<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02974959</url>
  </required_header>
  <id_info>
    <org_study_id>HSR 16-4171</org_study_id>
    <nct_id>NCT02974959</nct_id>
  </id_info>
  <brief_title>Vagus Nerve Stimulation to Treat Moderate Traumatic Brain Injury</brief_title>
  <official_title>Vagus Nerve Stimulation to Treat Mild To Moderate Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CentraCare</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ElectroCore INC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>CentraCare</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this single-center, prospective, randomized (1:1), double-blind,&#xD;
      sham-controlled parallel-arm pilot study is to provide initial evidence of use of the&#xD;
      noninvasive vagus nerve stimulator for treatment in patients recovering from concussion and&#xD;
      moderate traumatic brain injury to improve clinical recovery. The study compares the safety&#xD;
      and effectiveness of an active gammaCore treatment against a sham treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Our primary aim is to assess for evidence of the effectiveness of the nVNS in reducing&#xD;
      clinical symptoms such as motor and cognition deficits. As a primary endpoint, we will&#xD;
      analyze the difference between groups at all time points in standardized cognitive&#xD;
      assessments. We will also assess the levels of different inflammatory cytokines.&#xD;
&#xD;
      The secondary endpoints for moderate TBI are functional assessments and quality of life&#xD;
      questionnaires including a depression screen. Our secondary aim is to assess the safety of a&#xD;
      non-invasive VNS (nVNS) in a subset of patients who have suffered a moderate TBI. We do not&#xD;
      anticipate any significant difference between heart rate variability (HRV) in active compared&#xD;
      to sham treatments and no difference symptoms experienced during treatment sessions.&#xD;
&#xD;
      We propose a single-center, prospective, randomized (1:1), double-blind, sham-controlled,&#xD;
      parallel-arm pilot study. We determined that an N of 30 patients would be needed to reach&#xD;
      significance. Moderate TBI will be defined by the Head Injury Interdisciplinary Special&#xD;
      Interest Group of the American Congress of Rehabilitation Medicine (full list in inclusion&#xD;
      criteria) seeking care at HCMC within 2 weeks of injury. Recruited subjects will be&#xD;
      randomized to active treatment or sham-treatment control arms. Randomization to active or&#xD;
      sham gammaCore treatment will occur during the screening visit after enrollment, and&#xD;
      intervention will begin at the baseline visit that occurs 72 hours (+/- 1 day) after&#xD;
      enrollment. Informed consent will be obtained from patients or their proxy prior to&#xD;
      enrollment. If a proxy elects to enroll a patient, who then recovers during the course of the&#xD;
      study, they will be able to withdraw from the study if they so desire. We anticipate&#xD;
      enrollment to take approximately 6 months, and enrolled subjects will be followed through the&#xD;
      final week 18 follow up visit, estimating a completion date 9 months after the first&#xD;
      enrollment.&#xD;
&#xD;
      The treatment will include 12 weeks of active interventional therapy, with seven visits,&#xD;
      including the screening visit that takes place within 2 weeks of injury. From the baseline&#xD;
      visit, there will be a follow up phone call at 1 week, and a follow up visit at 2, 6, 12 and&#xD;
      18 weeks. During each of these visits, data assessing heart rate variability will be obtained&#xD;
      using a chest strap heart rate monitor and a non-invasive heart rate variability monitor will&#xD;
      be used to measure minute phenomenon in heartbeats. This will be done while supine, during&#xD;
      treatment and after an orthostatic challenge (i.e. standing or sitting upright). An EKG will&#xD;
      be obtained at each visit to assess for bradycardia.&#xD;
&#xD;
      The nVNS therapy will be performed using the gammaCore-R (electroCore LLC, NJ), which is an&#xD;
      external hand-held vagal nerve stimulator. The gammaCore-R produces a low voltage electric&#xD;
      signal consisting of five 5000 Hz pulses that are repeated at a rate of 25 Hz. The strength&#xD;
      of the stimulation is lower than that required to activate efferent vagal nerve fibers that&#xD;
      mediates cardiac specific effects and will only be used on the left vagus nerve, which has&#xD;
      fewer cardiac projections. It allows for a 120 second stimulation session. The stimulation&#xD;
      will occur twice daily, one time in the morning and one time in the evening. This should be&#xD;
      done as close to 12 hours apart as possible and should occur twice daily for the entire 12&#xD;
      week study period. The sham device appears identical to the gammaCore but does not provide a&#xD;
      frequency of stimulation powerful enough to stimulate either efferent or afferent fibers of&#xD;
      the vagus nerve. However, it does supply a low frequency current which will cause a tingling&#xD;
      of this skin to improve blinding of the patients. After the 12 week visit, the device will be&#xD;
      returned. However, both the treating physician and the patient will remain blinded to the&#xD;
      study arms until the completion of the study at week 18. Blood samples (10 mL or two&#xD;
      teaspoons) will be drawn at the screening visit, as well as the 12 and 18-week time points&#xD;
