Clinical trial NCT02025439: Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Official title: Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Traumatic Brain Injury
Keywords: Traumatic Brain Injury
Transcranial Magnetic Stimulation
Amantadine
Vegetative State
Minimally Conscious State
Lead sponsor: Edward Hines Jr. VA Hospital
Sponsor class: FED
First posted: 2014-01-01
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Intensity of Adverse Event
timeFrame: 30 days after treatment "alone" and an additional 30 days after treatment "combined" (i.e., 60 days)
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Hines
country: United States
facility: Edward Hines, Jr. VA Hospital
state: Illinois
Study officials:
affiliation: Edward Hines Jr. VA Hospital
name: Theresa BenderPape, DrPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pape TL, Rosenow J, Lewis G. Transcranial magnetic stimulation: a possible treatment for TBI. J Head Trauma Rehabil. 2006 Sep-Oct;21(5):437-51. doi: 10.1097/00001199-200609000-00063.
citation: Louise-Bender Pape T, Rosenow J, Lewis G, Ahmed G, Walker M, Guernon A, Roth H, Patil V. Repetitive transcranial magnetic stimulation-associated neurobehavioral gains during coma recovery. Brain Stimul. 2009 Jan;2(1):22-35. doi: 10.1016/j.brs.2008.09.004. Epub 2008 Oct 23.