Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. METHODS AND ANALYSIS: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). ETHICS AND DISSEMINATION: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. TRIAL REGISTRATION NUMBER: UMIN000018752.

Postoperative Status of Global Sagittal Alignment With Compensation in Adult Spinal Deformity.

STUDY DESIGN: A retrospective study of consecutive patients undergoing surgery for adult spinal deformity (ASD). OBJECTIVE: The aim of this study was to classify postoperative ASD patients by sagittal compensation and characterize the features of each group. SUMMARY OF BACKGROUND DATA: Sagittal compensatory mechanisms to keep the erect position would function in not only nonoperative ASD patients but also in postoperative patients. However, details of sagittal compensatory mechanisms after surgery have been unclear, because the majority of previous studies examined the compensatory mechanisms in nonoperative patients. METHODS: A total of 73 postoperative ASD patients were recruited. Spinopelvic parameters and Oswestry Disability Index (ODI) were measured before surgery, at 1-month and 2-year follow-up. The changes in parameters (Δ) between postoperative 1-month and 2-year were also evaluated. Cluster analysis based on pelvic tilt (PT) and sagittal vertical axis (SVA) at 2-year follow-up was performed, and then the parameters were compared among clusters. RESULTS: Cluster analysis identified three clusters: the physiological group (n = 38, PT = 19.6°, SVA = 17.2 mm), the compensated group (n = 23, PT = 34.3°, SVA = 45.6 mm), and the decompensated group (n = 12, PT = 36.6°, SVA = 118.8 mm). Comparisons of the parameters among the groups showed that the physiological group had smaller pelvic incidence minus lumbar lordosis (PI-LL) and better ODI. The compensated group had significantly larger Δ thoracic kyphosis (TK), Δ proximal junctional angle (PJA), and ΔPT than the physiological group. The decompensated group had significantly higher PI and higher age. CONCLUSION: Three groups were defined in terms of postoperative compensatory mechanisms. Patients in the physiological group had little postoperative alignment change and good ODI value. The compensated group had pelvic retroversion to keep SVA in the physiological range, but the compensation in the thoracic spine was unlikely to work. High PI and advanced age were characteristics of the decompensated group. LEVEL OF EVIDENCE: 4.