<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/NCT03821337</url>
  </required_header>
  <id_info>
    <org_study_id>D3006-P</org_study_id>
    <secondary_id>RX003006</secondary_id>
    <secondary_id>Pro00084970</secondary_id>
    <nct_id>NCT03821337</nct_id>
  </id_info>
  <brief_title>Transcranial Magnetic Stimulation (rTMS) as a Tool to Decrease Pain and Improve Functioning</brief_title>
  <acronym>TMS</acronym>
  <official_title>An Exploratory Investigation Utilizing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Tool to Decrease Pain and Improve Functioning in Veterans With Opioid Use Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite the availability of opioid replacement therapies, many opioid use disordered Veterans&#xD;
      are not able to remain abstinent. Repetitive Transcranial Magnetic Stimulation (rTMS) is a&#xD;
      non-invasive neuromodulation technique with a consistent, rapidly expanding literature base&#xD;
      reporting positive outcomes in substance using populations. This pilot application will&#xD;
      investigate a novel multi-session rTMS paradigm to determine feasibility and tolerability of&#xD;
      this intervention in opioid use disordered Veterans.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Opioid use disorders (OUDs) are common among Veterans. Despite the availability of opioid&#xD;
      replacement therapies, many individuals continue to abuse opioids and relapse rates remain&#xD;
      high. Veterans are nearly twice as likely to die from accidental opioid overdose than the&#xD;
      general population. Approximately 60% of Veterans returning from the Middle East and more&#xD;
      than 50% of older Veterans in the VA health care system have chronic pain. Further,&#xD;
      post-traumatic stress disorder, a common comorbidity in the Veteran population, has been&#xD;
      shown to negatively impact early engagement and retention of individuals in OUD treatment. As&#xD;
      is the case with other substance use disorders, opioid craving is commonly described by&#xD;
      abstinent patients whether or not they are stabilized on buprenorphine. Subsequently, a&#xD;
      treatment that reduces pain and craving, while also improving early engagement and retention&#xD;
      in treatment, would improve recovery from opioid addiction. Repetitive Transcranial Magnetic&#xD;
      Stimulation (rTMS) is capable of non-invasively altering cortical function. rTMS is an&#xD;
      FDA-approved treatment for major depressive disorder. Preliminary evidence suggests that rTMS&#xD;
      can also reduce pain in chronic pain conditions and craving in substance use disorders.&#xD;
      Single sessions of rTMS produce small temporary effects, while multiple sessions of rTMS&#xD;
      result in larger, more durable effects. The investigators' group recently completed a&#xD;
      blinded, sham-controlled crossover trial in non-treatment seeking OUD participants. A single&#xD;
      session of rTMS reduced cue-induced craving and increased thermal pain thresholds. Given that&#xD;
      multiple sessions of rTMS produce larger and more durable treatment effects than single&#xD;
      sessions of rTMS, it follows that multiple treatment sessions applied to OUD patients may&#xD;
      result in a clinically relevant reduction in pain and cue-induced craving, which could&#xD;
      improve clinical and functional outcomes.&#xD;
&#xD;
      In this SPiRE pilot proposal, the investigators will perform a randomized, double-blind,&#xD;
      sham-controlled trial delivering an accelerated course of rTMS to a cohort of OUD Veterans&#xD;
      with chronic pain receiving treatment through the Ralph H. Johnson VA Medical Center&#xD;
      Substance Treatment and Recovery program. The goal of this proposal is to evaluate the&#xD;
      feasibility and acceptability of delivering rTMS to the dorsolateral pre-frontal cortex in&#xD;
      Veterans with OUD and chronic pain. The investigators will also preliminarily explore the&#xD;
      feasibility of evaluating potential outcome measurements in preparation for a larger trial,&#xD;
      including abstinence, treatment retention, community reintegration and functional outcomes,&#xD;
      pain, and opioid craving. Positive results from this pilot project will inform a future MERIT&#xD;
      application and have the potential to significantly improve treatment outcomes in this&#xD;
      difficult to treat Veteran population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    COVID-19 placed all Charleston VA projects on hold. Recently gained approval to open studies&#xD;
    with COVID-19 precautions&#xD;
  </why_stopped>
  <start_date type="Actual">October 11, 2019</start_date>
  <completion_date type="Actual">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">December 31, 2021</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>Double-blind, Randomized, Placebo-Controlled Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Retention: Total Number of rTMS Sessions Completed</measure>
    <time_frame>Through study completion, an average of 3 weeks</time_frame>
    <description>Total number of rTMS sessions completed out of 6 sessions per day for three days over a three week period.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability: The Total Number of Treatment Emergent Adverse Events</measure>
    <time_frame>Through study completion, an average of 3 weeks</time_frame>
