<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/NCT03291431</url>
  </required_header>
  <id_info>
    <org_study_id>41896</org_study_id>
    <nct_id>NCT03291431</nct_id>
  </id_info>
  <brief_title>Intermittent Theta Burst for the Treatment of Alcohol Use Disorders in Veterans</brief_title>
  <official_title>Intermittent Theta Burst TMS for the Treatment of Alcohol Use Disorders in Veterans</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Stanford University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the efficacy of intermittent theta burst repetitive&#xD;
      transcranial magnetic stimulation (iTBS) as a treatment for Veterans with an alcohol use&#xD;
      disorder (AUD) to decrease the exceedingly high rate of relapse associated with this&#xD;
      condition. iTBS has demonstrated equivalent efficacy and safety to repetitive transcranial&#xD;
      magnetic stimulation employing 10Hz stimulation protocols in treatment of depressive&#xD;
      disorders. The advantage of iTBS is that it can be delivered in approximately 5 minutes where&#xD;
      conventional 10Hz repetitive transcranial magnetic stimulation (rTMS) protocols are typically&#xD;
      20-25 minutes. It is hypothesized that Veterans with AUD who receive active iTBS applied to&#xD;
      the left dorsolateral prefrontal cortex (DLPFC), compared to controls (i.e., Veterans with&#xD;
      AUD who receive sham iTBS), will show significant decreases alcohol craving, depressive&#xD;
      symptomatology and cigarette consumptions, as well as improved neurocognition, a longer&#xD;
      period of abstinence, and a lower overall rate of relapse over 6 months following standard&#xD;
      psychosocial treatment for AUD at VA substance treatment clinics. In exploratory analyses, it&#xD;
      is also predicted that magnetic resonance measures of left DLPFC glutamate concentration,&#xD;
      volume of anterior frontal cortical brain regions, and performance on fMRI tasks&#xD;
      interrogating the function of the salience/reward circuits will serve as biomarkers of iTBS&#xD;
      treatment response. The goal of this proposal is to implement treatment that effectively&#xD;
      promotes sustained abstinence in Veterans with AUD, given long-term abstinence is related to&#xD;
      optimal neurobiological, neuropsychological and psychosocial recovery and functioning.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Recruitment difficulties due to Covid-19 pandemic&#xD;
  </why_stopped>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Actual">July 30, 2022</completion_date>
  <primary_completion_date type="Actual">January 30, 2022</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants Who Were Abstinent Through Month 6</measure>
    <time_frame>6 months</time_frame>
    <description>Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio</measure>
    <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
    <description>Left dorsolateral prefrontal region glutamate/creatine ratio pre and post active/sham iTBS. Data were recorded in international units (IU) and converted to Z scores based on the entire sample (unit normal distribution, mean of 0, standard deviation of 1). Higher Z scores (standard deviation above the mean) indicate a greater metabolite concentration ratio and better functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Dorsolateral Prefrontal Cortex Thickness</measure>
    <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
    <description>Left dorsolateral prefrontal cortex thickness pre and post active/sham iTBS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>General Depressive Symptoms</measure>
    <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
    <description>Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anhedonic Depressive Symptoms</measure>
    <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
    <description>Anhedonic depressive symptoms from Mood and Anxiety Symptom Questionnaire (MASQ, 30-item version; score range: 10 to 50, high scores correspond to more severe symptoms).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Alcohol Use Disorder</condition>
  <condition>Depressive Disorder</condition>
  <condition>Cigarette Smoking</condition>
  <arm_group>
    <arm_group_label>Active iTBS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be randomized to active or sham iTBS.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham iTBS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Participants will be randomized to active or sham iTBS.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Intermittent theta burst transcranial magnetic stimulation</intervention_name>
    <description>20 iTBS sessions (active or sham) administered over the course of 2 weeks</description>
    <arm_group_label>Active iTBS</arm_group_label>
    <arm_group_label>Sham iTBS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  21-65 years of age&#xD;
&#xD;
          -  Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)&#xD;
             criteria for alcohol use disorder, and alcohol is self-identified as primary substance&#xD;
             of misuse.&#xD;
&#xD;
          -  Actively in treatment at VA Palo Alto HCS Addiction Treatment Service&#xD;
&#xD;
          -  Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form&#xD;
             prior to participation in study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of Schizophrenia Spectrum Disorders, Bipolar Disorders, a&#xD;
&#xD;
          -  Current substance use disorder that exceeds the severity of the AUD (based on DSM-5&#xD;
             diagnostic criteria)&#xD;
&#xD;
          -  Current use of an FDA approved medication (i.e., disulfiram, acamprosate, and&#xD;
