Vagus Nerve Stimulation to Treat Moderate Traumatic Brain Injury
Condition: Traumatic Brain Injury; Acute Brain Injuries
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this single-center, prospective, randomized (1:1), double-blind,
      sham-controlled parallel-arm pilot study is to provide initial evidence of use of the
      noninvasive vagus nerve stimulator for treatment in patients recovering from concussion and
      moderate traumatic brain injury to improve clinical recovery. The study compares the safety
      and effectiveness of an active gammaCore treatment against a sham treatment.
    

Detailed description: 
      Our primary aim is to assess for evidence of the effectiveness of the nVNS in reducing
      clinical symptoms such as motor and cognition deficits. As a primary endpoint, we will
      analyze the difference between groups at all time points in standardized cognitive
      assessments. We will also assess the levels of different inflammatory cytokines.

      The secondary endpoints for moderate TBI are functional assessments and quality of life
      questionnaires including a depression screen. Our secondary aim is to assess the safety of a
      non-invasive VNS (nVNS) in a subset of patients who have suffered a moderate TBI. We do not
      anticipate any significant difference between heart rate variability (HRV) in active compared
      to sham treatments and no difference symptoms experienced during treatment sessions.

      We propose a single-center, prospective, randomized (1:1), double-blind, sham-controlled,
      parallel-arm pilot study. We determined that an N of 30 patients would be needed to reach
      significance. Moderate TBI will be defined by the Head Injury Interdisciplinary Special
      Interest Group of the American Congress of Rehabilitation Medicine (full list in inclusion
      criteria) seeking care at HCMC within 2 weeks of injury. Recruited subjects will be
      randomized to active treatment or sham-treatment control arms. Randomization to active or
      sham gammaCore treatment will occur during the screening visit after enrollment, and
      intervention will begin at the baseline visit that occurs 72 hours (+/- 1 day) after
      enrollment. Informed consent will be obtained from patients or their proxy prior to
      enrollment. If a proxy elects to enroll a patient, who then recovers during the course of the
      study, they will be able to withdraw from the study if they so desire. We anticipate
      enrollment to take approximately 6 months, and enrolled subjects will be followed through the
      final week 18 follow up visit, estimating a completion date 9 months after the first
      enrollment.

      The treatment will include 12 weeks of active interventional therapy, with seven visits,
      including the screening visit that takes place within 2 weeks of injury. From the baseline
      visit, there will be a follow up phone call at 1 week, and a follow up visit at 2, 6, 12 and
      18 weeks. During each of these visits, data assessing heart rate variability will be obtained
      using a chest strap heart rate monitor and a non-invasive heart rate variability monitor will
      be used to measure minute phenomenon in heartbeats. This will be done while supine, during
      treatment and after an orthostatic challenge (i.e. standing or sitting upright). An EKG will
      be obtained at each visit to assess for bradycardia.

      The nVNS therapy will be performed using the gammaCore-R (electroCore LLC, NJ), which is an
      external hand-held vagal nerve stimulator. The gammaCore-R produces a low voltage electric
      signal consisting of five 5000 Hz pulses that are repeated at a rate of 25 Hz. The strength
      of the stimulation is lower than that required to activate efferent vagal nerve fibers that
      mediates cardiac specific effects and will only be used on the left vagus nerve, which has
      fewer cardiac projections. It allows for a 120 second stimulation session. The stimulation
      will occur twice daily, one time in the morning and one time in the evening. This should be
      done as close to 12 hours apart as possible and should occur twice daily for the entire 12
      week study period. The sham device appears identical to the gammaCore but does not provide a
      frequency of stimulation powerful enough to stimulate either efferent or afferent fibers of
      the vagus nerve. However, it does supply a low frequency current which will cause a tingling
      of this skin to improve blinding of the patients. After the 12 week visit, the device will be
      returned. However, both the treating physician and the patient will remain blinded to the
      study arms until the completion of the study at week 18. Blood samples (10 mL or two
      teaspoons) will be drawn at the screening visit, as well as the 12 and 18-week time points
      for biomarker analysis.
    

Intervention name(s): gammaCore active device; gammaCore sham device
Intervention type(s): Device; Device
Intervention description(s): The nVNS therapy will be performed using the gammaCore-R (electroCore LLC, NJ), which is an external hand-held vagal nerve stimulator. The gammaCore-R produces a low voltage electric signal consisting of five 5000 Hz pulses that are repeated at a rate of 25 Hz. It allows for a 120 second stimulation session. The stimulation will occur twice daily, one time in the morning and one time in the evening. This should be done as close to 12 hours apart as possible and should occur twice daily for the entire 12 week study period.; The sham device appears identical to the gammaCore but does not provide a frequency of stimulation powerful enough to stimulate either efferent or afferent fibers of the vagus nerve. However, it does supply a low frequency current which will cause a tingling of this skin to improve blinding of the patients.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized control trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment