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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

Tracking Information
First Submitted Date  ICMJE December 23, 2013
First Posted Date  ICMJE January 1, 2014
Last Update Posted Date April 25, 2016
Study Start Date  ICMJE February 2014
Estimated Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2014)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 30, 2013)
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.
Change History Complete list of historical versions of study NCT02025439 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2014)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 30, 2013)
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.
Current Other Pre-specified Outcome Measures
 (submitted: February 25, 2014)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: December 30, 2013)
  • 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.
  • Change from Baseline in Disorders of Consciousness Scale (DOCS) [ 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.
 
Descriptive Information
Brief Title  ICMJE Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Official Title  ICMJE Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Traumatic Brain Injury
Intervention  ICMJE
  • Device: rTMS
    Other Name: Repetitive Transcranial Magnetic Stimulation
  • Drug: Amantadine
    Other Names:
    • Symadine
    • Symmetrel
Study Arms  ICMJE
  • 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.
    Intervention: Device: rTMS
  • 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.
    Intervention: Drug: Amantadine
  • 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.
    Interventions:
    • Device: rTMS
    • Drug: Amantadine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: December 30, 2013)
4
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2016
Estimated Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02025439
Other Study ID Numbers  ICMJE 1R21HD075192( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Theresa Pape, Edward Hines Jr. VA Hospital
Study Sponsor  ICMJE Edward Hines Jr. VA Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Theresa Pape, DrPH Edward Hines Jr. VA Hospital
PRS Account Edward Hines Jr. VA Hospital
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP