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Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness

Primary Purpose

Traumatic Brain Injury

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
rTMS
Amantadine
Sponsored by
Edward Hines Jr. VA Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Traumatic Brain Injury, Transcranial Magnetic Stimulation, Amantadine, Vegetative State, Minimally Conscious State

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Northwestern Memorial Hospital
  • Edward Hines, Jr. VA Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

rTMS Alone followed by rTMS+AMA

AMA Alone followed by rTMS+AMA

Arm Description

Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.After first completing rTMS Alone, subjects 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.

Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days. After first completing Amantadine Alone subjects 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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Full Information

First Posted
December 23, 2013
Last Updated
August 10, 2020
Sponsor
Edward Hines Jr. VA Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02025439
Brief Title
Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Official Title
Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
February 2014 (undefined)
Primary Completion Date
July 2016 (Actual)
Study Completion Date
July 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Edward Hines Jr. VA Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury
Keywords
Traumatic Brain Injury, Transcranial Magnetic Stimulation, Amantadine, Vegetative State, Minimally Conscious State

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
rTMS Alone followed by rTMS+AMA
Arm Type
Experimental
Arm Description
Subjects assigned to rTMS Alone will receive 30 sessions of rTMS. Two rTMS sessions will be provided per day, four days per week.After first completing rTMS Alone, subjects 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.
Arm Title
AMA Alone followed by rTMS+AMA
Arm Type
Experimental
Arm Description
Subjects who are assigned to the Amantadine Alone group will receive 28 doses of Amantadine (100mg BID) every day for 28 days. After first completing Amantadine Alone subjects 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.
Intervention Type
Device
Intervention Name(s)
rTMS
Other Intervention Name(s)
Repetitive Transcranial Magnetic Stimulation
Intervention Type
Drug
Intervention Name(s)
Amantadine
Other Intervention Name(s)
Symadine, Symmetrel
Primary Outcome Measure Information:
Title
Intensity of Adverse Event
Description
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Theresa BenderPape, DrPH
Organizational Affiliation
Edward Hines Jr. VA Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Edward Hines, Jr. VA Hospital
City
Hines
State/Province
Illinois
ZIP/Postal Code
60141
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
16983227
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.
Results Reference
background
PubMed Identifier
20633400
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.
Results Reference
background

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Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness

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