LONG TERM FOLLOW-UP OF SPINAL CORD INJURY IN THE AUTOLOGOUS MACROPHAGE TRIAL.

Abstract

PURPOSE/HYPOTHESIS: Our aim was to assess: a) Effectiveness of treatment with autologous macrophage injection (AMI) in spinal cord injury (SCI), in the 12-month Phase I trial conducted by Proneuron Biotechnologies and b) long-term neurological and functional status of SCI patients beyond the trial's 12 month period. NUMBER OF SUBJECTS: Fourteen patients with acute complete SCI were enrolled in this open label, non-randomized trial, 12 were followed between 22 and 48 months. MATERIALS/METHODS: Patients were treated with AMI within 14 days of injury and assessed over time on motor and sensory function using the American Spinal Injury Association Standards (ASIA) and Functional Independence Measure (FIM). Long-term follow-up assessed ASIA, FIM, and bowel and bladder function. We examined dichotomous ASIA-Change (change/no change) using the exact binomial confidence interval (CI) and FIM scores over time: a) For the complete sample, b) comparing patients changing on ASIA and those that did not and c) comparing our FIM scores with those of the population as provided by the National Spinal Cord Injury Database (NSCID). FIM was analyzed using repeated measures analysis of variance (ANOVA), FIM being the within-subjects factor and ASIA-Change the between-subjects factor. RESULTS: Of the 14 subjects, three (21%; 95% CI: 0.05-0.51) regained sensory and motor function resulting in conversion from ASIA A to C. The lower bound of the CI being above 0.00, this result is significant at p<0.05. One patient changed to B within this period but regressed to A at 12 months. ASIA classification was maintained for all subjects from 12 months to long-term follow-up. FIM scores improved significantly over time (p=0.005), but did not differ between those who did and did not convert on ASIA (p=0.840 for the Time x ASIA-Change interaction). A strong rise in FIM occured between baseline and 6 months, with increases tapering towards 12 months. Minimal change was observed at long-term follow-up. Our distribution of FIM was as expected from NSCID: 75% of subjects were within 1SD of the Standards and 100% between 2SD. Two patients converting to ASIA C regained some voluntary bladder control within one year and continued to improve long-term. CONCLUSIONS: The 21% rate of recovery observed is higher than the 1%-5% natural recovery rates typically cited for complete SCI. Due to the small sample this result should be interpreted with caution. Patterns of FIM in our sample were: a) Similar for those recovering on ASIA and those without recovery and b) similar to the SCI population as a whole. No meaningful changes on either ASIA or FIM occurred between the end of the study and long-term follow-up. CLINICAL RELEVANCE: Autologous Macrophage injection for patients with spinal cord injury is a promising therapy for SCI and is currently being explored in a Phase II trial. Although neurological status is often the primary outcome in spinal cord injury trials, function is important to consider. FIM scores failed to distinguish between patients converting on ASIA and those that did not, suggesting that FIM may lack convergent validity.