<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/NCT03288779</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00083070</org_study_id>
    <nct_id>NCT03288779</nct_id>
  </id_info>
  <brief_title>Theta Burst Stimulation for Schizophrenia</brief_title>
  <official_title>Theta Burst Stimulation for Schizophrenia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Duke 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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose and objective Schizophrenia is a chronic debilitating illness with cognitive deficits&#xD;
      that cause serious impairment in psychosocial recovery and with few treatments to remediate&#xD;
      these deficits. One area that holds great promise for the development of novel, effective&#xD;
      therapies is noninvasive brain stimulation. The investigators have used one form of brain&#xD;
      stimulation, transcranial magnetic stimulation (TMS), for some time to modulate and enhance&#xD;
      cognitive function in the brain, especially working memory (WM) function, which has a central&#xD;
      role in most executive processing that occurs in the brain. Theta burst stimulation (TBS) is&#xD;
      a paradigm of TMS which has been shown to effectively modulate WM. Moreover, TBS can modulate&#xD;
      gamma neural oscillations in the brain and neural activity, both of which have been&#xD;
      implicated in the physiology of WM and pathophysiology of the disease process in&#xD;
      schizophrenia, making these measures highly valuable for assessing physiological effects of&#xD;
      TBS on cognition, quality of life and cortical inhibition. The purpose of this study is to&#xD;
      evaluate the effect of TBS on WM in patients with schizophrenia, to develop evidence for&#xD;
      potential brain stimulation techniques to treat cognitive deficits in schizophrenia.&#xD;
&#xD;
      Study activities and population group: Study subjects will be inpatient schizophrenic&#xD;
      individuals with minimal positive symptoms and predominant cognitive deficits at Duke&#xD;
      University Hospital. In an initial session they will be screened and taught a WM task.&#xD;
      Following this, one TBS session will follow in which TBS will target dorsolateral prefrontal&#xD;
      cortex. They will perform the WM task before, with and after the TBS, with an expected&#xD;
      pre-post enhancement of WM performance.&#xD;
&#xD;
      Implications - There is a great need for treatments for cognitive deficits in schizophrenia.&#xD;
      The results of this study will serve to generate pilot data for a much larger grant to&#xD;
      develop a TBS therapy for remediating such cognitive deficits.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose of the study Aim1: Evaluate the effect of theta burst stimulation (TBS) on working&#xD;
      memory (WM) in patients with schizophrenia. Hypothesis 1 - There will be significant&#xD;
      improvement in WM compared to baseline with one session of TBS.&#xD;
&#xD;
      Background and Significance Schizophrenia is an illness known to have cognitive deficits,&#xD;
      with a chronic and variable course. There is extensive research on cognitive deficits, with&#xD;
      working memory, processing speed and verbal memory being some of the domains affected. Some&#xD;
      modalities of treatment that have been tried to reverse these cognitive deficits are&#xD;
      medications and cognitive behavioral therapy with minimal benefits. A few studies have shown&#xD;
      modulation of working memory with routine repetitive transcranial magnetic stimulation at&#xD;
      frequencies not exceeding 10 to 20 Hz of stimulation. Other studies have shown the working&#xD;
      memory to be related to gamma oscillations. A few studies have also shown that transcranial&#xD;
      magnetic stimulation (TMS) modulates these gamma oscillations as well. There is an extensive&#xD;
      body of literature that shows that working memory has contributions from theta and gamma&#xD;
      oscillations in the brain. Theta burst stimulation (TBS) is a form of transcranial magnetic&#xD;
      stimulation (TMS), that entrains gamma and theta frequencies in the brain. It could be the&#xD;
      most appropriate form of brain stimulation for improving cognition in schizophrenia patients&#xD;
      because it has been shown to modulate brain oscillations in small samples of patients. The&#xD;
      area for targeting would be the dorsolateral prefrontal cortex which is the site of origin of&#xD;
      the gamma oscillations and plays a significant role in working memory.&#xD;
&#xD;
      Design and Procedures The study is designed to be a pilot one evaluating the effect of TBS on&#xD;
      WM in patients with schizophrenia. The investigators plan to screen 20 subjects to have 10&#xD;
      participants. Working memory will be tested using delayed match sample task (DMS) and brief&#xD;
      assessment of cognition in schizophrenia battery (BACS).&#xD;
&#xD;
      Transcranial Magnetic Stimulation (TMS) administration The patient would be transported from&#xD;
      the inpatient unit to the TMS lab following screening and consent process. They would be&#xD;
      accompanied by nursing staff. During their visit to the TMS lab a sample TMS session&#xD;
      including motor threshold determination will be conducted. Subjects would be allowed to&#xD;
      practice the DMS task to allow for the ceiling in practice effect of the task. The BACS would&#xD;
      be administered before and after the TMS session.&#xD;
&#xD;
      Treatment Sessions Subjects would be administered left sided theta burst stimulation&#xD;
      (TBS).The subject will be seated in a chair. A 64-channel electrode cap may be applied to the&#xD;
      head for EEG recording. Electromyogram (EMG) electrodes will be applied to the right hand for&#xD;
      motor evoked potential (MEP) recording. Subjects will perform the DMS task while sitting in&#xD;
