<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/NCT02983448</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-7147</org_study_id>
    <nct_id>NCT02983448</nct_id>
  </id_info>
  <brief_title>Noninvasive Neuromodulation to Reserve Diastolic Dysfunction</brief_title>
  <acronym>NERDD</acronym>
  <official_title>Noninvasive Neuromodulation to Reserve Diastolic Dysfunction</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oklahoma</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Oklahoma</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a 2x2 cross over pilot study using low level transcutaneous vagus nerve stimulation&#xD;
      (LLTS) to reverse diastolic dysfunction in patients with diastolic dysfunction. All patients&#xD;
      will receive 2 separate, 1-hour sequences, at least 1 day apart, of active and sham LLTS, but&#xD;
      the sequence will be randomized. Patients will be randomly assigned (1:1) to active/sham or&#xD;
      sham/active LLTS. LLTS will be performed using a transcutaneous electrical nerve stimulation&#xD;
      (TENS) device with electrodes attached to the tragus of the ear, which is innervated by&#xD;
      auricular branch of the vagus nerve. Echocardiography will be performed after 30 minutes of&#xD;
      LLTS or sham stimulation to assess diastolic function. Five-minute ECGs will be obtained for&#xD;
      HRV analysis every 15 minutes of stimulation (total of 4 recordings).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Actual">April 2018</completion_date>
  <primary_completion_date type="Actual">March 2018</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Echocardiographic Markers of Diastolic Dysfunction</measure>
    <time_frame>after 1 hour of stimulation</time_frame>
    <description>Global longitudinal strain</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Heart Rate Variability Measures</measure>
    <time_frame>after 1 hour of stimulation</time_frame>
    <description>low frequency to high frequency ratio. This is a measure of sympathovagal balance. A lower value reflects a more favorable balance between sympathetic and parasympathetic (vagal) tone.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Heart Failure, Diastolic</condition>
  <arm_group>
    <arm_group_label>Sham stimulation first</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Sham stimulation delivered at the earlobe (devoid of vagal innervation) is given on first session.&#xD;
Transcutaneous vagus nerve stimulation delivered at the tragus (vagal innervation) is given on second session.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Active stimulation first</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.&#xD;
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>transcutaneous vagus nerve stimulation</intervention_name>
    <description>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
    <arm_group_label>Active stimulation first</arm_group_label>
    <arm_group_label>Sham stimulation first</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male and female patients older than 18 year old&#xD;
&#xD;
          2. Evidence of diastolic dysfunction on echocardiogram within 24 months of study&#xD;
             enrollment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Left ventricular dysfunction (Left ventricular ejection fraction &lt;40%)&#xD;
&#xD;
          2. Significant valvular disorder (i.e., prosthetic valve or hemodynamically relevant&#xD;
             valvular diseases)&#xD;
&#xD;
          3. Recent (&lt;6 months) stroke or myocardial infarction&#xD;
&#xD;
          4. Severe heart failure (NYHA class III or IV)&#xD;
&#xD;
          5. Recurrent vaso-vagal syncopal episodes&#xD;
&#xD;
          6. Unilateral or bilateral vagotomy&#xD;
&#xD;
          7. Pregnancy or breast feeding&#xD;
&#xD;
          8. Sick sinus syndrome (without a pacemaker), 2nd or 3rd degree AV block, bifascicular&#xD;
             block or prolonged (PR&gt;300ms) 1st degree AV block&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 1, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 6, 2016</study_first_posted>
  <results_first_submitted>April 19, 2019</results_first_submitted>
  <results_first_submitted_qc>May 20, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">June 11, 2019</results_first_posted>
  <last_update_submitted>June 13, 2019</last_update_submitted>
  <last_update_submitted_qc>June 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Oklahoma</investigator_affiliation>
    <investigator_full_name>Stavros Stavrakis</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure, Diastolic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 17, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT02983448/ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 10, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/48/NCT02983448/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Sham Stimulation First</title>
          <description>Sham stimulation delivered at the earlobe (devoid of vagal innervation) is given on first session.&#xD;
Transcutaneous vagus nerve stimulation delivered at the tragus (vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
        </group>
        <group group_id="P2">
          <title>Active Stimulation First</title>
          <description>Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.&#xD;
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Participants</title>
          <description>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="24"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68.2" spread="11.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Echocardiographic Markers of Diastolic Dysfunction</title>
        <description>Global longitudinal strain</description>
        <time_frame>after 1 hour of stimulation</time_frame>
        <population>All patients received both active and sham transcutaneous vagus nerve stimulation, with the order being randomized. The comparison is between active and sham stimulation.</population>
