E Bernd Ringelstein1, Vincent Thijs, Bo Norrving, Angel Chamorro, Franz Aichner, Martin Grond, Jeff Saver, Rico Laage, Armin Schneider, Frank Rathgeb, Gerhard Vogt, Gabriele Charissé, Jochen B Fiebach, Stefan Schwab, Wolf R Schäbitz, Rainer Kollmar, Marc Fisher, Miroslav Brozman, David Skoloudik, Franz Gruber, Joaquin Serena Leal, Roland Veltkamp, Martin Köhrmann, Jörg Berrouschot. 1. 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.).
Abstract
BACKGROUND AND PURPOSE: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. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.
RCT Entities:
BACKGROUND AND PURPOSE: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 strokepatients. 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. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.
Authors: Anke Wouters; Patrick Dupont; Erich B Ringelstein; Bo Norrving; Angel Chamorro; Martin Grond; Rico Laage; Armin Schneider; Guido Wilms; Götz Thomalla; Robin Lemmens; Vincent N Thijs Journal: J Cereb Blood Flow Metab Date: 2015-06-03 Impact factor: 6.200
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Authors: Amish N Raval; Eric G Schmuck; Girma Tefera; Cathlyn Leitzke; Cassondra Vander Ark; Derek Hei; John M Centanni; Ranil de Silva; Jill Koch; Richard G Chappell; Peiman Hematti Journal: Cytotherapy Date: 2014-09-18 Impact factor: 5.414