      the chair during the TMS session. EEG and EMG will be recorded throughout the treatment&#xD;
      sessions. For theta burst stimulation the active motor threshold would be 80 % as used in&#xD;
      most theta burst studies detailed in this review. Subjects would receive theta burst&#xD;
      stimulation comprising 50 Hz bursts given at 3 to 5 Hz for close to 10 minutes which&#xD;
      comprises 60 trains and 1800 pulses. The subject will be monitored until MEPs return to&#xD;
      baseline. A side effects checklist will be completed at the beginning and at the end of the&#xD;
      experimental session. All sessions will be performed by one of the protocol investigators, or&#xD;
      by a trained and accredited research assistant supervised by the protocol investigators.&#xD;
&#xD;
      Clinical and cognitive assessments/tasks PANSS The Positive and negative symptoms scale is&#xD;
      used to assess the severity of schizophrenia. It has three subscales - positive, negative and&#xD;
      general psychopathology. Each of these subscales had 7 items, the maximum scores on each of&#xD;
      these subscales in 49, minimum score being 7.&#xD;
&#xD;
      DMS task The DMS task is a modified version of the Sternberg task and has been adapted for&#xD;
      use in cognitive paradigms accompanying transcranial magnetic stimulation. Each trial will&#xD;
      last 13 s, with the following sequence of three task stages: encoding, retention and probe&#xD;
      stages.&#xD;
&#xD;
      BACS - Tasks to be done from the actual BACS battery of tests List Learning (Verbal Memory).&#xD;
      Patients are presented with 15 words and then asked to recall as many as possible. This&#xD;
      procedure is repeated 5 times. There are two alternate forms.&#xD;
&#xD;
      Digit Sequencing Task (verbal working Memory). Patients are presented with clusters of&#xD;
      numbers of increasing length. They are asked to tell the experimenter the numbers in order,&#xD;
      from lowest to highest.&#xD;
&#xD;
      Token Motor Task (Motor Speed). Patients are given 100 plastic tokens and asked to place them&#xD;
      into a container as quickly as possible for 60 seconds.&#xD;
&#xD;
      Verbal Fluency. Tests of Category Instances (Semantic Fluency) and Controlled Oral Word&#xD;
      Association Test (Letter Fluency) are administered. Patients are given 60 seconds to name as&#xD;
      many words as possible within a given semantic category, and in two separate trials, patients&#xD;
      are given 60 seconds to generate as many words as possible that begin with a given letter.&#xD;
      The total number of words from the three trials is the outcome measure.&#xD;
&#xD;
      Tower of London (Reasoning and Problem Solving). Patients look at two pictures&#xD;
      simultaneously. Each picture shows 3 different-colored balls arranged on 3 pegs, with the&#xD;
      balls in a unique arrangement in each picture. The patients are told about the rules in the&#xD;
      task and are asked to provide the least number of times the balls in one picture would have&#xD;
      to be moved to make the arrangement of balls identical to that of the other, opposing&#xD;
      picture. There are two alternate forms.&#xD;
&#xD;
      Symbol Coding (Attention and Processing Speed). As quickly as possible, patients write&#xD;
      numerals 1-9 as matches to symbols on a response sheet for 90 seconds.&#xD;
&#xD;
      Each of the six measures are compared to a healthy control sample to create z-scores, and a&#xD;
      composite score is calculated by summing these z-scores and calculating a z-score of that&#xD;
      sum. The composite score has high test-retest reliability in patients with schizophrenia and&#xD;
      healthy controls (ICCs &gt; .80).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 24, 2017</start_date>
  <completion_date type="Actual">June 30, 2018</completion_date>
  <primary_completion_date type="Actual">June 30, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Brief Assessment of Cognition (BACS) Composite T Score</measure>
    <time_frame>30 minutes</time_frame>
    <description>Performance on tasks included in the Brief Assessment of Cognition in Schizophrenia (BACS) battery, task performed and results recorded on IPAD. The mean change from baseline in total cognitive score on the BACS was calculated as a weighted average of T-scores (normalized for age) from BACS subtests including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Semantic Fluency, Letter Fluency, and Tower of London. The minimum and maximum values possible for this composite T-score of the change from baseline were -131 and 131, respectively. Higher values (positive changes from baseline) indicate better performance.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Gamma and Theta Oscillations as Measured by EEG</measure>
    <time_frame>one session, approximately 30 minutes</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Schizophrenia</condition>
  <condition>Schizoaffective Disorder</condition>
  <arm_group>
    <arm_group_label>Theta Burst Stimulation Arm</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This is a pilot open label study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Theta Burst Stimulation</intervention_name>
    <description>Transcranial magnetic stimulation with theta burst stimulation</description>
    <arm_group_label>Theta Burst Stimulation Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients aged 18-65 years of age with schizophrenia or schizoaffective disorder&#xD;
&#xD;
          -  No other mental health diagnoses&#xD;
&#xD;
          -  Right handed males and females&#xD;
&#xD;
          -  May have mild positive symptoms (score of &lt;/= 21)&#xD;
&#xD;
          -  May have negative symptoms&#xD;
&#xD;
          -  Ability to provide informed consent&#xD;
&#xD;
          -  No restriction on concomitant medications given&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intellectual disability&#xD;
