<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/NCT03281629</url>
  </required_header>
  <id_info>
    <org_study_id>HP-00077085</org_study_id>
    <secondary_id>UG3DA047685</secondary_id>
    <nct_id>NCT03281629</nct_id>
  </id_info>
  <brief_title>Circuitry-Guided Smoking Cessation in Schizophrenia</brief_title>
  <official_title>Circuitry-Guided Smoking Cessation in Schizophrenia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Maryland, Baltimore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Maryland, Baltimore</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In a double-blinded, randomized, parallel controlled design, patients with schizophrenia&#xD;
      spectrum disorder will be exposed to active or sham repetitive transcranial magentic&#xD;
      stimulation (TMS) which was guided by functional magnetic resonance image (MRI). Smoking&#xD;
      reduction/cessation and brain functional connectivity changes will be assessed at baseline,&#xD;
      different stages of rTMS and/or follow-ups.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Neuroimaging studies suggest that high rate of smoking in patients with schizophrenia may be&#xD;
      due to an overlap of nicotine addiction related circuitries and schizophrenia related&#xD;
      circuitries, such that schizophrenia impact some of the same circuitries that increase risks&#xD;
      for severe nicotine addiction in general. Those identified overlapping circuitries have been&#xD;
      linked to several key features of nicotine addiction and can be represented by resting state&#xD;
      functional connectivities. Transcranial magnetic stimulation (TMS) provides a non-invasive&#xD;
      means for altering brain electrical neural activity. TMS has been approved by FDA for&#xD;
      treatment of depression. Other applications have not been approved but it has been used in a&#xD;
      wide range of clinical research especially in neurology and psychiatry. There are&#xD;
      preliminarily significant improvements in treatments of smoking cessation in schizophrenia&#xD;
      using TMS with small samples, but those treatments are not robust in larger samples. The high&#xD;
      inter-subject variability limits the efficacy of TMS treatment in schizophrenia patients. We&#xD;
      aim to develop a TMS method targeting special brain circuits that are both smoking cessation&#xD;
      and schizophrenia related. If the corresponding brain circuits were successfully modulated,&#xD;
      the treatment efficacy will be significantly improved and schizophrenia patients will benefit&#xD;
      from the TMS treatment of smoking cessation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 19, 2018</start_date>
  <completion_date type="Actual">February 15, 2022</completion_date>
  <primary_completion_date type="Actual">February 28, 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>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cigarette Per Day</measure>
    <time_frame>7 months</time_frame>
    <description>Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Functional Magnetic Resonance Imaging (fMRI)</measure>
    <time_frame>4 months</time_frame>
    <description>Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cotinine</measure>
    <time_frame>1 month</time_frame>
    <description>Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>End-expired Carbon Monoxide (CO)</measure>
    <time_frame>1 month</time_frame>
    <description>End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG)</measure>
    <time_frame>4 months</time_frame>
    <description>EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">44</enrollment>
  <condition>Smoking Cessation</condition>
  <condition>Nicotine Addiction</condition>
  <condition>Schizophrenia</condition>
  <arm_group>
    <arm_group_label>Active TMS stimulation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Real active rTMS stimulation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham TMS stimulation</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham repetitive TMS stimulation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Active TMS stimulation</intervention_name>
    <description>Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
    <arm_group_label>Active TMS stimulation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham TMS stimulation</intervention_name>
    <description>Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
    <arm_group_label>Sham TMS stimulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female between ages 18-60&#xD;
&#xD;
          -  Ability to give written informed consent (age 18 or above)&#xD;
&#xD;
          -  Smoking in the last one year or more and average cigarette per day ≥ 5 in the past 4&#xD;
             weeks.&#xD;
&#xD;
          -  For patient participants, Evaluation to Sign Consent (ESC) above10.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any history of seizures&#xD;
&#xD;
          -  Had smoking cessation treatment, clinical trial, or nicotine replacements within the&#xD;
             past four weeks.&#xD;
&#xD;
          -  Significant alcohol or other drug use (substance dependence within 6 months or&#xD;
             substance abuse within 1 month) other than nicotine or marijuana dependence.&#xD;
&#xD;
          -  Any major medical illnesses that may affect normal brain functioning. Examples of&#xD;
             these conditions include, but not limited to, stroke, CNS infection or tumor, other&#xD;
             significant brain neurological conditions.&#xD;
&#xD;
          -  Taking &gt; 400 mg clozapine/day&#xD;
&#xD;
          -  Failed TMS screening questionnaire&#xD;
&#xD;
          -  Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable&#xD;
             cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators,&#xD;
             cochlear implants, or electrodes) or any other metal object within or near the head,&#xD;
             excluding the mouth, that cannot be safely removed.&#xD;
&#xD;
          -  History of head injury with loss of consciousness over 10 minutes; history of brain&#xD;
             surgery&#xD;
&#xD;
          -  Can not refrain from using alcohol and/or marijuana 24 hours or more &amp; cigarette&#xD;
             smoking one hour or more prior to experiments.&#xD;
&#xD;
          -  Woman who is pregnant (child-bearing potential but not on contraceptive and missing&#xD;
             menstrual period; or by self report; or by positive pregnancy test).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xiaoming Du, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Maryland, Baltimore</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Maryland, Baltimore</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21228</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>September 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <results_first_submitted>September 23, 2022</results_first_submitted>
