<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/NCT04437498</url>
  </required_header>
  <id_info>
    <org_study_id>N3418-I</org_study_id>
    <secondary_id>I01RX003418</secondary_id>
    <nct_id>NCT04437498</nct_id>
  </id_info>
  <brief_title>Vagal Nerve Stimulation in mTBI</brief_title>
  <acronym>VNS mTBI</acronym>
  <official_title>Non-Invasive Vagal Nerve Stimulation in Veterans With Mild Traumatic Brain Injury (mTBI)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Atlanta VA Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are important&#xD;
      conditions for the Veterans Administration (VA) that frequently occur together in combat&#xD;
      Veterans from the conflicts in Afghanistan and Iraq. In many Veterans these become chronic,&#xD;
      raising the risk the burden of neurotrauma can worsen over time. This study will examine a&#xD;
      new intervention called non-invasive Vagal Nerve Stimulation (nVNS) and its effects on memory&#xD;
      and symptoms of PTSD and mTBI as well as brain and physiology in Veterans with mTBI and PTSD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This projects will assess the effects of non-invasive Vagal Nerve Stimulation (nVNS) on&#xD;
      neurobiology and cognition in combat Veterans with mild Traumatic Brain Injury (mTBI) and&#xD;
      co-morbid posttraumatic stress disorder (PTSD) during the performance of stressful tasks&#xD;
      (traumatic scripts, mental arithmetic) and verbal declarative memory tasks using measurement&#xD;
      of memory performance, peripheral inflammatory markers in blood (IL6) and cardiovascular&#xD;
      responses using wearable gated sensing devices and electro- and seismocardiography, as well&#xD;
      as brain response (anterior cingulate, hippocampus) measured with High Resolution Positron&#xD;
      Emission Tomography (HR-PET) and radiolabelled water (15O[H2O]). The investigators&#xD;
      hypothesize that nVNS but not sham control will result in enhanced memory, and hippocampal&#xD;
      activation with memory encoding, and reduced cardiovascular, sympathetic, and inflammatory&#xD;
      responses to stress. The investigators will also assess the effects of nVNS and sham on&#xD;
      memory retention when applied to the encoding phase of a declarative memory learning task&#xD;
      repeated daily over a four day period and on ratings of PTSD and pain in Veterans with mTBI&#xD;
      and co-morbid PTSD and repeat assessments after three months of twice daily treatments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 25, 2021</start_date>
  <completion_date type="Anticipated">January 15, 2026</completion_date>
  <primary_completion_date type="Anticipated">September 20, 2025</primary_completion_date>
  <phase>N/A</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>Veterans are randomized to double blind treatment with active non-invasive Vagal Nerve Stimulation (nVNS) or a sham control.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>code for active and sham devices kept by non study personnel.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>CAPS</measure>
    <time_frame>three months</time_frame>
    <description>The Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) is a measure of PTSD symptoms with a range of 0-80 and higher score indicating more severe PTSD symptoms. We will compare change from baseline to post treatment with active vagal nerve stimulation (VNS) or sham stimulation twice daily.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>insula</measure>
    <time_frame>10 minutes</time_frame>
    <description>Blood flow in the insula is measured with positron emission tomography (PET) and radiolabelled water during the performance of stress tasks. We compare blood flow in the insula to whole brain blood flow ratio during stress tasks (listening to personalized traumatic scripts) versus control tasks in the VNS versus sham groups with hypothesis of blocked insula blood flow with VNS</description>
  </primary_outcome>
  <primary_outcome>
    <measure>HVLT-R % retention</measure>
    <time_frame>baseline versus three months</time_frame>
    <description>The Hopkins Verbal Learning Test-Revised (HVLT-R) is a test of declarative memory learning that involves the learning of 12 nouns, four from each of three semantic categories, learned over three learning trials, followed 20 minutes later by a delayed free recall trial and recognition trial composed of 24 words with 12 false positives. The percent (%) retention is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3. HLVT-R % retention has a range of 0-100 with 100 being best and 0 worst performance. Baseline and three months post treatment paired with sham or active stimulation are compared.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in IL6 Concentration in Blood with Stress</measure>
    <time_frame>Baseline to 120 minutes after stress</time_frame>
    <description>Interleukin-6 (IL6) response to stress paired with active or sham stimulation. IL6 is an inflammatory biomarker measured in blood. We compare IL6 response to stress in VNS versus sham treated groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>hippocampal activation</measure>