&#xD;
          -  Any organic brain illness Presence of dementia symptoms or traumatic brain injury&#xD;
             Primary diagnosis of substance use Seizure disorder Actively symptomatic with PANSS&#xD;
             positive symptom sub-scale &gt;21. Concurrently receiving electroconvulsive therapy (ECT)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gopalkumar Rakesh, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, Fenton WS, Frese F, Goldberg TE, Heaton RK, Keefe RS, Kern RS, Kraemer H, Stover E, Weinberger DR, Zalcman S, Marder SR. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004 Sep 1;56(5):301-7. doi: 10.1016/j.biopsych.2004.06.023.</citation>
    <PMID>15336511</PMID>
  </reference>
  <reference>
    <citation>Keefe RS, Fox KH, Harvey PD, Cucchiaro J, Siu C, Loebel A. Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res. 2011 Feb;125(2-3):161-8. doi: 10.1016/j.schres.2010.09.015. Epub 2010 Dec 31.</citation>
    <PMID>21075600</PMID>
  </reference>
  <reference>
    <citation>Young JW, Geyer MA. Developing treatments for cognitive deficits in schizophrenia: the challenge of translation. J Psychopharmacol. 2015 Feb;29(2):178-96. doi: 10.1177/0269881114555252. Epub 2014 Dec 16.</citation>
    <PMID>25516372</PMID>
  </reference>
  <reference>
    <citation>Barr MS, Farzan F, Arenovich T, Chen R, Fitzgerald PB, Daskalakis ZJ. The effect of repetitive transcranial magnetic stimulation on gamma oscillatory activity in schizophrenia. PLoS One. 2011;6(7):e22627. doi: 10.1371/journal.pone.0022627. Epub 2011 Jul 27.</citation>
    <PMID>21818354</PMID>
  </reference>
  <reference>
    <citation>Farzan F, Barr MS, Sun Y, Fitzgerald PB, Daskalakis ZJ. Transcranial magnetic stimulation on the modulation of gamma oscillations in schizophrenia. Ann N Y Acad Sci. 2012 Aug;1265:25-35. doi: 10.1111/j.1749-6632.2012.06543.x. Epub 2012 Jul 23.</citation>
    <PMID>22823464</PMID>
  </reference>
  <reference>
    <citation>Hasan A, Brinkmann C, Strube W, Palm U, Malchow B, Rothwell JC, Falkai P, Wobrock T. Investigations of motor-cortex cortical plasticity following facilitatory and inhibitory transcranial theta-burst stimulation in schizophrenia: a proof-of-concept study. J Psychiatr Res. 2015 Feb;61:196-204. doi: 10.1016/j.jpsychires.2014.12.006. Epub 2014 Dec 19. Erratum In: J Psychiatr Res. 2016 Sep;80:1-2.</citation>
    <PMID>25555304</PMID>
  </reference>
  <reference>
    <citation>Tikka SK, Nizamie SH, Venkatesh Babu GM, Aggarwal N, Das AK, Goyal N. Safety and Efficacy of Adjunctive Theta Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study. J ECT. 2017 Mar;33(1):43-51. doi: 10.1097/YCT.0000000000000343.</citation>
    <PMID>27428476</PMID>
  </reference>
  <reference>
    <citation>Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, Seidman LJ, Schmahmann JD, Pascual-Leone A. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010 Dec;124(1-3):91-100. doi: 10.1016/j.schres.2010.08.015.</citation>
    <PMID>20817483</PMID>
  </reference>
  <reference>
    <citation>Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015 Jun 15;77(12):1031-40. doi: 10.1016/j.biopsych.2015.03.010. Epub 2015 Mar 17.</citation>
    <PMID>25863358</PMID>
  </reference>
  <reference>
    <citation>Barr MS, Farzan F, Rusjan PM, Chen R, Fitzgerald PB, Daskalakis ZJ. Potentiation of gamma oscillatory activity through repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex. Neuropsychopharmacology. 2009 Oct;34(11):2359-67. doi: 10.1038/npp.2009.79. Epub 2009 Jul 15.</citation>
    <PMID>19606086</PMID>
  </reference>
  <reference>
    <citation>Keefe RS, Poe M, Walker TM, Harvey PD. The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome. J Clin Exp Neuropsychol. 2006 Feb;28(2):260-9. doi: 10.1080/13803390500360539.</citation>
    <PMID>16484097</PMID>
  </reference>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 20, 2017</study_first_posted>
  <results_first_submitted>June 20, 2019</results_first_submitted>
  <results_first_submitted_qc>November 6, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 25, 2019</results_first_posted>
  <last_update_submitted>November 6, 2019</last_update_submitted>
  <last_update_submitted_qc>November 6, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
    <mesh_term>Psychotic Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 4, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03288779/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>We recruited 6 patients with diagnoses of schizophrenia, which included 4 inpatients and 2 outpatients.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Patients With a Diagnosis of Schizophrenia</title>
          <description>We recruited 6 patients with diagnoses of schizophrenia. Inpatient subjects were recruited towards the latter half of their inpatient stay, after their positive symptoms had decreased in severity. PANSS was performed at recruitment and subjects were chosen for the study only if their positive symptom score was less than or equal to 21. Our other inclusion criteria for the study were patients in the age group of 18-50 years, right handed, with no other comorbid DSM-5 diagnoses (including substance use disorder), and able to give informed consent. Subjects with organic basis for their psychopathology or intellectual disability, were excluded from the study.&#xD;
Intervention administered - Theta Burst Stimulation (TBS) with Brief Assessment of Cognition in Schizophrenia (BACS) administered before and after TBS.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Patients With a Diagnosis of Schizophrenia</title>
