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Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness

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ClinicalTrials.gov Identifier: NCT02025439
Recruitment Status : Unknown
Verified April 2016 by Theresa Pape, Edward Hines Jr. VA Hospital.
Recruitment status was:  Active, not recruiting
First Posted : January 1, 2014
Last Update Posted : April 25, 2016
Sponsor:
Information provided by (Responsible Party):
Theresa Pape, Edward Hines Jr. VA Hospital

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.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Device: rTMS Drug: Amantadine Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Study Start Date : February 2014
Estimated Primary Completion Date : August 2016
Estimated Study Completion Date : September 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: rTMS Alone
Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.
Device: rTMS
Other Name: Repetitive Transcranial Magnetic Stimulation

Active Comparator: Amantadine Alone
Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days.
Drug: Amantadine
Other Names:
  • Symadine
  • Symmetrel

Active Comparator: rTMS plus Amantadine
All subjects, after first completing Amantadine Alone arm or rTMS Alone arm, will receive rTMS plus Amantadine. A total of 30 rTMS sessions are provided, 2 rTMS sessions per day, four days per week, while receiving 200mg of Amantadine daily.
Device: rTMS
Other Name: Repetitive Transcranial Magnetic Stimulation

Drug: Amantadine
Other Names:
  • Symadine
  • Symmetrel




Primary Outcome Measures :
  1. Safety [ Time Frame: Daily for 7 weeks ]
    To demonstrate that a combination of rTMS and Amantadine provided within established safety guidelines is tolerated without adverse events. Safety parameters monitored include vital signs, fatigue, skin integrity, neuroanatomical correlates and electroencephalography.


Secondary Outcome Measures :
  1. Disorders of Consciousness Scale (DOCS) Neurobehavioral Growth Trajectories [ Time Frame: Change from baseline measured weekly for 7 weeks ]
    The DOCS is a 25-item neurobehavioral tests that measures best response to stimuli. The DOCS will be used because it provides modality (auditory, visual, tactile) measures related to specific neural pathways. The DOCS will be charted to measure neurobehavioral growth trajectories over time.

  2. Change from Baseline in Functional magnetic resonance imaging (fMRI) [ Time Frame: Change from baseline fMRI measured at 3 weeks and 6 weeks ]
    Functional MRI data will be collected to characterize neural activity within and between brain regions. We will collect task fMRI data, resting state fMRI data and diffusion tensor imaging data.


Other Outcome Measures:
  1. Change from Baseline in Disability Rating Scale (DRS) [ Time Frame: Change from Baseline measured weekly for 7 weeks ]
    The DRS is a scale intended to measure accurately general functional changes over the course of traumatic brain injury recovery. The DRS will be used as a safety outcome measure in this study.

  2. Change from Baseline in Coma Recovery Scale-Revised (CRS-R) [ Time Frame: Change from baseline measured weekly for 7 weeks ]
    The CRS-R is a scale that consists of 23 items that comprise 6 subscales addressing auditory, visual, motor, oromotor, communication and arousal functions. The lowest item on each subscale represents reflexive activity while the highest items represent cognitively-mediated behaviors. The purpose of the scale is to assist with differential diagnosis, prognostic assessment and treatment planning in patients with disorders of consciousness.



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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02025439


Locations
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United States, Illinois
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611
Edward Hines, Jr. VA Hospital
Hines, Illinois, United States, 60141
Sponsors and Collaborators
Edward Hines Jr. VA Hospital
Investigators
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Principal Investigator: Theresa Pape, DrPH Edward Hines Jr. VA Hospital

Publications:
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Responsible Party: Theresa Pape, Deputy ACOS, Clinical Neuroscientist, Edward Hines Jr. VA Hospital
ClinicalTrials.gov Identifier: NCT02025439     History of Changes
Other Study ID Numbers: 1R21HD075192 ( U.S. NIH Grant/Contract )
First Posted: January 1, 2014    Key Record Dates
Last Update Posted: April 25, 2016
Last Verified: April 2016
Keywords provided by Theresa Pape, Edward Hines Jr. VA Hospital:
Traumatic Brain Injury
Transcranial Magnetic Stimulation
Amantadine
Vegetative State
Minimally Conscious State
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Amantadine
Antiparkinson Agents
Anti-Dyskinesia Agents
Antiviral Agents
Anti-Infective Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents