Granulocyte-colony stimulating factor (G-CSF) in stroke patients with concomitant vascular disease--a randomized controlled trial

Abstract

Background: G-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke.

Methods: Here, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day), or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study.

Results: Adverse events (AEs) were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl), and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function.

Conclusions: These results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits.

Trial registration: ClinicalTrials.gov NCT00298597.

Conflict of interest statement

Competing Interests: AS, RL, GV are employees of SYGNIS Bioscience GmbH. WK is employee of HAPAACS. This was an investigator-initiated trial, and SYGNIS Bioscience provided study material, but was not involved in trial design, study protocol generation, study conduct, or regulatory issues. AS, RL, GV and WK were involved in generating the statistical analysis plan, and conducted statistical analysis of trial outcome. AS, WRS are inventors on a number of patent applications claiming the use of G-CSF for neurological diseases including stroke. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Flowchart of study.

Shown is a flowchart of the trial with the number of patients in the different study populations (safety and FAS (full analysis set)).

Figure 2. Time schedule of procedures and tests performed.

Shown are the different test series performed over 38 days.

Figure 3. G-CSF levels and hematological parameters.

a, serum concentrations of G-CSF measured at 4 time points throughout the study. Two days after the end of treatment (day 12/13) levels have returned to normal. Levels were measured at day 0, day 4 or 5, day 8 or 9, and day 12 or 13. b-c, hematological parameters. b, Leukocytes are already elevated at day 2, and reach their peakk at day 8. 7 days after end of medication levels have returned to normal (day 17). Error bars indicate standard errors of the mean (SEM). c, Thrombocyte counts decrease under G-CSF treatment. Lowest numbers are reached by day 10. Numbers normalize 7 days after end of treatment. d, No influence of treatment on erythrocyte numbers was detected.

Figure 4. Exploratory efficacy outcome measures.

a, motor learning task: Magnitude of learning is reflected by the difference in reaction times between random and sequential elements [ms]. B, Jebsen Taylor Test of hand function: Performance in this test was reflected by total time needed to complete the six subtests [s]. c, verbal learning task: Magnitude of learning is reflected by the [percentage] of correct responses (words learned). D, finger tapping speed: Performance in this test was reflected by the [number of key presses] within the time interval. Curves were fitted using a cubic spline function with a lambda of 0.05.