  <results_first_submitted_qc>December 21, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">January 18, 2023</results_first_posted>
  <last_update_submitted>December 21, 2022</last_update_submitted>
  <last_update_submitted_qc>December 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Maryland, Baltimore</investigator_affiliation>
    <investigator_full_name>Xiaoming Du</investigator_full_name>
    <investigator_title>Assistant Professsor</investigator_title>
  </responsible_party>
  <keyword>Transcranial magnetic stimulation</keyword>
  <keyword>schizophrenia</keyword>
  <keyword>MRI</keyword>
  <keyword>smoking</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tobacco Use Disorder</mesh_term>
    <mesh_term>Schizophrenia</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>February 1, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT03281629/Prot_SAP_002.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 7, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT03281629/ICF_003.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Fourteen enrolled participants were excluded from the study before assignment to groups. Six of them were excluded because they failed inclusion/exclusion criteria; six of them were excluded due to schedule conflict; one was excluded because the participant cannot fit into MRI scanner; one was excluded because the participant changed mind and decided to quit.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Active TMS Stimulation</title>
          <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
        </group>
        <group group_id="P2">
          <title>Sham TMS Stimulation</title>
          <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>The two participants dropped out due to COVID-19 lockdown.</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Participant's schedule change and cannot participate in the study</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 TMS Stimulation</title>
          <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
        </group>
        <group group_id="B2">
          <title>Sham TMS Stimulation</title>
          <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</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="18"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="30"/>
          </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="18"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="30"/>
                  </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="44.3" spread="11.8"/>
                    <measurement group_id="B2" value="41.9" spread="12.8"/>
                    <measurement group_id="B3" value="43.3" spread="12.1"/>
                  </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="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </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="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="29"/>
                  </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="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="13"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cigarette Per Day</title>
        <description>Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption.</description>
        <time_frame>7 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active TMS Stimulation</title>
            <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS Stimulation</title>
            <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
        </group_list>
        <measure>
          <title>Cigarette Per Day</title>
          <description>Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption.</description>
          <units>cigarettes per day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline versus End-of-Treatment (1 month)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.2" spread="4.9"/>
                    <measurement group_id="O2" value="-3.0" spread="5.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline versus 3-month follow up (4 months time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.71" spread="3.10"/>
                    <measurement group_id="O2" value="-2.50" spread="3.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline versus 6-month follow up (7 months time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.50" spread="2.04"/>
                    <measurement group_id="O2" value="-3.50" spread="4.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Functional Magnetic Resonance Imaging (fMRI)</title>
        <description>Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point).</description>
        <time_frame>4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active TMS Stimulation</title>
            <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS Stimulation</title>
            <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
        </group_list>
        <measure>
          <title>Functional Magnetic Resonance Imaging (fMRI)</title>
          <description>Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point).</description>
          <units>z score of functional connectivity</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline versus End-of-Treatment (1 month time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.025" spread="0.047"/>
                    <measurement group_id="O2" value="-0.014" spread="0.047"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline versus 3-month follow up (4 months time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.044" spread="0.045"/>
                    <measurement group_id="O2" value="-0.034" spread="0.011"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cotinine</title>
        <description>Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
        <time_frame>1 month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active TMS Stimulation</title>
            <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS Stimulation</title>
            <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
        </group_list>
        <measure>
          <title>Cotinine</title>
          <description>Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
          <units>ng/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-112" spread="1114"/>
                    <measurement group_id="O2" value="31" spread="561"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>End-expired Carbon Monoxide (CO)</title>
        <description>End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
        <time_frame>1 month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active TMS Stimulation</title>
            <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS Stimulation</title>