          <description>We recruited 6 patients with diagnoses of schizophrenia. Inpatient subjects were recruited towards the latter half of their inpatient stay, after their positive symptoms had decreased in severity. PANSS was performed at recruitment and subjects were chosen for the study only if their positive symptom score was less than or equal to 21. Our other inclusion criteria for the study were patients in the age group of 18-50 years, right handed, with no other comorbid DSM-5 diagnoses (including substance use disorder), and able to give informed consent. Subjects with organic basis for their psychopathology or intellectual disability, were excluded from the study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" 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="33" spread="7"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Brief Assessment of Cognition (BACS) Composite T Score</title>
          <units>Composite T- Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26.3" spread="17.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Brief Assessment of Cognition (BACS) Composite T Score</title>
        <description>Performance on tasks included in the Brief Assessment of Cognition in Schizophrenia (BACS) battery, task performed and results recorded on IPAD. The mean change from baseline in total cognitive score on the BACS was calculated as a weighted average of T-scores (normalized for age) from BACS subtests including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Semantic Fluency, Letter Fluency, and Tower of London. The minimum and maximum values possible for this composite T-score of the change from baseline were -131 and 131, respectively. Higher values (positive changes from baseline) indicate better performance.</description>
        <time_frame>30 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Theta Burst Stimulation Arm</title>
            <description>This is a pilot open label study.&#xD;
Theta Burst Stimulation: Transcranial magnetic stimulation with theta burst stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>Brief Assessment of Cognition (BACS) Composite T Score</title>
          <description>Performance on tasks included in the Brief Assessment of Cognition in Schizophrenia (BACS) battery, task performed and results recorded on IPAD. The mean change from baseline in total cognitive score on the BACS was calculated as a weighted average of T-scores (normalized for age) from BACS subtests including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Semantic Fluency, Letter Fluency, and Tower of London. The minimum and maximum values possible for this composite T-score of the change from baseline were -131 and 131, respectively. Higher values (positive changes from baseline) indicate better performance.</description>
          <units>Composite T- Score</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.33" lower_limit="18.5" upper_limit="56.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Gamma and Theta Oscillations as Measured by EEG</title>
        <time_frame>one session, approximately 30 minutes</time_frame>
        <population>No EEG data was collected</population>
        <group_list>
          <group group_id="O1">
            <title>Theta Burst Stimulation Arm</title>
            <description>This is a pilot open label study.&#xD;
Theta Burst Stimulation: Transcranial magnetic stimulation with theta burst stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Gamma and Theta Oscillations as Measured by EEG</title>
          <population>No EEG data was collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Patients With a Diagnosis of Schizophrenia</title>
          <description>We recruited 6 patients with diagnoses of schizophrenia. Inpatient subjects were recruited towards the latter half of their inpatient stay, after their positive symptoms had decreased in severity. PANSS was performed at recruitment and subjects were chosen for the study only if their positive symptom score was less than or equal to 21. Our other inclusion criteria for the study were patients in the age group of 18-50 years, right handed, with no other comorbid DSM-5 diagnoses (including substance use disorder), and able to give informed consent. Subjects with organic basis for their psychopathology or intellectual disability, were excluded from the study.</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="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
              </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="6"/>
              </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>Steven T Szabo</name_or_title>
      <organization>DukeUMC</organization>
      <phone>3524540101 ext 3524540101</phone>
      <email>steven.szabo@duke.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/NCT03288779
org study id: Pro00083070
nct id: NCT03288779
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
Purpose and objective Schizophrenia is a chronic debilitating illness with cognitive deficits
      that cause serious impairment in psychosocial recovery and with few treatments to remediate
      these deficits. One area that holds great promise for the development of novel, effective
      therapies is noninvasive brain stimulation. The investigators have used one form of brain
      stimulation, transcranial magnetic stimulation (TMS), for some time to modulate and enhance
      cognitive function in the brain, especially working memory (WM) function, which has a central
      role in most executive processing that occurs in the brain. Theta burst stimulation (TBS) is
      a paradigm of TMS which has been shown to effectively modulate WM. Moreover, TBS can modulate
      gamma neural oscillations in the brain and neural activity, both of which have been
      implicated in the physiology of WM and pathophysiology of the disease process in
      schizophrenia, making these measures highly valuable for assessing physiological effects of
      TBS on cognition, quality of life and cortical inhibition. The purpose of this study is to
      evaluate the effect of TBS on WM in patients with schizophrenia, to develop evidence for
      potential brain stimulation techniques to treat cognitive deficits in schizophrenia.

