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rTMS to Improve Cognitive Function in TBI (rTMS TBI)

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ClinicalTrials.gov Identifier: NCT02152540
Recruitment Status : Active, not recruiting
First Posted : June 2, 2014
Last Update Posted : June 7, 2018
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
This project will study 40 Veterans identified with symptoms understood to characterize mild to moderate Traumatic Brain Injury (TBI) including Post Traumatic Stress Disorder (PTSD). Following screening and informed consent, Veterans will be randomly assigned to treatment with repetitive Transcranial Magnetic Stimulation (rTMS) or sham rTMS (placebo). Additional examinations will compare brain imaging (structural and functional MRI scans at rest) across participants at baseline, after acute rTMS treatment, and at 6 month followup. The VA population differs significantly from populations that have been included in prior trials of rTMS for many conditions such as depression, chronic pain, and PTSD. Many returning Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) personnel and Veterans with concussion histories report cognitive problems, such as impaired attention, verbal fluency, poor planning, reduced working memory, and mental flexibility. The investigators hope to show the efficacy and durability of rTMS in treating these symptoms safely in Veterans with co-morbidities.

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

Detailed Description:

The goal of the present study is to evaluate the efficacy and durability of benefits of repetitive Transcranial Magnetic Stimulation (rTMS) as a promising non-invasive therapeutic treatment for executive function deficits reported in Veterans with mild to moderate Traumatic Brain Injury (TBI) patients. Although much progress has been made towards understanding the various deficits following TBI, progress has yet to be made towards identifying and assessing therapeutic treatment options that are responsive to TBI symptoms. Many returning OEF/OIF Veterans with concussion histories report cognitive symptoms that may last for months or years, and affect every day function. Symptoms faced by Veterans with mild to moderate TBI include executive function deficits such as impaired attention (including shifting sets), verbal fluency, poor planning, reduced working memory, and mental flexibility. The primary objective is to assess the efficacy of rTMS in Veterans with mild to moderate TBI in improving executive functioning.

A recent VA study reported improvements in PTSD and related symptoms in Veterans with PTSD who received rTMS (Watts et al., 2012). Repetitive TMS is a method of delivering therapeutic, non-invasive brain stimulation that is currently being used at the VA Palo Alto and Stanford University in a number of clinical trials.

For this pilot study the investigators propose to enroll 40 Veterans diagnosed with mild to moderate TBI (age range 20-65). Inclusion Criteria: mild and moderate TBI will be defined as: post-traumatic amnesia (PTA < 1 day for mild; 1 day> x < 7days for moderate). Because of the extensively documented co-occurrence of TBI with PTSD, (Veterans with TBI with and without PTSD will be enrolled). PTSD will be assessed using standard clinical measures. Exclusionary criteria: patients will be screened for TMS and MRI safety. The duration of the study will be two years, with a 1.5 year enrollment period, and a final half-year of follow-up completion. Following a preliminary telephone screen, Veterans will be scheduled for onsite informed consent, screening, and baseline assessments. Using an electronic randomization form, participants will be enrolled into two groups: active rTMS or sham rTMS. As this is a double blind placebo controlled study, only the subject ID number is provided to the nurse administrating the rTMS treatment. After randomization, the rTMS nurse will test the motor threshold (MT) for rTMS. Each participant will be in the trial for a total of approximately (28) weeks: 1-2 weeks screening, (2) weeks acute treatment phase (including MRI pre and post rTMS) and 24 weeks (6 month) follow-up phase (with MRI, neuropsychological testing and self-report measures). Left Dorsolateral Prefrontal Cortex (DLPFC) will be the stimulation site as it is shown to be affective in treatment of depression and approved by FDA. All participants will receive a minimum of 20 treatments before being evaluated for change in executive function (primary outcome measure).

The primary hypothesis is that Veterans receiving active rTMS will show improvement more than sham treated Veterans in (performance between baseline and last assessment of >1 SD on either the Trail Making Test part B, Delis-Kaplan Executive Function System [D-KEFS] Verbal Fluency and/or D-KEFS Color-Word Interference Test). Additional analysis will include: Sustained Improvement on executive function composite score; secondary consequences of TBI scores on Quality of Life (QOL) scale, moderators of response such as age, severity of symptoms at baseline, type of comorbidity (e.g., PTSD); and, functional brain activity changes with rTMS treatment. This pilot study will be one of the first to demonstrate rTMS as a treatment for executive function deficit in Veterans with mild to moderate TBI. Additionally, it would also report on the efficacy of using functional MRI (fMRI) as a biomarker to capture this improvement in executive function.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Repetitive Transcranial Magnetic Stimulation to Improve Cognitive Function in TBI
Actual Study Start Date : October 1, 2014
Actual Primary Completion Date : September 30, 2017
Estimated Study Completion Date : September 30, 2018

Arm Intervention/treatment
Experimental: rTMS
Those receiving experimental treatment will receive 20 sessions of rTMS. The treatment will be delivered by trained medical personnel.
Device: rTMS
Repetitive Transcranial Magnetic Stimulation

Placebo Comparator: Sham rTMS
Those receiving the sham rTMS will receive 20 sessions of sham rTMS. The treatment will be delivered by trained medical personnel.
Device: Sham rTMS
Placebo Device that simulates active rTMS treatment




Primary Outcome Measures :
  1. Trail Making Test part B [ Time Frame: One month ]
    The primary hypothesis is that Veterans receiving active rTMS will show improvement more than sham treated Veterans in performance between baseline and last assessment of >1 SD on the Trail Making Test part B. This test is known for its accurate assessment of executive function in mild and moderate TBI.


