Results of a phase II placebo-controlled randomized trial of minocycline in acute
spinal cord injury.
Author(s): Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ.
Affiliation(s): Department of Clinical Neurosciences and the Hotchkiss Brain Institute,
University of Calgary, Calgary, AB, Canada. scasha@ucalgary.ca
Publication date & source: 2012, Brain. , 135(Pt 4):1224-36
Preclinical studies have attributed neuroprotective properties to the antibiotic
minocycline. Animal studies and early clinical trials support its use in several
neurological diseases. In animal spinal cord injury models, minocycline improved
neurological and histological outcomes, reduced neuronal and oligodendroglial
apoptosis, decreased microglial activation and reduced inflammation. A
single-centre, human, double-blind, randomized, placebo-controlled study of
minocycline administration after spinal cord injury was undertaken for the
purposes of dose optimization, safety assessment and to estimate outcome changes
and variance. Neurological, functional, pharmacological and adverse event
outcomes were compared between subjects administered 7 days of intravenous
minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord
injury. The secondary outcome used to assess neurological differences between
groups that may warrant further investigation was motor recovery over 1 year
using the American Spinal Cord Injury Association examination. Recruitment and
analyses were stratified by injury severity and injury location a priori given
the expected influence of these on the sensitivity of the motor exam. Minocycline
administered at higher than previously reported human doses produced steady-state
concentrations of 12.7 µg/ml (95% confidence interval 11.6-13.8) in serum and 2.3
µg/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking
efficacious serum levels measured in animal studies. Transient elevation of serum
liver enzymes in one patient was the only adverse event likely related to the
study drug. Overall, patients treated with minocycline experienced six points
greater motor recovery than those receiving placebo (95% confidence interval -3
to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic
spinal cord injury (n = 16). A difference of 14 motor points that approached
significance was observed in patients with cervical injury (95% confidence
interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury
may have experienced a larger difference (results not statistically significant,
n = 9). Functional outcomes exhibited differences that lacked statistical
significance but that may be suggestive of improvement in patients receiving the
study drug. The minocycline regimen established in this study proved feasible,
safe and was associated with a tendency towards improvement across several
outcome measures. Although this study does not establish the efficacy of
minocycline in spinal cord injury the findings are encouraging and warrant
further investigation in a multi-centre phase III trial. ClinicalTrials.gov
number NCT00559494.
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