      for biomarker analysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2016</start_date>
  <completion_date type="Actual">November 2020</completion_date>
  <primary_completion_date type="Actual">June 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized control trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Only the study coordinator had access to the master list which noted whether the device was active or a sham. This information was not provided to or accessible by the participants, care providers, investigators, or outcome assessors.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Safety/bradycardia</measure>
    <time_frame>18 weeks</time_frame>
    <description>We will evaluate for bradycardia after using the device at all time points using an EKG and heart rate variability (Beats/minute for each)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy-cognition</measure>
    <time_frame>initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks</time_frame>
    <description>We will assess whether vagus nerve simulation impacts clinical recovery from TBI as assessed by neuro-cognitive assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy-eye tracking</measure>
    <time_frame>initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks</time_frame>
    <description>We will evaluate for changes in eye tracking metrics</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy-serum biomarkers</measure>
    <time_frame>initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks</time_frame>
    <description>Evaluate for changes in serum biomarkers with treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <condition>Acute Brain Injuries</condition>
  <arm_group>
    <arm_group_label>gammaCore active device</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this arm will be using an active device which delivers a treatment dose of current to the vagus nerve twice daily for 120 seconds</description>
  </arm_group>
  <arm_group>
    <arm_group_label>gammaCore Sham device</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Patients in this arm will be using a sham device which does not deliver a treatment dose of current, but will deliver enough current to cause tingling on the skin.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>gammaCore active device</intervention_name>
    <description>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.</description>
    <arm_group_label>gammaCore active device</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>gammaCore sham device</intervention_name>
    <description>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.</description>
    <arm_group_label>gammaCore Sham device</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written Informed Consent obtained by Subject or Subject's proxy.&#xD;
&#xD;
          2. Is between the ages of 18 and 60 years, male or female.&#xD;
&#xD;
          3. Meets the criteria of the Head Injury Interdisciplinary Special Interest Group of the&#xD;
             American Congress of Rehabilitation Medicine, which defines a head injury as a&#xD;
             traumatically induced physiologic disruption of brain function, as manifested by one&#xD;
             of the following:&#xD;
&#xD;
               -  Any period of loss of consciousness (LOC),&#xD;
&#xD;
               -  Any loss of memory for events immediately before or after the accident,&#xD;
&#xD;
               -  Any alteration in mental state at the time of the accident,&#xD;
&#xD;
               -  Focal neurologic deficits, which may or may not be transient.&#xD;
&#xD;
          4. Meets the criteria for moderate TBI as defined by the Head Injury Interdisciplinary&#xD;
             Special Interest Group of the American Congress of Rehabilitation Medicine, which are&#xD;
             as follows:&#xD;
&#xD;
               -  Length of stay at least 48 hours,&#xD;
&#xD;
               -  Glasgow Coma Scale (GCS score of 9-12 or higher)&#xD;
&#xD;
               -  Operative intracranial lesion,&#xD;
&#xD;
               -  Abnormal CT scan findings.&#xD;
&#xD;
          5. Has had a craniotomy, but those with hydrocephalus or active intracranial pressure&#xD;
             elevation will be excluded.&#xD;
&#xD;
          6. Able to accurately communicate the sensation of amplitude of intensity by the&#xD;
             stimulation treatment with the GammaCore device.&#xD;
&#xD;
          7. Has a stable orthopedic or other traumatic body injury.&#xD;
&#xD;
          8. Is capable of completing all study assessments.&#xD;
&#xD;
          9. Agrees to use the GammaCore device as intended and follow all of the requirements of&#xD;
             the study, including follow-up visits.&#xD;
&#xD;
         10. Agrees to record usage of the GammaCore device, all required study data, and report&#xD;
             any adverse effects to the sponsor/investigator within 24 hours of any such adverse&#xD;
             event.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Has an active DNR/DNI (do not resuscitate/ do not intubate) request.&#xD;
&#xD;
          2. Has dissent among family members / next of kin regarding level of care.&#xD;
&#xD;
          3. Has a penetrating injury.&#xD;
&#xD;
          4. Has concurrent active severe medical problems or conditions, which could prevent&#xD;
             survival during the course of the study.&#xD;
&#xD;
          5. Has pre-existing central nervous system disease or associated comorbidities that may&#xD;
             not allow for an 18-week follow-up visit.&#xD;