             naltrexone) for treatment of AUD,&#xD;
&#xD;
          -  Active current suicidal intent or plan (patients with a previous clinical flag for&#xD;
             risk for suicide will be required to have an established safety plan involving their&#xD;
             primary psychiatrist and the treatment team before entering the clinical trial),&#xD;
&#xD;
          -  Any form of previous TMS or electroconvulsive treatment.&#xD;
&#xD;
          -  Thyroid disease,&#xD;
&#xD;
          -  Unstable congestive heart failure, angina, other severe cardiac illness as defined by&#xD;
             treatment regimen changes in the prior 3 months&#xD;
&#xD;
          -  Cerebrovascular accident&#xD;
&#xD;
          -  Cancer if &lt; 1 year since end of treatment&#xD;
&#xD;
          -  Unstable diabetes&#xD;
&#xD;
          -  COPD requiring oxygen supplementation&#xD;
&#xD;
          -  Alzheimer's disease&#xD;
&#xD;
          -  Parkinson's disease&#xD;
&#xD;
          -  Any Biomedical implants with ferromagnetic content&#xD;
&#xD;
          -  Neurostimulation devices, cardiac pacemakers or any magnetic resonance&#xD;
             contraindications&#xD;
&#xD;
          -  Traumatic brain injury with self-reported or observed loss of consciousness &gt; 30&#xD;
             minutes&#xD;
&#xD;
          -  Any primary or traumatically induced seizure disorder&#xD;
&#xD;
          -  Lack of fluency in English, Wechsler Adult Reading Test below the 7th percentile&#xD;
             (i.e., moderate or greater impairment in estimated general intelligence),&#xD;
&#xD;
          -  Females who are pregnant or actively attempting pregnancy (conservative exclusion for&#xD;
             magnetic resonance research),&#xD;
&#xD;
          -  Current use of any medication or substance that is documented to lower seizure&#xD;
             threshold or has been identified as a contraindication for TMS treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Timothy C Durazzo, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Palo Alto VA Health Care System</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <results_first_submitted>February 24, 2023</results_first_submitted>
  <results_first_submitted_qc>June 20, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 22, 2023</results_first_posted>
  <last_update_submitted>June 20, 2023</last_update_submitted>
  <last_update_submitted_qc>June 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Timothy Durazzo, PhD</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>alcohol use disorder</keyword>
  <keyword>intermittent theta burst</keyword>
  <keyword>Veterans</keyword>
  <keyword>depressive disorder</keyword>
  <keyword>cigarette smoking</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcoholism</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Alcohol Drinking</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>August 1, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT03291431/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>November 29, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT03291431/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>From 20MAR20-31AUG21 no participants were recruited due the mandatory hiatus of recruitment of human participants (forced by the COVID-19 pandemic) and the Principal Investigator's mobilization to active military service. The PI discussed the recruitment issues with the Stanford NeuroChoice Initiative funding agency, and it was decided to discontinue recruitment in JUL21.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Active iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
        </group>
        <group group_id="P2">
          <title>Sham iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Participant self-discharged against medical advice from treatment program during active study phase</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Residential treatment team requested participant withdraw due to multiple conflicting appointments.</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Active iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
        </group>
        <group group_id="B2">
          <title>Sham iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</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="8"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="17"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="32.0" spread="9.8"/>
                    <measurement group_id="B2" value="48.5" spread="12.4"/>
                    <measurement group_id="B3" value="42.3" spread="11.1"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="13"/>
                  </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>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="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </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="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="11"/>
                  </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="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Education</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13.5" spread="1.5"/>
                    <measurement group_id="B2" value="13.3" spread="1.8"/>
                    <measurement group_id="B3" value="13.4" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Who Were Abstinent Through Month 6</title>
        <description>Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
          <group group_id="O2">
            <title>Sham iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Were Abstinent Through Month 6</title>
