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rTMS: A Treatment to Restore Function After Severe TBI

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ClinicalTrials.gov Identifier: NCT02366754
Recruitment Status : Recruiting
First Posted : February 19, 2015
Last Update Posted : September 6, 2019
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
Theresa Pape, Edward Hines Jr. VA Hospital

Tracking Information
First Submitted Date  ICMJE January 26, 2015
First Posted Date  ICMJE February 19, 2015
Last Update Posted Date September 6, 2019
Actual Study Start Date  ICMJE February 2016
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2015)
Disability Rating Scale [ Time Frame: Change from Baseline in DRS total score at an average 22 days ]
The DRS consists of 8 items that address: arousability, awareness and responsivity; cognitive ability for self-care; dependence on others; and psychosocial adaptability. Scores on the DRS range from 0 to 29 with higher scores indicating greater levels of disability.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02366754 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2015)
  • Disorders of Consciousness Scale-25 [ Time Frame: Change from Baseline in DOCS-25 score at 7 days, 14 days, 21 days, 28 days and 50 days ]
    Neurobehavioral measure that evaluates the subject's responses to sounds, touch, objects, people, tastes, movements and smells
  • Coma Near Coma Scale [ Time Frame: Change from Baseline in CNC total score at an average 22 days ]
    Neurobehavioral measure that evaluates the subject's responses to sounds, touch, objects, people, tastes, movements and smells
  • Coma Recovery Scale-Revised [ Time Frame: Change from Baseline in CRS-R total score at an average 22 days ]
    Neurobehavioral measure that evaluates the subject's responses to sounds, touch, objects, people, tastes, movements and smells
  • Modified Tardieu Scale [ Time Frame: Change from Baseline in Modified Tardieu total score at an average 22 days ]
    Spasticity measure for the following muscles: shoulder flexion, elbow flexion/extension, wrist flexion/extension, hip flexion/extension, knee flexion/extension and ankle extension. The scoring is based on 3 velocities of movement where the higher the rating, the higher degree of muscle tone.
  • Modified Ashworth Scale [ Time Frame: Change from Baseline in Modified Ashworth total score at an average 22 days ]
    Spasticity measure for the following muscles: shoulder flexion, elbow flexion/extension, wrist flexion/extension, hip flexion/extension, knee flexion/extension and ankle extension. The individual muscle scores will be compared between time points. The higher the rating on the Modified Ashworth the greater degree of muscle tone demonstrated during testing.
  • Spaulding Limb Movement Protocol [ Time Frame: Change from Baseline in Spaudling Limb Movement total score at an average 22 days ]
    Measures limb movement in response to execution of motor commands in response to 1-step commands that engage upper extremity movements with and without object use.
  • Consciousness Screening Algorithm [ Time Frame: Change from Baseline in consciousness level at 7 days, 14 days, 21 days, 28 days and 50 days ]
  • Functional Neuroimaging [ Time Frame: Change from Baseline in amount of activation and connectivity at an average 22 days ]
    Activation in response to a task, resting state and diffusion tensor imaging
  • EEG Power Spectrum [ Time Frame: Change Baseline in EEG frequency power at an average 22 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE rTMS: A Treatment to Restore Function After Severe TBI
Official Title  ICMJE rTMS: A Treatment to Restore Function After Severe TBI
Brief Summary The purpose of this study is to address the need for targeted treatments that induce functional and structural changes in the brain, ultimately improving neurobehavioral functioning, the investigators propose examining the therapeutic effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS). The objective is to improve functional recovery for persons remaining in vegetative (VS) and minimally conscious (MCS) states 3 to 24 months after severe TBI. The approach is to determine the neurobehavioral effect of rTMS, the relationship between neurobehavioral changes and net neural effects, and to identify and define the neural mechanisms related to neurobehavioral improvements by providing 30 active or placebo rTMS sessions.
Detailed Description

The specific aims (SA) of the CDMRP study are:

SA-1: To determine presence, direction and sustainability of rTMS induced neurobehavioral effects using the DRS (lower scores indicate more function).

SA-2: To determine presence, direction and sustainability of rTMS-induced changes in functional neural activation and whether these changes correlate with improving neurobehavioral function.

SA-3: To determine the rTMS effect on white fiber tracts and whether rTMS-related effects correlate with neurobehavioral gains. White fiber tracts will be examined according to changes in Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AD).

SA-4: To confirm rTMS safety for severe TBI. The investigators hypothesize that there will be no difference between active and placebo groups according to average number of research related adverse events (AE) during treatment.

To accomplish these aims, the investigators will conduct a double blind, randomized, placebo controlled clinical trial where 58 persons remaining in states of disordered consciousness for 3 to 24 months after TBI are randomized to the active rTMS group or the placebo rTMS group.

