Axis

Abstract

Background and Purpose-Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. Methods-Four intravenous dose regimens (total cumulative doses of 30 -180 g/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. Results-Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions Ͼ14 -17 cm 3 . Conclusions-We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. (Stroke. 2010; 41:2545-2551.)Key Words: clinical trial Ⅲ granulocyte colony-stimulating factor Ⅲ hematopoietic growth factor Ⅲ leukocytes G ranulocyte-colony stimulating factor (G-CSF) is a growth factor of approximately 20 kDa that was initially identified as the main driver for generation of neutrophilic granulocytes and is in widespread clinical use for the treatment of chemotherapy-associated neutropenia. We and others have uncovered that G-CSF also acts as a potent neuronal growth factor. G-CSF acts antiapoptotically on neurons, stimulates neurogenesis, and enhances vessel reformation in the ischemic brain ( 1 ). Also, G-CSF is released by neurons in response to cerebral ischemia. 1 Systemically administered G-CSF passes the intact blood-brain barrier and decreases infarct size ( 2 ). Meta-analyses of the existing data and comparison to other experimental stroke drugs strengthen confidence in the efficacy of G-CSF in rodent models of stroke. 3,4 Importantly, G-CSF not only is acutely protective but also improves functional recovery after stroke, even when treatment is initiated at delayed time intervals. 5 The main advantages o...

Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

“…24 A small trial with β-human chorionic gonadotropin/erythropoietin initiated treatment 24 to 48 hours after stroke while an initial trial with granulocyte colony-stimulating factor 25 delayed treatment initiation after stroke ≤30 days. However, those studies were primarily concerned with establishing safety.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…While they passed initial small-scale phase I clinical safety trials, they failed to show improvement or further worsened stroke outcome in larger multiphase II/III trials. [113][114][115] These failures are not only due to the vast genetic differences between human and rodent brains, but could also be attributed to the lack of full characterization of these agents experimentally to allow for rigorous design of clinical trials with appropriate patient population, dosing regimen, and end points. A more complete understanding of the mechanisms of actions of these drugs is imperative for translating them from bench to bedside.…”

G-CSF as an Adjunctive Therapy with Umbilical Cord Blood Cell Transplantation for Traumatic Brain Injury

“…Moreover, G-CSF stimulated endogenous neurogenesis and vascularization (48,104). Recently, clinical studies are under way to determine the safety and efficacy of G-CSF for acute ischemic stroke (93,103,107). G-CSF has also been shown to enhance memory and neurobehavioral function in AD animal models (81).…”