      Study activities and population group: Study subjects will be inpatient schizophrenic
      individuals with minimal positive symptoms and predominant cognitive deficits at Duke
      University Hospital. In an initial session they will be screened and taught a WM task.
      Following this, one TBS session will follow in which TBS will target dorsolateral prefrontal
      cortex. They will perform the WM task before, with and after the TBS, with an expected
      pre-post enhancement of WM performance.

      Implications - There is a great need for treatments for cognitive deficits in schizophrenia.
      The results of this study will serve to generate pilot data for a much larger grant to
      develop a TBS therapy for remediating such cognitive deficits.
Purpose of the study Aim1: Evaluate the effect of theta burst stimulation (TBS) on working
      memory (WM) in patients with schizophrenia. Hypothesis 1 - There will be significant
      improvement in WM compared to baseline with one session of TBS.

      Background and Significance Schizophrenia is an illness known to have cognitive deficits,
      with a chronic and variable course. There is extensive research on cognitive deficits, with
      working memory, processing speed and verbal memory being some of the domains affected. Some
      modalities of treatment that have been tried to reverse these cognitive deficits are
      medications and cognitive behavioral therapy with minimal benefits. A few studies have shown
      modulation of working memory with routine repetitive transcranial magnetic stimulation at
      frequencies not exceeding 10 to 20 Hz of stimulation. Other studies have shown the working
      memory to be related to gamma oscillations. A few studies have also shown that transcranial
      magnetic stimulation (TMS) modulates these gamma oscillations as well. There is an extensive
      body of literature that shows that working memory has contributions from theta and gamma
      oscillations in the brain. Theta burst stimulation (TBS) is a form of transcranial magnetic
      stimulation (TMS), that entrains gamma and theta frequencies in the brain. It could be the
      most appropriate form of brain stimulation for improving cognition in schizophrenia patients
      because it has been shown to modulate brain oscillations in small samples of patients. The
      area for targeting would be the dorsolateral prefrontal cortex which is the site of origin of
      the gamma oscillations and plays a significant role in working memory.