        <group_list>
          <group group_id="O1">
            <title>Sham Stimulation</title>
            <description>Sham stimulation delivered at the earlobe (devoid of vagal innervation) is given on first session.&#xD;
Transcutaneous vagus nerve stimulation delivered at the tragus (vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
          </group>
          <group group_id="O2">
            <title>Active Stimulation</title>
            <description>Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.&#xD;
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
          </group>
        </group_list>
        <measure>
          <title>Echocardiographic Markers of Diastolic Dysfunction</title>
          <description>Global longitudinal strain</description>
          <population>All patients received both active and sham transcutaneous vagus nerve stimulation, with the order being randomized. The comparison is between active and sham stimulation.</population>
          <units>percent</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-21.2" spread="3"/>
                    <measurement group_id="O2" value="-23.0" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Heart Rate Variability Measures</title>
        <description>low frequency to high frequency ratio. This is a measure of sympathovagal balance. A lower value reflects a more favorable balance between sympathetic and parasympathetic (vagal) tone.</description>
        <time_frame>after 1 hour of stimulation</time_frame>
        <population>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized. The comparison is between active and sham stimulation.</population>
        <group_list>
          <group group_id="O1">
            <title>Sham Stimulation</title>
            <description>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
          </group>
          <group group_id="O2">
            <title>Active Stimulation</title>
            <description>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
          </group>
        </group_list>
        <measure>
          <title>Heart Rate Variability Measures</title>
          <description>low frequency to high frequency ratio. This is a measure of sympathovagal balance. A lower value reflects a more favorable balance between sympathetic and parasympathetic (vagal) tone.</description>
          <population>All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized. The comparison is between active and sham stimulation.</population>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.1" spread="0.4"/>
                    <measurement group_id="O2" value="1.8" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>through study completion (1 week)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Sham Intervention</title>
          <description>Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.&#xD;
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
        </group>
        <group group_id="E2">
          <title>Active Intervention</title>
          <description>Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.&#xD;
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.&#xD;
transcutaneous vagus nerve stimulation: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Stavros Stavrakis</name_or_title>
      <organization>University of Oklahoma Health Sciences Center</organization>
      <phone>405-271-4742 ext 37507</phone>
      <email>stavros-stavrakis@ouhsc.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02983448
org study id: IRB-7147
nct id: NCT02983448
lead sponsor: 
has dmc: No
This is a 2x2 cross over pilot study using low level transcutaneous vagus nerve stimulation
      (LLTS) to reverse diastolic dysfunction in patients with diastolic dysfunction. All patients
      will receive 2 separate, 1-hour sequences, at least 1 day apart, of active and sham LLTS, but
      the sequence will be randomized. Patients will be randomly assigned (1:1) to active/sham or
      sham/active LLTS. LLTS will be performed using a transcutaneous electrical nerve stimulation
      (TENS) device with electrodes attached to the tragus of the ear, which is innervated by
      auricular branch of the vagus nerve. Echocardiography will be performed after 30 minutes of
      LLTS or sham stimulation to assess diastolic function. Five-minute ECGs will be obtained for
      HRV analysis every 15 minutes of stimulation (total of 4 recordings).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Echocardiographic Markers of Diastolic Dysfunction
time frame: after 1 hour of stimulation
description: Global longitudinal strain
measure: Heart Rate Variability Measures
time frame: after 1 hour of stimulation
description: low frequency to high frequency ratio. This is a measure of sympathovagal balance. A lower value reflects a more favorable balance between sympathetic and parasympathetic (vagal) tone.
arm group label: Sham stimulation first
arm group type: Placebo Comparator
description: Sham stimulation delivered at the earlobe (devoid of vagal innervation) is given on first session.
Transcutaneous vagus nerve stimulation delivered at the tragus (vagal innervation) is given on second session.
arm group label: Active stimulation first
arm group type: Active Comparator
description: Transcutaneous vagus nerve stimulation delivered at the earlobe (vagal innervation) is given on first session.
Sham stimulation delivered at the tragus (devoid of vagal innervation) is given on second session.
intervention type: Device
intervention name: transcutaneous vagus nerve stimulation
description: All patients will receive both active and sham transcutaneous vagus nerve stimulation, with the order being randomized
arm group label: Active stimulation first
arm group label: Sham stimulation first
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Oklahoma
investigator full name: Stavros Stavrakis
investigator title: Assistant Professor
mesh term: Heart Failure, Diastolic
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 