          <description>Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Chi-Square comparison of frequencies</non_inferiority_desc>
            <p_value>0.99</p_value>
            <p_value_desc>A p-value of &lt;0.05 is considered statistically significant.</p_value_desc>
            <method>Chi-squared</method>
            <param_type>Pearson Chi-Square</param_type>
            <param_value>0.17</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio</title>
        <description>Left dorsolateral prefrontal region glutamate/creatine ratio pre and post active/sham iTBS. Data were recorded in international units (IU) and converted to Z scores based on the entire sample (unit normal distribution, mean of 0, standard deviation of 1). Higher Z scores (standard deviation above the mean) indicate a greater metabolite concentration ratio and better functioning.</description>
        <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
        <population>Participants with available data are included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
          <group group_id="O2">
            <title>Sham iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio</title>
          <description>Left dorsolateral prefrontal region glutamate/creatine ratio pre and post active/sham iTBS. Data were recorded in international units (IU) and converted to Z scores based on the entire sample (unit normal distribution, mean of 0, standard deviation of 1). Higher Z scores (standard deviation above the mean) indicate a greater metabolite concentration ratio and better functioning.</description>
          <population>Participants with available data are included in the analysis.</population>
          <units>z-score</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.31" spread="0.29"/>
                    <measurement group_id="O2" value="0.02" spread="0.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.25" spread="0.29"/>
                    <measurement group_id="O2" value="0.29" spread="0.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Linear mixed modeling</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.68</p_value>
            <p_value_desc>p &lt; .05 considered statistically significant.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Slope</param_type>
            <param_value>-0.20</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <estimate_desc>Rate of change compared between groups using linear mixed modeling.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Left Dorsolateral Prefrontal Cortex Thickness</title>
        <description>Left dorsolateral prefrontal cortex thickness pre and post active/sham iTBS</description>
        <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>General Depressive Symptoms</title>
        <description>Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms).</description>
        <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
        <population>Participants with available data are included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
          <group group_id="O2">
            <title>Sham iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>General Depressive Symptoms</title>
          <description>Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms).</description>
          <population>Participants with available data are included in the analysis.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.4" spread="3.4"/>
                    <measurement group_id="O2" value="18.0" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Follow-up</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.0" spread="4.0"/>
                    <measurement group_id="O2" value="11.9" spread="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear mixed modeling</non_inferiority_desc>
            <p_value>0.70</p_value>
            <p_value_desc>p &lt; .05 considered statistically significant.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Slope</param_type>
            <param_value>-1.99</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
            <estimate_desc>Rate of change compared between groups using linear mixed modeling.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Anhedonic Depressive Symptoms</title>
        <description>Anhedonic depressive symptoms from Mood and Anxiety Symptom Questionnaire (MASQ, 30-item version; score range: 10 to 50, high scores correspond to more severe symptoms).</description>
        <time_frame>baseline and follow-up (approximately 2 weeks)</time_frame>
        <population>Participants with available data are included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
          <group group_id="O2">
            <title>Sham iTBS</title>
            <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Anhedonic Depressive Symptoms</title>
          <description>Anhedonic depressive symptoms from Mood and Anxiety Symptom Questionnaire (MASQ, 30-item version; score range: 10 to 50, high scores correspond to more severe symptoms).</description>
          <population>Participants with available data are included in the analysis.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.1" spread="2.8"/>
                    <measurement group_id="O2" value="32.7" spread="2.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Follow-up</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.5" spread="3.3"/>
                    <measurement group_id="O2" value="30.5" spread="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Linear mixed modeling</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.11</p_value>
            <p_value_desc>p &lt; .05 considered statistically significant.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Slope</param_type>
