Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke Results of the AX200 for Ischemic Stroke Trial
Por:
Ringelstein, EB, Thijs, V, Norrving, B, Chamorro, A, Aichner, F, Grond, M, Saver, J, Laage, R, Schneider, A, Rathgeb, F, Vogt, G, Charisse, G, Fiebach, JB, Schwab, S, Schabitz, WR, Kollmar, R, Fisher, M, Brozman, M, Skoloudik, D, Gruber, F, Leal, JS, Veltkamp, R, Kohrmann, M, Berrouschot, J, Martí-Fàbregas J., AXIS 2 Investigators
Publicada:
1 oct 2013
Resumen:
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 mu g/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.
Filiaciones:
Ringelstein, EB:
Univ Munster, Dept Neurol, D-48149 Munster, Germany
Thijs, V:
Univ Louvain, Dept Neurol, Louvain, Belgium
VIB, Vesalius Res Ctr, Louvain, Belgium
Norrving, B:
Lund Univ, Neurol Sect, Dept Clin Sci, Lund, Sweden
Chamorro, A:
Univ Barcelona, Dept Neurol, Barcelona, Spain
Aichner, F:
Nervenklin Wagner Jauregg, Dept Neurol, Linz, Austria
Grond, M:
Kreiskrankenhaus Siegen, Dept Neurol, Siegen, Germany
Saver, J:
Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA
Laage, R:
SYGNIS Biosci GmbH, Dept Clin Res, Heidelberg, Germany
Schneider, A:
SYGNIS Biosci GmbH, Dept Clin Res, Heidelberg, Germany
Rathgeb, F:
SYGNIS Biosci GmbH, Dept Clin Res, Heidelberg, Germany
Vogt, G:
SYGNIS Biosci GmbH, Dept Clin Res, Heidelberg, Germany
Charisse, G:
SYGNIS Biosci GmbH, Dept Clin Res, Heidelberg, Germany
Fiebach, JB:
Charite, Ctr Stroke Res, Berlin, Germany
Schwab, S:
Univ Erlangen Nurnberg, Dept Neurol, Erlangen, Germany
Schabitz, WR:
Evangel Krankenhaus Bielefeld, Dept Neurol, Bielefeld, Germany
Kollmar, R:
Univ Erlangen Nurnberg, Dept Neurol, Erlangen, Germany
Fisher, M:
UMass Mem Med Ctr, Dept Neurol, Worcester, MA USA
Brozman, M:
Hosp Nitra, Dept Neurol, Fac Med, Nitra, Slovakia
Skoloudik, D:
Univ Ostrava, Dept Neurol, CZ-70103 Ostrava, Czech Republic
Gruber, F:
Allgemeines Krankenhaus Linz, Dept Neurol, Linz, Austria
Leal, JS:
Hosp Univ Dr Josep Trueta Girona, Dept Neurol, Girona, Spain
Veltkamp, R:
Heidelberg Univ, Dept Neurol, Heidelberg, Germany
Kohrmann, M:
Univ Erlangen Nurnberg, Dept Neurol, Erlangen, Germany
Berrouschot, J:
Klinikum Altenburger Land GmbH, Dept Neurol, Altenburg, Germany
Martí-Fàbregas J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
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