&#xD;
          6. Has an abscess, infection or lesion (including lymphadenopathy) at the gammaCore&#xD;
             treatment site.&#xD;
&#xD;
          7. Has known or suspected moderate to severe atherosclerotic cardiovascular disease,&#xD;
             carotid artery disease (e.g. bruits or history of TIA or CVA).&#xD;
&#xD;
          8. Has a clinically significant irregular heart rate or rhythm.&#xD;
&#xD;
          9. Has uncontrolled hypertension (systolic bp &gt; 200 or diastolic bp &gt;100), recent (within&#xD;
             the last 3 months) heart attack, recent (within the last 3 months) stroke, known&#xD;
             aortic aneurysm, or congestive heart failure (CHF).&#xD;
&#xD;
         10. Is currently implanted with an electrical and/or neurostimulator device, including but&#xD;
             not limited to cardiac pacemaker, defibrillator, vagal neurostimulator, deep brain&#xD;
             stimulator, spinal stimulator, bone growth stimulator, or cochlear implant.&#xD;
&#xD;
         11. Has a history of significant carotid endarterectomy, vagotomy, dysaesthesia or&#xD;
             vascular neck surgery on either side of the neck.&#xD;
&#xD;
         12. Has been implanted with metal cervical spine hardware.&#xD;
&#xD;
         13. Has a recent or repeated history of syncope.&#xD;
&#xD;
         14. Has a recent or repeated history of seizures.&#xD;
&#xD;
         15. Has known clotting disorder or hemophilia&#xD;
&#xD;
         16. Has anemia (hb&lt;12)&#xD;
&#xD;
         17. Is pregnant or nursing, or of childbearing potential and is unwilling to use an&#xD;
             accepted form of birth control (hormonal, barrier method, surgical, or abstention or&#xD;
             is at least two years post-menopause).&#xD;
&#xD;
         18. Is participating in any other therapeutic clinical investigation or has participated&#xD;
             in a clinical trial in the preceding 30 days.&#xD;
&#xD;
         19. Is an employee of the clinical study site or a relative of the Investigator.&#xD;
&#xD;
         20. Has an abnormal baseline electrocardiogram (ECG), including second and third degree&#xD;
             heart block, atrial fibrillation, atrial flutter, recent history of ventricular&#xD;
             tachycardia or ventricular fibrillation or clinically significant premature&#xD;
             ventricular contraction.&#xD;
&#xD;
         21. Has a known history or suspicion of substance abuse or addiction.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Uzma Samadani, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hennepin County Medical Center, Minneapolis</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Thomas Bergman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hennepin County Medical Center, Minneapolis</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hennepin County Medical Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55415</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>September 12, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>February 2, 2021</last_update_submitted>
  <last_update_submitted_qc>February 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974959
org study id: HSR 16-4171
nct id: NCT02974959
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized control trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Only the study coordinator had access to the master list which noted whether the device was active or a sham. This information was not provided to or accessible by the participants, care providers, investigators, or outcome assessors.
measure: Safety/bradycardia
time frame: 18 weeks
description: We will evaluate for bradycardia after using the device at all time points using an EKG and heart rate variability (Beats/minute for each)
measure: Efficacy-cognition
time frame: initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks
description: We will assess whether vagus nerve simulation impacts clinical recovery from TBI as assessed by neuro-cognitive assessments
measure: Efficacy-eye tracking
time frame: initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks
description: We will evaluate for changes in eye tracking metrics
measure: Efficacy-serum biomarkers
time frame: initial visit, 2 weeks, 6 weeks, 12 weeks, 18 weeks
description: Evaluate for changes in serum biomarkers with treatment
arm group label: gammaCore active device
arm group type: Experimental
description: Patients in this arm will be using an active device which delivers a treatment dose of current to the vagus nerve twice daily for 120 seconds
arm group label: gammaCore Sham device
arm group type: Sham Comparator
description: Patients in this arm will be using a sham device which does not deliver a treatment dose of current, but will deliver enough current to cause tingling on the skin.
intervention type: Device
intervention name: gammaCore active device
description: 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.
arm group label: gammaCore active device
intervention type: Device
intervention name: gammaCore sham device
description: 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.
arm group label: gammaCore Sham device
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Uzma Samadani, MD, PhD
role: Principal Investigator
affiliation: Hennepin County Medical Center, Minneapolis
last name: Thomas Bergman, MD
role: Principal Investigator
affiliation: Hennepin County Medical Center, Minneapolis
facility: 
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Wounds and Injuries
sharing ipd: Undecided