Traumatic Brain Injury
Conditions
Keywords
Traumatic Brain Injury, Transcranial Magnetic Stimulation, Amantadine, Vegetative State, Minimally Conscious State
Brief summary
The purpose of this study is to examine the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with Amantadine relative to rTMS Alone and Amantadine Alone for persons in chronic states of seriously impaired consciousness. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or accelerates functional recovery.
Detailed description
The R21 research objective is to examine the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with Amantadine (TMS + Amantadine) relative to rTMS Alone and Amantadine Alone for persons in chronic states of seriously impaired consciousness. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or accelerates functional recovery. This hypothesis is based on (a) preliminary data indicating partially improved neurobehavioral functioning mechanistically related to rTMS-induced neural activity and connectivity as well as improved integrity of white fiber tracts, (b) relationship between dopamine (DA) and common traumatic brain injury (TBI) impairments, (c) role of DA in mediating consciousness, (d) the commonality between and DA and rTMS-targeted pathways, (e) clinical efficacy and safety of Amantadine, (f) mechanisms of action of Amantadine, and (g) the association between rTMS and Amantadine with up-regulating brain derived neurotrophic factor. The rationale is that pairing rTMS with Amantadine will have a complementary and synergistic effect on factors promoting conscious behavior. The specific aims are to: (1) Demonstrate that rTMS+Amantadine is safely tolerated, (2) Determine neurobehavioral effect of rTMS+Amantadine, and (3) Characterize pre-and post-treatment neural changes in neural activation. Aim 1 is based on our preliminary safety data and safety data regarding Amantadine. To address Aims 2 & 3 we use a repeated measures baseline control design with randomized treatment orders yielding three treatment groups; rTMS + Amantadine, rTMS Alone and Amantadine Alone. Analyses for Aims 2 and 3 involve comparing these treatment groups according to neurobehavioral growth trajectories, mean amount of neural activation and connectivity within and between brain regions, and indices of fiber tract directionality.
Interventions
DEVICErTMS
DRUGAmantadine
Sponsors
Edward Hines Jr. VA Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* 18-64 years of age * Suffered a severe brain injury of traumatic origin at least 1-year prior to study enrollment * Remain in a state of disordered consciousness * Brain injuries will include injury with resulting coup-contre-coup injuries, excluding persons with trauma due to blunt injuries and/or non-traumatic encephalopathy
Exclusion criteria
* Have 1 or more Amantadine contraindications: On monoamino oxidase inhibitor-B, hypersensitivity/idiosyncrasy to sympathomimetic amines, uncontrolled hypertension, glaucoma or Congestive Heart Failure * Have contraindications to Amantadine Dose of 200 mg Daily as determined by estimated Glomerular Filtration Rate (eGFR) ≤ 60 (ml/min) * Abnormal results of Liver Function Test at screening * Receiving anti-epileptic medications to control active seizures or have had a documented seizure within three months of study enrollment * Incurred large cortically based ischemic infarction/encephalomalacia subsequent to TBI * Have documented history of previous TBI, psychiatric illness (DSM criteria) and/or organic brain syndrome such as Alzheimer's * Are using medications which may interfere with Amantadine and cannot be safely titrated or discontinued * Are pregnant * Have implanted cardiac pacemaker or defibrillator, cochlear implant, nerve stimulator, intracranial metal clips * Have MRI and/or TMS contraindications such as: History of claustrophobia, metal in eyes/face, shrapnel/bullet remnants in brain * Are fully conscious as indicated by a score of 6 on the Motor Function scale and/or a score of 2 on the Communication scale of the CRS-R, * Are within first year of injury * Are \<18 years of age and \> 65 years of age * Have an injury or condition due to blunt trauma only or non-traumatic encephalopathy * Have programmable CSF shunt or are ventilator dependent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intensity of Adverse Event | 30 days after treatment alone and an additional 30 days after treatment combined (i.e., 60 days) | If an adverse event occurred, the intensity was also indicated. The intensity of an adverse event was determined using a scale from 1-5 with 5 being the worst. The purpose of the study is to examine safety of rTMS combined with AMA relative to rTMS Alone and AMA alone. Results are not reported per arm rather, the arms are combined so as to compare the outcome when the interventions are provided separately (i.e., rTMS alone and amantadine alone) vs interventions are combined (rTMS +Amantadine alone). |
Countries
United States
Participant flow
Pre-assignment details
nothing to report
Participants by arm
| Arm | Count |
|---|---|
| rTMS First Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.
rTMS | 2 |
| Amantadine First Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days.
Amantadine | 2 |
| Total | 4 |
Baseline characteristics
| Characteristic | Amantadine First | rTMS First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Continuous | 33 years | 24 years | 28 years |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 4 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 4 / 4 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 4 | 0 / 2 |
Outcome results
Primary
Intensity of Adverse Event
If an adverse event occurred, the intensity was also indicated. The intensity of an adverse event was determined using a scale from 1-5 with 5 being the worst. The purpose of the study is to examine safety of rTMS combined with AMA relative to rTMS Alone and AMA alone. Results are not reported per arm rather, the arms are combined so as to compare the outcome when the interventions are provided separately (i.e., rTMS alone and amantadine alone) vs interventions are combined (rTMS +Amantadine alone).
Time frame: 30 days after treatment alone and an additional 30 days after treatment combined (i.e., 60 days)
Population: Results are reported both per arm at the end of 30 days when a single treatment (either rTMS or AMA) was ended, and additional results are reported with both arms combined to report the outcome after 60 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rTMS Alone | Intensity of Adverse Event | 0.5 score on a scale | Standard Deviation 0.52 |
| rTMS+AMA | Intensity of Adverse Event | 0.98 score on a scale | Standard Deviation 0.38 |
| AMA Alone | Intensity of Adverse Event | 0.33 score on a scale | Standard Deviation 0.51 |
p-value: <0.05t-test, 2 sided