Secondary Outcome Measures :
  1. Sustained improvement on executive function [ Time Frame: 6-month post treatment follow up ]
    At the end of the 6 month post treatment followup TBI patients who received rTMS would be more likely to continue to have greater "executive function improvement" on Trail making test part B than patients who received Sham rTMS.

  2. Quality of Life (QOL) scale [ Time Frame: One month ]
    This scale would show significantly greater improvement in patients with mild to moderate TBI who received rTMS treatment.

  3. Moderators of Response [ Time Frame: one month ]
    Moderators of response such as age, severity of symptoms at baseline, time to injury, type of comorbidity, PTSD, sleep depression, substance abuse, medication use, cognitive exercises, fatigue, TBI type, duration of illness, prior treatment resistance (rTMS/ECT) or any combination of these, may affect or moderate the treatment response.

  4. Functional Brain connectivity [ Time Frame: Six month follow-up ]
    Greater functional connectivity will be observed in hub centers of the Default Mode Network (DMN), particularly the precuneus/posterior cingulate area as measured by resting state fMRI/diffusion tensor imaging (DTI) at follow up compared to baseline in those TBI patients treated with rTMS compared to those treated with sham.

  5. Mediators of response [ Time Frame: 6 month follow up ]
    Mediators of response to treatment: to establish a preliminary understanding of the underlying mechanisms related to rTMS modulation of synaptic repair in TBI we will also look at brain-derived neurotrophic factor (BDNF) samples in our population.



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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Veteran of any combat era
  • Both Genders
  • 20-65years
  • (History of (Post Traumatic Amnesia < 1 day for mild TBI; 1 day> x < 7days for moderate TBI))
  • Ability to obtain a Motor Threshold (MT) will be determined during the screening process.
  • If on a psychotropic medication regimen, that regimen will be stable for at least 4 weeks prior to entry to the study and patient will be willing to remain on a stable regimen during the acute treatment phase.
  • Has an adequately stable condition and environment to enable attendance at scheduled clinic visits.
  • For female participants, agrees to use one of the following acceptable methods of birth control: abstinence, oral contraceptive; Norplant
  • Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form prior to participating in any study-specific procedures or assessments.

Exclusion Criteria:

  • Pregnant or lactating female.
  • Unable to be safely withdraw, at least two-weeks prior to treatment commencement, from medications that substantially increase the risk of having seizures
  • Have a cardiac pacemaker or a cochlear implant
  • Have an implanted device (deep brain stimulation) or metal in the brain (see standard MRI exclusion criteria including metal screening section in telephone screen, Appendix A).
  • Have a mass lesion, cerebral infarct or other active central nervous system (CNS) disease, including a seizure disorder.
  • Known current psychosis as determined by DSM-IV coding in chart (Axis I, psychotic disorder, schizophrenia) or a history of a non-mood psychotic disorder.
  • Diagnosis of Bipolar Affective Disorder (as determined by chart review and intake interview)
  • Current amnesic disorders, dementia, mini mental state examination (MMSE) 24 or delirium.
  • Current substance abuse (not including caffeine or nicotine) as determined by positive toxicology screen, or by history via AUDIT, within 3 months prior to screening
  • Prior history of seizures
  • Severe TBI or open head injury
  • TBI within last two months or in acute stage
  • Participation in another concurrent clinical trial
  • Patients with prior exposure to rTMS/ECT
  • Active current suicidal intent or plan. Patient at risk for suicide will be required to establish a written safety plan involving their primary psychiatrist and the treatment team before entering the clinical trial

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): NCT02152540


Locations
United States, California
VA Palo Alto Health Care System, Palo Alto, CA
Palo Alto, California, United States, 94304-1290
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Maheen M Adamson, PhD VA Palo Alto Health Care System, Palo Alto, CA

Additional Information:
Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02152540     History of Changes
Other Study ID Numbers: N1416-P
RX13-011 ( Other Grant/Funding Number: VA Rehab )
First Posted: June 2, 2014    Key Record Dates
Last Update Posted: June 7, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:
TBI
Transcranial Magnetic Stimulation, Repetitive
magnetic resonance imaging functional
Quality of life
Executive Function
Veterans

Additional relevant MeSH terms:
Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries