Safety and Feasibility of Minocycline in the Treatment of TBI

Abstract

Objectives: Minocycline has begun trials as a neuroprotective agent in spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS) and trials in acute stroke. The drug has been in human use for over 20 years as an anti-inflammatory agent for rheumatoid arthritis and Lupus erythamatosis. Tetracycline derivatives, including doxycycline and minocycline, have been shown to be neuroprotective when given after traumatic brain injury (TBI) and ischemia in rodents [113-117] In particular, reduced lesion volume and improved neurological outcome have been demonstrated following minocycline treatment of TBI[113]. The proposed mechanism for these observations is multifactorial, and includes inhibition of microglial activation, caspase-mediated apoptosis, and the excitotoxic NMDA pathway. Because comparable inflammatory, excitotoxic and apoptotic pathways have also been implicated in human TBI[114, 118], we hypothesize that administration of minocycline will confer neuroprotection after moderate to severe TBI in that milieu as well, with the potential for significant clinical benefit. Minocycline is highly lipophilic, and thus penetrates the human CNS.[119] In addition, it has been shown to be safe when used in non-traumatic human neurological disorders[120, 121]. The purpose of this preliminary study is to test the hypothesis that administration of minocycline to humans with moderate and severe TBI is both safe and feasible in the acute post-injury setting, and to characterize its disposition and effects on biomarkers of traumatic CNS injury in a Phase IIa trial. The data collected will serve as the basis for a larger for a Phase IIb clinical trial in a randomized placebo-controlled parallel group design, to investigate further its potential safety and efficacy as a therapeutic agent for severe human TBI.

Sample and setting: The sample for this phase IIa study will include 14 participants who will receive IV minocycline over 7 days during their acute care treatment. Follow-up data collection will occur at the end of the trial, during inpatient rehabilitation and three months post-injury.

Main Outcome Measures:Outcome measures to be utilized will be the Disability Rating Scale, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test – 2nd Edition, Trails B, and SF-12. Other physiologic data will be collected to monitor for drug effects and toxicity. Specifically, patients will be monitored for development of gastrointestinal irritation, diarrhea, and phototoxicity by history and physical examination. Hepatotoxicity and super-infections including pseudomembranous colitis will be monitored by serum studies of liver enzymes and white-blood cell counts along with appropriate microbiologic cultures.

Design and Procedures: People with TBI who are concurrently admitted to RIM’s TBI inpatient rehabilitation service and who meet the safety standards for neuroimaging (see methods section) will be scanned using three newly developed neuroimaging techniques: Susceptibility Weighted Imaging (SWI), Diffusion Tensor Imaging (DTI), and Magnetic Resonance Spectroscopy Imaging (MRSI). Neuroimaging data will only be collected during the inpatient rehabilitation stay, but neuropsychological and functional outcome data will be collected at the end of their inpatient rehabilitation stay and at 1 year follow-up.

Expected Results: This is a Phase IIa study designed to establish optimal dosage, gather preliminary functional outcome data, and conduct a clinical feasibility assessment.

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