            <param_value>0.30</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline through 6 months after conclusion of treatment</time_frame>
      <desc>Participants were systematically screened for any biomedical, psychiatric or other physical condition that was associated with serious adverse events or adverse events.</desc>
      <group_list>
        <group group_id="E1">
          <title>Active iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</description>
        </group>
        <group group_id="E2">
          <title>Sham iTBS</title>
          <description>Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks</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="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </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="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </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>
    <limitations_and_caveats>The study was terminated early before enrolling the planned number of participants, therefore the data analysis is underpowered.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Timothy C. Durazzo/Project PI</name_or_title>
      <organization>Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences</organization>
      <phone>650-493-5000 ext 62982</phone>
      <email>tdurazzo@stanford.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/NCT03291431
org study id: 41896
nct id: NCT03291431
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
The purpose of this study is to evaluate the efficacy of intermittent theta burst repetitive
      transcranial magnetic stimulation (iTBS) as a treatment for Veterans with an alcohol use
      disorder (AUD) to decrease the exceedingly high rate of relapse associated with this
      condition. iTBS has demonstrated equivalent efficacy and safety to repetitive transcranial
      magnetic stimulation employing 10Hz stimulation protocols in treatment of depressive
      disorders. The advantage of iTBS is that it can be delivered in approximately 5 minutes where
      conventional 10Hz repetitive transcranial magnetic stimulation (rTMS) protocols are typically
      20-25 minutes. It is hypothesized that Veterans with AUD who receive active iTBS applied to
      the left dorsolateral prefrontal cortex (DLPFC), compared to controls (i.e., Veterans with
      AUD who receive sham iTBS), will show significant decreases alcohol craving, depressive
      symptomatology and cigarette consumptions, as well as improved neurocognition, a longer
      period of abstinence, and a lower overall rate of relapse over 6 months following standard
      psychosocial treatment for AUD at VA substance treatment clinics. In exploratory analyses, it
      is also predicted that magnetic resonance measures of left DLPFC glutamate concentration,
      volume of anterior frontal cortical brain regions, and performance on fMRI tasks
      interrogating the function of the salience/reward circuits will serve as biomarkers of iTBS
      treatment response. The goal of this proposal is to implement treatment that effectively
      promotes sustained abstinence in Veterans with AUD, given long-term abstinence is related to
      optimal neurobiological, neuropsychological and psychosocial recovery and functioning.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants Who Were Abstinent Through Month 6
time frame: 6 months
description: Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session.
measure: Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio
time frame: baseline and follow-up (approximately 2 weeks)
description: Left dorsolateral prefrontal region glutamate/creatine ratio pre and post active/sham iTBS. Data were recorded in international units (IU) and converted to Z scores based on the entire sample (unit normal distribution, mean of 0, standard deviation of 1). Higher Z scores (standard deviation above the mean) indicate a greater metabolite concentration ratio and better functioning.
measure: Left Dorsolateral Prefrontal Cortex Thickness
time frame: baseline and follow-up (approximately 2 weeks)
description: Left dorsolateral prefrontal cortex thickness pre and post active/sham iTBS
measure: General Depressive Symptoms
time frame: baseline and follow-up (approximately 2 weeks)
description: Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms).
measure: Anhedonic Depressive Symptoms
time frame: baseline and follow-up (approximately 2 weeks)
description: Anhedonic depressive symptoms from Mood and Anxiety Symptom Questionnaire (MASQ, 30-item version; score range: 10 to 50, high scores correspond to more severe symptoms).
arm group label: Active iTBS
arm group type: Active Comparator
description: Participants will be randomized to active or sham iTBS.
arm group label: Sham iTBS
arm group type: Sham Comparator
description: Participants will be randomized to active or sham iTBS.
intervention type: Device
intervention name: Intermittent theta burst transcranial magnetic stimulation
description: 20 iTBS sessions (active or sham) administered over the course of 2 weeks
arm group label: Active iTBS
arm group label: Sham iTBS
criteria: 
gender: All
minimum age: 21 Years
maximum age: 65 Years
healthy volunteers: No
last name: Timothy C Durazzo, PhD
role: Principal Investigator
affiliation: Stanford University
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Timothy Durazzo, PhD
investigator title: Associate Professor
mesh term: Alcoholism
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Alcohol Drinking
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study was terminated early before enrolling the planned number of participants, therefore the data analysis is underpowered.
point of contact: 