    <description>Number of adverse events experienced by Veterans receiving medication assisted treatment for opioid use disorder who undergo 18 sessions of active or sham rTMS.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Opioid Use Disorder</condition>
  <arm_group>
    <arm_group_label>rTMS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham TMS</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>repetitive Trans Magnetic Stimulation</intervention_name>
    <description>Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
    <arm_group_label>rTMS</arm_group_label>
    <other_name>rTMS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham TMS</intervention_name>
    <description>Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</description>
    <arm_group_label>Sham TMS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must be able to provide informed consent and function at an intellectual&#xD;
             level sufficient to allow accurate completion of all assessment instruments.&#xD;
&#xD;
          -  Participants must meet moderate to severe DSM-5 criteria for OUD. While individuals&#xD;
             may also meet criteria for use disorders of other substances (with the exception of&#xD;
             alcohol or benzodiazepines), they must identify opioids as their primary substance of&#xD;
             abuse.&#xD;
&#xD;
          -  Participants must report chronic pain for at least the past three months and have a&#xD;
             Brief Pain Inventory score.&#xD;
&#xD;
          -  Participants must be receiving treatment through the STAR program.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants who are pregnant.&#xD;
&#xD;
          -  Participants with a history of/or current psychotic disorder.&#xD;
&#xD;
          -  Participants with a history of dementia or other cognitive impairment.&#xD;
&#xD;
          -  Participants with active suicidal ideation, or a suicide attempt within the past 90&#xD;
             days will be excluded.&#xD;
&#xD;
          -  Participants with contraindications to receiving rTMS (including a history of&#xD;
             seizures, or any implanted metal above the neck).&#xD;
&#xD;
          -  Those with unstable general medical conditions.&#xD;
&#xD;
          -  Those who are currently using naltrexone or tramadol.&#xD;
&#xD;
          -  Those with current alcohol or benzodiazepine use disorders due to increased risk of&#xD;
             seizure.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Aimee L. Mcrae-Clark, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ralph H. Johnson VA Medical Center, Charleston, SC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ralph H. Johnson VA Medical Center, Charleston, SC</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29401-5799</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 28, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <results_first_submitted>October 28, 2022</results_first_submitted>
  <results_first_submitted_qc>November 29, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">December 21, 2022</results_first_posted>
  <last_update_submitted>November 29, 2022</last_update_submitted>
  <last_update_submitted_qc>November 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Opioid use disorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Opioid-Related Disorders</mesh_term>
    <mesh_term>Substance-Related Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <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>September 2, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/37/NCT03821337/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <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>January 2, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/37/NCT03821337/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>rTMS</title>
          <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.&#xD;
repetitive Trans Magnetic Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
        </group>
        <group group_id="P2">
          <title>Sham TMS</title>
          <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.&#xD;
Sham TMS: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </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>
      <population>Veterans being treated for opioid use disorder. Only one subject completed rTMS sessions and they were in the rTMS group.</population>
      <group_list>
        <group group_id="B1">
          <title>rTMS</title>
          <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.&#xD;
repetitive Trans Magnetic Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
        </group>
        <group group_id="B2">
          <title>Sham TMS</title>
          <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.&#xD;
Sham TMS: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="1"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="1"/>
          </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="55" spread="NA">Standard Deviation is not calculable for 1 participant.</measurement>
                    <measurement group_id="B3" value="55" spread="0"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" 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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Retention: Total Number of rTMS Sessions Completed</title>
        <description>Total number of rTMS sessions completed out of 6 sessions per day for three days over a three week period.</description>
        <time_frame>Through study completion, an average of 3 weeks</time_frame>
