinical Sciences, Section of Neurology, Lund University, Lund, Sweden (B.N.); Department of Neurology, University of Barcelona, Barcelona, Spain (A.C.); Department of Neurology, Nervenklinik Wagner-Jauregg, Linz, Austria (F.A.); Department of Neurology, Kreiskrankenhaus Siegen, Siegen, Germany (M.G.); Department of Neurology, University of California, Los Angeles (J.S.); Clinical Research Department, SYGNIS Bioscience GmbH, Heidelberg, Germany (R.L., A.S., F.R., G.V., G.C.); Center for Stroke Research, Charité, Berlin, Germany (J.B.F.); Department of Neurology, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany (W.-R.S.); Department of Neurology, UMass Memorial Medical Center, Worcester, MA (M.F.); Department of Neurology, Medical Faculty Hospital Nitra, Nitra, Slovakia (M.B.); Department of Neurology, University Ostrava, Ostrava, Czech Republic (D.S.); Department of Neurology, Allgemeines Krankenhaus Linz, Linz, Austria (F.G.); Department of Neurology, Hospital Universitario Dr Josep Trueta de Girona, Girona, Spain (J.S.L.); Department of Neurology, University of Heidelberg, Heidelberg, Germany (R.V.); Department of Neurology, University of Erlangen, Erlangen, Germany (S.S., R.K., M.K.); and Department of Neurologie, Klinikum Altenburger Land GmbH, Altenburg, Germany (J.B.).
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020520:Brain Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011859:Radiography; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim
keywords: G-CSF; MRI; clinical trial; hematopoietic growth factor; leukocytes; phase II; stroke