Traumatic Brain Injury
Conditions
Keywords
Traumatic Brain Injury, Minocycline, Outcome
Brief summary
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.
Detailed description
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.
Interventions
DRUGMinocycline
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.
Sponsors
Wayne State University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male , 18 to 75 years of age, irrespective of race; * Ability to provide written informed consent or have legal representative provide written informed consent; * Must be enrolled in the study within 6 of injury and meet the following criteria: * GCS score of 12 or less within the first 4 hours of injury; * Evidence of neurological injury on computer tomography (CT) of the head; * No known allergy to minocycline or other contraindication to receiving this medication. * Presence of central venous catheter; * Participants must not have a known life-threatening disease prior to the brain injury: However, individuals with a stable medical illness in the opinion of the investigator may be allowed to enter the study; * Participants are not to be on any other interventional studies aimed at enhancing neurorecovery; * Participants are not to be receiving immunosuppressant agents prior to study enrollment.
Exclusion criteria
* Participant is a female; * Participants, guardians or legal representatives who are unwilling to cooperate with the investigation; * Participants who have received any other investigational drug within 30 days of injury; * Participants known to have severe ischemic heart disease or congestive heart failure, myocardial infarction, spinal cord injury with ongoing deficits, cancer or any other severe illnesses that in the opinion of the investigator would affect the assessment of therapy; * Participants with an ongoing neurological disease/condition or previous stroke or TBI; * Known clinical sequelae of spinal cord injury; * Massive cerebral hemisphere or brainstem hematoma, incompatible with survival; * History of major depression requiring the use of the medication at the time of injury; * Multiple trauma which in the opinion of the investigator, would jeopardize the assessment of therapy; * Participants who have any type of penetrating head injury; * Participants receiving chronic steroid treatment; * Participants receiving isotretinoin; * Lack of informed consent signed by either the participant or the subject's legal representative; * Prior TBI, brain tumor, cerebral vascular event, or other stable brain insult; * Prior history of Pseudotumor cerebri ; * Patients with known renal failure, BUN/ Creatinine 20:1; creatinine \> 2 mg/dl; * Patients with known hepatic failure, AST/ALT\> 3 x Upper Limit of Normal; * Thrombocytopenia \< 75,000/mm; * Known allergy or sensitivity to any of the tetracyclines or any of the components of the product formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disability Rating Scale | 4 weeks and 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drug Levels | 4 days after start | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 800 mg Loading Then 200 mg Q12 Minocycline 800 mg. loading followed by 200 mg. Q 12 hours.
Minocycline: 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. | 7 |
| 800 mg Loading Then 400 mg Q12 Minocycline 800 mg. loading followed by 400 mg. Q 12 hours.
Minocycline: 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. | 8 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | 800 mg Loading Then 400 mg Q12 | Total | 800 mg Loading Then 200 mg Q12 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 13 Participants | 5 Participants |
| Age, Continuous | 40 years | 43 years | 46 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment United States | 8 Participants | 15 Participants | 7 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 7 | 1 / 8 |
| other Total, other adverse events | 7 / 7 | 8 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 800 mg Loading Then 200 mg Q12 | Disability Rating Scale | DRS at 4 weeks | 12.5 units on a scale | Standard Deviation 7.7 |
| 800 mg Loading Then 200 mg Q12 | Disability Rating Scale | DRS at 3 months | 8.5 units on a scale | Standard Deviation 9.9 |
| 800 mg Loading Then 400 mg Q12 | Disability Rating Scale | DRS at 4 weeks | 9.7 units on a scale | Standard Deviation 6.9 |
| 800 mg Loading Then 400 mg Q12 | Disability Rating Scale | DRS at 3 months | 6.0 units on a scale | Standard Deviation 6.1 |
Comparison: DRS levels changes at from 4 weeks to 3 months comparing the different doses.p-value: 0.021ANCOVA
Comparison: Null hypothesis is that there is no difference between groups in the DRS scores at 3 months.p-value: 0.258t-test, 2 sided
Comparison: Null hypothesis is that there is no difference between groups in the DRS scores at 4 weeks.p-value: 0.541t-test, 2 sided
Secondary
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
Population: Those we were able to obtain levels on reliably and could run against standards. This only turned out to be the first tier level. Descriptive data only
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 800 mg Loading Then 200 mg Q12 | Drug Levels | 21.7 mcg/ml |
Post Hoc
Aspartate Aminotransferase (AST) Levels
AST levels measured daily from day 1 to day 7 evaluated by ANOVA. Mean values on day 7 reported for the two tiers. Elevations may indicate Liver dysfunction due to medication.
Time frame: day 1 change to day 7 day, ANOVA, mean value on day 7 reported
Population: Levels are compared for the two tiers
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 800 mg Loading Then 200 mg Q12 | Aspartate Aminotransferase (AST) Levels | 88.0 U/L |
| 800 mg Loading Then 400 mg Q12 | Aspartate Aminotransferase (AST) Levels | 264 U/L |
p-value: >0.05t-test, 2 sided