        <population>Veterans being treated for opioid use disorder. Only one subject completed rTMS sessions and they were in the active rTMS group.</population>
        <group_list>
          <group group_id="O1">
            <title>rTMS</title>
            <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.&#xD;
repetitive Trans Magnetic Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS</title>
            <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.&#xD;
Sham TMS: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</description>
          </group>
        </group_list>
        <measure>
          <title>Retention: Total Number of rTMS Sessions Completed</title>
          <description>Total number of rTMS sessions completed out of 6 sessions per day for three days over a three week period.</description>
          <population>Veterans being treated for opioid use disorder. Only one subject completed rTMS sessions and they were in the active rTMS group.</population>
          <units>Sessions completed</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tolerability: The Total Number of Treatment Emergent Adverse Events</title>
        <description>Number of adverse events experienced by Veterans receiving medication assisted treatment for opioid use disorder who undergo 18 sessions of active or sham rTMS.</description>
        <time_frame>Through study completion, an average of 3 weeks</time_frame>
        <population>Veterans receiving medication assisted treatment for opioid use disorder.</population>
        <group_list>
          <group group_id="O1">
            <title>rTMS</title>
            <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.&#xD;
repetitive Trans Magnetic Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS</title>
            <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.&#xD;
Sham TMS: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</description>
          </group>
        </group_list>
        <measure>
          <title>Tolerability: The Total Number of Treatment Emergent Adverse Events</title>
          <description>Number of adverse events experienced by Veterans receiving medication assisted treatment for opioid use disorder who undergo 18 sessions of active or sham rTMS.</description>
          <population>Veterans receiving medication assisted treatment for opioid use disorder.</population>
          <units>Adverse Events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Three weeks of once weekly treatment sessions.</time_frame>
      <desc>0 participants were at risk for adverse events in the sham condition because no participants were randomized to that condition.</desc>
      <group_list>
        <group group_id="E1">
          <title>rTMS</title>
          <description>Participants will receive 18 sessions of active rTMS delivered at 120% rMT.&#xD;
repetitive Trans Magnetic Stimulation: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.</description>
        </group>
        <group group_id="E2">
          <title>Sham TMS</title>
          <description>Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.&#xD;
Sham TMS: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland &amp; Howard, 2014).</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="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Program Manager</name_or_title>
      <organization>VA Medical Center</organization>
      <phone>843-792-0476</phone>
      <email>lisa.nunn@va.gov</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/NCT03821337
org study id: D3006-P
secondary id: RX003006
secondary id: Pro00084970
nct id: NCT03821337
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
Despite the availability of opioid replacement therapies, many opioid use disordered Veterans
      are not able to remain abstinent. Repetitive Transcranial Magnetic Stimulation (rTMS) is a
      non-invasive neuromodulation technique with a consistent, rapidly expanding literature base
      reporting positive outcomes in substance using populations. This pilot application will
      investigate a novel multi-session rTMS paradigm to determine feasibility and tolerability of
      this intervention in opioid use disordered Veterans.
Opioid use disorders (OUDs) are common among Veterans. Despite the availability of opioid
      replacement therapies, many individuals continue to abuse opioids and relapse rates remain
      high. Veterans are nearly twice as likely to die from accidental opioid overdose than the
      general population. Approximately 60% of Veterans returning from the Middle East and more
      than 50% of older Veterans in the VA health care system have chronic pain. Further,
      post-traumatic stress disorder, a common comorbidity in the Veteran population, has been
      shown to negatively impact early engagement and retention of individuals in OUD treatment. As
      is the case with other substance use disorders, opioid craving is commonly described by
      abstinent patients whether or not they are stabilized on buprenorphine. Subsequently, a
      treatment that reduces pain and craving, while also improving early engagement and retention
      in treatment, would improve recovery from opioid addiction. Repetitive Transcranial Magnetic
      Stimulation (rTMS) is capable of non-invasively altering cortical function. rTMS is an
      FDA-approved treatment for major depressive disorder. Preliminary evidence suggests that rTMS
      can also reduce pain in chronic pain conditions and craving in substance use disorders.