The primary outcome is neurobehavioral recovery slope as measured by the total Disability Rating Scale (DRS), which will be collected at bedside at Baseline, Midpoint (15th rTMS Session) and Endpoint (30th rTMS Session). The DRS-PI will be collected weekly via telephone interview for the three weeks between Endpoint and Follow up (3 weeks after 30th rTMS session). Secondary outcomes include four measures of functional neural activation: task related functional magnetic resonance imaging (fMRI), functional connectivity MRI (fcMRI), EEG-Rest and EEG-Task. The functional neural activation measures will be collected at baseline, endpoint and follow up. Motor Threshold Testing and Neurobehavioral measures in addition to the DRS and physical measures will also be collected as secondary outcomes. Motor Threshold testing, neurobehavioral and physical measures will be collected at baseline, midpoint, endpoint and follow up. The additional Neurobehavioral and physical measures are the Disorders of Consciousness Scale-25 (DOCS-25), Coma Recovery Scale Revised (CRS-R), Coma Near Coma Scale (CNC), Modified Tardieu Scale, Modified Ashworth Scale, Spaulding Limb Movement Protocol and the Consciousness Screening Algorithm.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Traumatic Brain Injury
Intervention  ICMJE
  • Device: rTMS
    Repetitive TMS is a non-invasive neural stimulation technique achieved via electromagnetic induction. An insulated metal coil is placed on the scalp and short discharges of electric current are directed through the coil producing a magnetic field. This magnetic field is accompanied by an electric field that passes through the skull inducing currents in the tissue beneath the coil. If a cell beneath the coil is viable, then rTMS initiates or inhibits an action potential affecting ongoing neural activity. 30 sessions of active rTMS are provided.
  • Device: Placebo rTMS
    The placebo coil simulates magnetic stimulation, but does not actually emit a pulse. The placebo coil looks, sounds and feels like an active rTMS coil. The placebo coil, visually identical to the active coil, provides a slight sensory sensation and discharge noise (i.e., clicking) nearly identical to that of the active coil.
Study Arms  ICMJE
  • Experimental: Active rTMS
    The intervention consists of 30 active rTMS sessions. Each session is comprised of 300 trains of paired pulses with the following parameters: 100µs paired pulses separated by 100ms inter-pulse-intervals and a five second inter-train-interval. Pulse intensity will be set at 110% of each participant's motor threshold. Active rTMS sessions will be provided two times per day with a 70mm figure-of-eight coil over the left dorsolateral prefrontal cortex. Two Magstim-2002 units and a Bistim2 module will be used to administer active rTMS. Participants assigned to the active rTMS group will receive a total of 1.8 seconds of stimulation. Active rTMS will be administered 2 times daily with the following weekly schedule: 2 days of rTMS, 1 day of rest, 2 days of rTMS, 2 days of rest.
    Intervention: Device: rTMS
  • Sham Comparator: Placebo rTMS
    The intervention consists of 30 placebo rTMS sessions. Each session is comprised of 300 paired-pulse trains with the following parameters: 100µs paired pulses separated by 100ms inter-pulse-intervals and a five second inter-train-interval. Placebo rTMS sessions will be provided two times per day with a 70mm figure-of-eight coil over the left DLPFC. Two Magstim-2002 units and a Bistim2 module will be used to administer placebo rTMS. The placebo coil simulates magnetic stimulation, but does not actually emit a pulse. Participants assigned to the placebo rTMS group will receive 0 seconds of stimulation. Placebo rTMS will be administered with the following weekly schedule: 2 days of rTMS, 1 day of rest, 2 days of rTMS, 2 days of rest.
    Intervention: Device: Placebo rTMS
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 18, 2015)
58
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • At study screening, persons have remained in states of Seriously Impaired Consciousness (SIC) for at least 3 and up to 24 months after TBI
  • 18 years of age or older
  • Traumatic Brain Injury etiology
  • Able to participate in all phases of study including follow-up re-admission
  • Able to identify legally authorized representative/surrogate who is able to read and understand informed consent document and provide written consent

Exclusion Criteria:

  • Primary injury is a non-traumatic brain injury (and is not secondary to TBI) (e.g., inflammatory, infectious, toxic and metabolic encephalopathies, anoxia, cancer, ischemic and hemorrhagic stroke)
  • History of TBI, psychiatric illness (DSM criteria) and or organic brain syndrome (e.g. Alzheimer's)
  • Left dorsal lateral pre-frontal cortex (DLPFC) is not accessible (e.g., left frontal lobectomy)
  • Incurred large cortically based ischemic infarction subsequent to TBI (size is determined collectively by neurosurgeon, neurologist, neuroradiologist and principal investigator)
  • At study screening, patient is receiving anti-epileptic medications to control active seizures
  • Have had a documented seizure within 3 months of study screening
  • Are ventilator dependent at time of study screening
  • Have recovered full consciousness at time of study screening as indicated by a Motor Function scale score of 6 and/or a Communication scale score of 2 on the CRS-R
  • Receiving central nervous system (CNS) stimulants that cannot be safely discontinued via titration
  • Patient did not speak English prior to injury (bedside testing is conducted in English)
  • Pregnant
  • Have implanted cardiac pacemaker or defibrillator, cochlear implant or nerve stimulator
  • Have MRI or TMS contraindications such as pre-injury claustrophobia, metal in eyes/face or brain
  • Other medical conditions, that in investigator's opinion, would preclude subject from completing study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ann Guernon, MS 708-202-8387 ext 23114 ann.guernon@va.gov
Contact: Sandra Kletzel, PhD 708-202-5735 sandra.kletzel@va.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02366754
Other Study ID Numbers  ICMJE CDMRP-PT130274
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 Northwestern University
Investigators  ICMJE
Principal Investigator: Theresa Pape, DrPH, MA Edward Hines Jr. VA Hospital
PRS Account Edward Hines Jr. VA Hospital
Verification Date September 2019

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