The purpose of this study is: 1. To assess the safety and feasibility of minocycline administration after TBI in a dose escalation study at two different doses over 7 days. 2. To assess the pharmacokinetic characteristics of two different dosing regimens of minocycline in TBI patients, the effect on biochemical markers of neuroprotective mechanisms, and effect on neurobehavioral and functional outcome. 3. To begin initial assessment of the efficacy of minocycline as a therapeutic agent for severe human TBI.
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 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. Tetracycline derivatives, including doxycycline and minocycline, have been shown to be neuroprotective when given after traumatic brain injury (TBI) and ischemia in rodents. In particular, reduced lesion volume and improved neurological outcome have been demonstrated following minocycline treatment of TBI. The proposed mechanism for these observations is multifactorial, and includes inhibition of microglial activation, caspase-mediated apoptosis, and the excitotoxic N-methyl-D-aspartic acid (NMDA) pathway. Because comparable inflammatory, excitotoxic and apoptotic pathways have also been implicated in human TBI, 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 central nervous system (CNS). In addition, it has been shown to be safe when used in non-traumatic human neurological disorders.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
Minocycline 800 mg loading followed by 200 mg Q12 or Minocycline 800 mg loading followed by 400 mg Q12 will be delivered in an open-label study for seven days intravenously in one of two different dosing tiers to assess safety and toxicity per FDA recommendations. There will be tow different arms or groups differing by the amount of minocycline given over 7 days.
Oakwood Dearborn Hospital
Dearborn, Michigan, United States
Oakwood Southshore Hospital
Trenton, Michigan, United States
Disability Rating Scale
The main outcome measure after the safety data was the Disability Rating Scale (DRS). It is a 29 point scale with 29 being a severe vegetative state. It is reliable across time and demonstrates better sensitivity than the Glasgow Outcome Scale.It has been a standard primary outcome measure for most pharmaceutical studies for TBI, and was required by the FDA for the IND approval.
Time frame: 4 weeks and 3 months
Drug Levels
Serum samples were collected for assessment of minocycline concentrations at the estimated time of steady-state concentrations. Serum concentrations were assessed on Day 4. Data reported will be pKa levels 2 hours after AM dose.
Time frame: 4 days after start
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NONE
Enrollment
15