      Single sessions of rTMS produce small temporary effects, while multiple sessions of rTMS
      result in larger, more durable effects. The investigators' group recently completed a
      blinded, sham-controlled crossover trial in non-treatment seeking OUD participants. A single
      session of rTMS reduced cue-induced craving and increased thermal pain thresholds. Given that
      multiple sessions of rTMS produce larger and more durable treatment effects than single
      sessions of rTMS, it follows that multiple treatment sessions applied to OUD patients may
      result in a clinically relevant reduction in pain and cue-induced craving, which could
      improve clinical and functional outcomes.

      In this SPiRE pilot proposal, the investigators will perform a randomized, double-blind,
      sham-controlled trial delivering an accelerated course of rTMS to a cohort of OUD Veterans
      with chronic pain receiving treatment through the Ralph H. Johnson VA Medical Center
      Substance Treatment and Recovery program. The goal of this proposal is to evaluate the
      feasibility and acceptability of delivering rTMS to the dorsolateral pre-frontal cortex in
      Veterans with OUD and chronic pain. The investigators will also preliminarily explore the
      feasibility of evaluating potential outcome measurements in preparation for a larger trial,
      including abstinence, treatment retention, community reintegration and functional outcomes,
      pain, and opioid craving. Positive results from this pilot project will inform a future MERIT
      application and have the potential to significantly improve treatment outcomes in this
      difficult to treat Veteran population.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Double-blind, Randomized, Placebo-Controlled Trial
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Retention: Total Number of rTMS Sessions Completed
time frame: Through study completion, an average of 3 weeks
description: Total number of rTMS sessions completed out of 6 sessions per day for three days over a three week period.
measure: Tolerability: The Total Number of Treatment Emergent Adverse Events
time frame: Through study completion, an average of 3 weeks
description: Number of adverse events experienced by Veterans receiving medication assisted treatment for opioid use disorder who undergo 18 sessions of active or sham rTMS.
arm group label: rTMS
arm group type: Experimental
description: Participants will receive 18 sessions of active rTMS delivered at 120% rMT.
arm group label: Sham TMS
arm group type: Placebo Comparator
description: Participants will receive 18 sessions of sham rTMS delivered through an inactive coil.
intervention type: Device
intervention name: repetitive Trans Magnetic Stimulation
description: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is able to alter cortical excitability and is FDA-approved to treat Major Depressive Disorder. Magnetic fields pass unimpeded through the scalp, skull and meninges, and can directly excite cortical areas.
arm group label: rTMS
other name: rTMS
intervention type: Device
intervention name: Sham TMS
description: Sham sessions will be delivered using an electronic sham system consisting of a coil that mimics the appearance and sound of TMS, combined with a TENS device which produces a small electric shock mimicking the feeling of real rTMS. This type of sham has been demonstrated to be indistinguishable from real rTMS, has been well tolerated (George et al., 2010; George et al., 2014) and successfully used in other clinical trials (Borckardt et al., 2008; Arana et al., 2008). During each session of rTMS the investigators will present a series of opioid related images, including those utilized in previous studies (Garland et al., 2015; Garland & Howard, 2014).
arm group label: Sham TMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Aimee L. Mcrae-Clark, PharmD
role: Principal Investigator
affiliation: Ralph H. Johnson VA Medical Center, Charleston, SC
facility: 
country: United States
responsible party type: Sponsor
mesh term: Opioid-Related Disorders
mesh term: Substance-Related Disorders
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 