    <time_frame>10 minutes</time_frame>
    <description>Blood flow in the hippocampus is measured with positron emission tomography (PET) and radiolabelled water during the performance of declarative memory tasks. We compare blood flow in the hippocampus to whole brain blood flow ratio during memory tasks versus control tasks in the VNS versus sham groups with hypothesis of increased hippocampal blood flow with VNS</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PPG amplitude</measure>
    <time_frame>Change from baseline to 5 seconds after the termination of stimulation paired with stress</time_frame>
    <description>Photoplethysmography (PPG) amplitude is a measure of peripheral vasoconstriction which is a marker of sympathetic response to stress with active or sham. PPG amplitude is the diameter of the blood vessel in the finger, we measure change from baseline to post active vagal nerve stimulation versus sham stimulation with stress.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>PTSD</condition>
  <condition>mTBI</condition>
  <arm_group>
    <arm_group_label>nVNS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>non invasive vagal nerve stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>sham stimulation</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>sham stimulation</intervention_name>
    <description>non invasive vagal nerve stimulation</description>
    <arm_group_label>sham</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>nVNS</intervention_name>
    <description>active vns stimulation</description>
    <arm_group_label>nVNS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Veterans with mTBI and PTSD&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  amnesia for the inciting event lasted longer than 24 hours&#xD;
&#xD;
          -  Glasgow Coma Scale Score after 30 minutes was less than 13&#xD;
&#xD;
          -  loss of consciousness more than 30 minutes&#xD;
&#xD;
          -  positive pregnancy test&#xD;
&#xD;
          -  meningitis or other neurological disorder other than mTBI&#xD;
&#xD;
          -  alcohol or substance abuse use disorder based on the SCID within the past 12 months&#xD;
&#xD;
          -  current or lifetime history of schizophrenia, schizoaffective disorder, bipolar&#xD;
             disorder, anorexia nervosa or bulimia, based on the SCID&#xD;
&#xD;
          -  active suicidal ideation based on criteria outlined below&#xD;
&#xD;
          -  a history of serious medical or neurological illness, such as cardiovascular,&#xD;
             gastrointestinal, hepatic, renal, neurologic or other systemic illness&#xD;
&#xD;
          -  active neuroleptic, opiate, or benzodiazepine treatment&#xD;
&#xD;
          -  structural abnormality on brain MRI or CT&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Doug J Bremner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Atlanta VA Medical and Rehab Center, Decatur, GA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Doug J Bremner, MD</last_name>
    <phone>(404) 712-9569</phone>
    <email>James.Bremner@va.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anna Woodbury, MD</last_name>
    <phone>(404) 321-6111</phone>
    <phone_ext>6939</phone_ext>
    <email>Anna.Woodbury@va.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Atlanta VA Medical and Rehab Center, Decatur, GA</name>
      <address>
        <city>Decatur</city>
        <state>Georgia</state>
        <zip>30033-4004</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ashley N Scales</last_name>
      <phone>404-321-6111</phone>
      <phone_ext>23952</phone_ext>
      <email>Ashley.Scales@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Michael Hart, MD</last_name>
      <phone>(404) 321-6111</phone>
      <phone_ext>206170</phone_ext>
      <email>Michael.Hart3@va.gov</email>
    </contact_backup>
    <investigator>
      <last_name>Doug J Bremner, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 18, 2020</study_first_posted>
  <last_update_submitted>May 17, 2023</last_update_submitted>
  <last_update_submitted_qc>May 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vagus nerve</keyword>
  <keyword>stress disorders, posttraumatic</keyword>
  <keyword>traumatic brain injury</keyword>
  <keyword>memory</keyword>
  <keyword>hippocampus</keyword>
  <keyword>emission tomography</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>three months after study end</ipd_time_frame>
    <ipd_access_criteria>de identified data for three years</ipd_access_criteria>
  </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/NCT04437498
org study id: N3418-I
secondary id: I01RX003418
nct id: NCT04437498
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are important
      conditions for the Veterans Administration (VA) that frequently occur together in combat
      Veterans from the conflicts in Afghanistan and Iraq. In many Veterans these become chronic,
      raising the risk the burden of neurotrauma can worsen over time. This study will examine a
      new intervention called non-invasive Vagal Nerve Stimulation (nVNS) and its effects on memory
      and symptoms of PTSD and mTBI as well as brain and physiology in Veterans with mTBI and PTSD.
