Randomized-Controlled Trial of Minocycline for Spinal Cord Injury Shows Promise (2013)

Neurosurgeons see firsthand the devastating effects of spinal cord injury on the lives of our patients. Extensive investigations have been undertaken over the last several decades to identify and implement therapies that might improve neurological recovery. For example, high-dose corticosteroid therapy garnered much attention, but has ultimately proven to yield little or no clinical benefit after spinal cord injury. Unfortunately, numerous agents have been explored with almost nothing to show for it in the clinical realm. The model drug treatment for spinal cord injury would be well tolerated with few side effects, have established pharmacokinetics and pharmacodynamics such that therapeutic levels can be achieved at the spinal cord with ease, and which possesses mechanistic evidence as a neuroprotectant. Minocycline, a tetracycline family derivative, is a drug that fits each of these criteria and was recently evaluated in a phase II randomized-controlled trial for the treatment of spinal cord injury (Casha S et al. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012;135(Pt 4):1224-1236). Minocycline has a long track-record of safe human use. It has been studied extensively as a neuroprotectant and possesses actions ranging from limiting excitotoxicity to mitochondrial stabilization. Clinical investigations in humans using minocycline to treat neurological disease have been encouraging although none have demonstrated efficacy, and preclinical work in animal models of spinal cord injury support its potential therapeutic use. Casha et al sought to investigate the utility of minocycline in the treatment of spinal cord injury by establishing safety and tolerance of meaningful doses, determining the feasibility of treatment, and observing potential therapeutic effects via a phase II placebo-controlled randomized trial. Fifty-two patients were enrolled in this study that was conducted from 2004 to 2008. To be included, patients had to have presented within 12 hours of injury. Patients were stratified into 3 groups according to injury severity (using the American Spinal Cord Injury Association, or ASIA, neurological exam). Minocycline was administered intravenously with a loading dose followed by Q12 hour dosing for 7 days to achieve previously described therapeutic serum and CSF steady state concentrations. Neurological outcomes were assessed from the day of injury until 12 months post-injury. Overall, in the 44 patients with follow up data available beyond 3 months, patients who were administered minocycline demonstrated a 6-point improvement in motor scores. In patients with cervical spinal cord injuries, those who received minocycline were observed to have a 14 point increase in motor score. Patients with cervical spinal cord injuries that were incomplete showed the greatest improvement in motor scores with minocycline, 22. Importantly, functional recovery as determined by several outcome measures was also improved in the minocycline-treated patients. There were no differences in the 2 treatment groups for patients with thoracic injuries. Although these findings did not achieve statistical significance, they achieved the goals of the trial. Minocycline therapy proved to be easy to administer and establish potentially therapeutic target concentrations. It was safe at higher doses than previously utilized for a neuroprotectant study. Only 1 patient had an adverse reaction to the drug (eg elevated liver enzymes). Finally, although the study was not sufficiently powered to reveal a therapeutic advantage of minocycline over placebo, there was a trend toward improved neurological and functional recovery in select spinal cord injured patients. Several key observations can be made about this trial. First, this study underscores the need to evaluate specific subpopulations of spinal cord injured patients. For instance, a patient with a cord transection would not be expected to respond to a drug therapy. A complete injury where the cord is anatomically intact may be responsive, but would not be predicted to recover as well as an incomplete injury. When all injuries are grouped together, a potentially meaningful effect may be lost. In other words, the heterogeneity of human spinal cord injury must be accounted for to detect potentially important clinical differences. This study indicates that cervical injuries, specifically incomplete injuries, may receive the most benefit from minocycline therapy. Second, it is critical in these studies to use the most sensitive and clinically relevant outcome measures. There were no differences in ASIA motor scores for patients harboring thoracic injuries. However, ASIA motor scores are not particularly sensitive to segmental clinical recovery in the thoracic region, suggesting that alternative measures should be used when studying injuries to this population. Finally, this study should serve as the basis for a large multi-centered trial that can be adequately powered to detect potential clinical efficacy. These investigators should be lauded for their efforts to produce high quality prospective data in such a difficult and clinically relevant area.Figure 1: Change in ASIA motor score in the minocycline and placebo groups. Graphic depiction of the changes in ASIA motor score (baseline score subtracted from measured score at each time-point ± SEM) over time in all subjects, thoracic injured subjects, cervical injured subjects, subjects with cervical motor-complete and cervical motor-incomplete injury as indicated in subheadings. For cervical SCI P = 0.05, all other groups did not achieve or approach statistical significance.