            <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
        </group_list>
        <measure>
          <title>End-expired Carbon Monoxide (CO)</title>
          <description>End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).</description>
          <units>ppm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.67" spread="9.04"/>
                    <measurement group_id="O2" value="-2.40" spread="4.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG)</title>
        <description>EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point).</description>
        <time_frame>4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active TMS Stimulation</title>
            <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
          <group group_id="O2">
            <title>Sham TMS Stimulation</title>
            <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</description>
          </group>
        </group_list>
        <measure>
          <title>Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG)</title>
          <description>EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point).</description>
          <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="18"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline versus End-pf-Treatment (1 month time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.0" spread="37.0"/>
                    <measurement group_id="O2" value="-38.0" spread="64.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline versus 3-month follow up (4 months time point)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.5" spread="15.5"/>
                    <measurement group_id="O2" value="35.1" spread="32.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From baseline to the time when the participant completes or quits the study (up to 7 months).</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Active TMS Stimulation</title>
          <description>Real active rTMS stimulation.&#xD;
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.</description>
        </group>
        <group group_id="E2">
          <title>Sham TMS Stimulation</title>
          <description>Sham repetitive TMS stimulation.&#xD;
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.</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="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </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="14" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Uncomfortable click sounds</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Facial muscle twitching</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="18"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Eye blinks</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </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>Dr. Xiaoming Du</name_or_title>
      <organization>Maryland Psychiatric Research Center, University of Maryland School of Medicine</organization>
      <phone>410 402 6036</phone>
      <email>xdu@som.umaryland.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/NCT03281629
org study id: HP-00077085
secondary id: UG3DA047685
nct id: NCT03281629
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
In a double-blinded, randomized, parallel controlled design, patients with schizophrenia
      spectrum disorder will be exposed to active or sham repetitive transcranial magentic
      stimulation (TMS) which was guided by functional magnetic resonance image (MRI). Smoking
      reduction/cessation and brain functional connectivity changes will be assessed at baseline,
      different stages of rTMS and/or follow-ups.
Neuroimaging studies suggest that high rate of smoking in patients with schizophrenia may be
      due to an overlap of nicotine addiction related circuitries and schizophrenia related
      circuitries, such that schizophrenia impact some of the same circuitries that increase risks
      for severe nicotine addiction in general. Those identified overlapping circuitries have been
      linked to several key features of nicotine addiction and can be represented by resting state
      functional connectivities. Transcranial magnetic stimulation (TMS) provides a non-invasive
      means for altering brain electrical neural activity. TMS has been approved by FDA for
      treatment of depression. Other applications have not been approved but it has been used in a
      wide range of clinical research especially in neurology and psychiatry. There are
      preliminarily significant improvements in treatments of smoking cessation in schizophrenia
      using TMS with small samples, but those treatments are not robust in larger samples. The high
      inter-subject variability limits the efficacy of TMS treatment in schizophrenia patients. We
      aim to develop a TMS method targeting special brain circuits that are both smoking cessation
      and schizophrenia related. If the corresponding brain circuits were successfully modulated,
      the treatment efficacy will be significantly improved and schizophrenia patients will benefit
      from the TMS treatment of smoking cessation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Double (Participant, Outcomes Assessor)
measure: Cigarette Per Day
time frame: 7 months
description: Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption.
measure: Functional Magnetic Resonance Imaging (fMRI)
time frame: 4 months
description: Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point).
measure: Cotinine
time frame: 1 month
description: Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).
measure: End-expired Carbon Monoxide (CO)
time frame: 1 month
description: End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).
measure: Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG)
time frame: 4 months
description: EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point).
arm group label: Active TMS stimulation
arm group type: Active Comparator
description: Real active rTMS stimulation.
arm group label: Sham TMS stimulation
arm group type: Sham Comparator
description: Sham repetitive TMS stimulation.
intervention type: Device
intervention name: Active TMS stimulation
description: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.
arm group label: Active TMS stimulation
intervention type: Device
intervention name: Sham TMS stimulation
description: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.
arm group label: Sham TMS stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Xiaoming Du, MD
role: Principal Investigator
affiliation: University of Maryland, Baltimore
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Maryland, Baltimore
investigator full name: Xiaoming Du
investigator title: Assistant Professsor
mesh term: Tobacco Use Disorder
mesh term: Schizophrenia
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 