This projects will assess the effects of non-invasive Vagal Nerve Stimulation (nVNS) on
      neurobiology and cognition in combat Veterans with mild Traumatic Brain Injury (mTBI) and
      co-morbid posttraumatic stress disorder (PTSD) during the performance of stressful tasks
      (traumatic scripts, mental arithmetic) and verbal declarative memory tasks using measurement
      of memory performance, peripheral inflammatory markers in blood (IL6) and cardiovascular
      responses using wearable gated sensing devices and electro- and seismocardiography, as well
      as brain response (anterior cingulate, hippocampus) measured with High Resolution Positron
      Emission Tomography (HR-PET) and radiolabelled water (15O[H2O]). The investigators
      hypothesize that nVNS but not sham control will result in enhanced memory, and hippocampal
      activation with memory encoding, and reduced cardiovascular, sympathetic, and inflammatory
      responses to stress. The investigators will also assess the effects of nVNS and sham on
      memory retention when applied to the encoding phase of a declarative memory learning task
      repeated daily over a four day period and on ratings of PTSD and pain in Veterans with mTBI
      and co-morbid PTSD and repeat assessments after three months of twice daily treatments.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Veterans are randomized to double blind treatment with active non-invasive Vagal Nerve Stimulation (nVNS) or a sham control.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: code for active and sham devices kept by non study personnel.
measure: CAPS
time frame: three months
description: The Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) is a measure of PTSD symptoms with a range of 0-80 and higher score indicating more severe PTSD symptoms. We will compare change from baseline to post treatment with active vagal nerve stimulation (VNS) or sham stimulation twice daily.
measure: insula
time frame: 10 minutes
description: Blood flow in the insula is measured with positron emission tomography (PET) and radiolabelled water during the performance of stress tasks. We compare blood flow in the insula to whole brain blood flow ratio during stress tasks (listening to personalized traumatic scripts) versus control tasks in the VNS versus sham groups with hypothesis of blocked insula blood flow with VNS
measure: HVLT-R % retention
time frame: baseline versus three months
description: The Hopkins Verbal Learning Test-Revised (HVLT-R) is a test of declarative memory learning that involves the learning of 12 nouns, four from each of three semantic categories, learned over three learning trials, followed 20 minutes later by a delayed free recall trial and recognition trial composed of 24 words with 12 false positives. The percent (%) retention is calculated by dividing the delayed recall trial by the higher of learning trial 2 or 3. HLVT-R % retention has a range of 0-100 with 100 being best and 0 worst performance. Baseline and three months post treatment paired with sham or active stimulation are compared.
measure: Change in IL6 Concentration in Blood with Stress
time frame: Baseline to 120 minutes after stress
description: Interleukin-6 (IL6) response to stress paired with active or sham stimulation. IL6 is an inflammatory biomarker measured in blood. We compare IL6 response to stress in VNS versus sham treated groups.
measure: hippocampal activation
time frame: 10 minutes
description: Blood flow in the hippocampus is measured with positron emission tomography (PET) and radiolabelled water during the performance of declarative memory tasks. We compare blood flow in the hippocampus to whole brain blood flow ratio during memory tasks versus control tasks in the VNS versus sham groups with hypothesis of increased hippocampal blood flow with VNS
measure: PPG amplitude
time frame: Change from baseline to 5 seconds after the termination of stimulation paired with stress
description: Photoplethysmography (PPG) amplitude is a measure of peripheral vasoconstriction which is a marker of sympathetic response to stress with active or sham. PPG amplitude is the diameter of the blood vessel in the finger, we measure change from baseline to post active vagal nerve stimulation versus sham stimulation with stress.
arm group label: nVNS
arm group type: Experimental
description: non invasive vagal nerve stimulation
arm group label: sham
arm group type: Sham Comparator
description: sham stimulation
intervention type: Device
intervention name: sham stimulation
description: non invasive vagal nerve stimulation
arm group label: sham
intervention type: Device
intervention name: nVNS
description: active vns stimulation
arm group label: nVNS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Doug J Bremner, MD
role: Principal Investigator
affiliation: Atlanta VA Medical and Rehab Center, Decatur, GA
last name: Doug J Bremner, MD
phone: (404) 712-9569
email: James.Bremner@va.gov
last name: Anna Woodbury, MD
phone: (404) 321-6111
phone ext: 6939
email: Anna.Woodbury@va.gov
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: three months after study end
ipd access criteria: de identified data for three years