      Design and Procedures The study is designed to be a pilot one evaluating the effect of TBS on
      WM in patients with schizophrenia. The investigators plan to screen 20 subjects to have 10
      participants. Working memory will be tested using delayed match sample task (DMS) and brief
      assessment of cognition in schizophrenia battery (BACS).

      Transcranial Magnetic Stimulation (TMS) administration The patient would be transported from
      the inpatient unit to the TMS lab following screening and consent process. They would be
      accompanied by nursing staff. During their visit to the TMS lab a sample TMS session
      including motor threshold determination will be conducted. Subjects would be allowed to
      practice the DMS task to allow for the ceiling in practice effect of the task. The BACS would
      be administered before and after the TMS session.

      Treatment Sessions Subjects would be administered left sided theta burst stimulation
      (TBS).The subject will be seated in a chair. A 64-channel electrode cap may be applied to the
      head for EEG recording. Electromyogram (EMG) electrodes will be applied to the right hand for
      motor evoked potential (MEP) recording. Subjects will perform the DMS task while sitting in
      the chair during the TMS session. EEG and EMG will be recorded throughout the treatment
      sessions. For theta burst stimulation the active motor threshold would be 80 % as used in
      most theta burst studies detailed in this review. Subjects would receive theta burst
      stimulation comprising 50 Hz bursts given at 3 to 5 Hz for close to 10 minutes which
      comprises 60 trains and 1800 pulses. The subject will be monitored until MEPs return to
      baseline. A side effects checklist will be completed at the beginning and at the end of the
      experimental session. All sessions will be performed by one of the protocol investigators, or
      by a trained and accredited research assistant supervised by the protocol investigators.

      Clinical and cognitive assessments/tasks PANSS The Positive and negative symptoms scale is
      used to assess the severity of schizophrenia. It has three subscales - positive, negative and
      general psychopathology. Each of these subscales had 7 items, the maximum scores on each of
      these subscales in 49, minimum score being 7.

      DMS task The DMS task is a modified version of the Sternberg task and has been adapted for
      use in cognitive paradigms accompanying transcranial magnetic stimulation. Each trial will
      last 13 s, with the following sequence of three task stages: encoding, retention and probe
      stages.

      BACS - Tasks to be done from the actual BACS battery of tests List Learning (Verbal Memory).
      Patients are presented with 15 words and then asked to recall as many as possible. This
      procedure is repeated 5 times. There are two alternate forms.

      Digit Sequencing Task (verbal working Memory). Patients are presented with clusters of
      numbers of increasing length. They are asked to tell the experimenter the numbers in order,
      from lowest to highest.

      Token Motor Task (Motor Speed). Patients are given 100 plastic tokens and asked to place them
      into a container as quickly as possible for 60 seconds.

      Verbal Fluency. Tests of Category Instances (Semantic Fluency) and Controlled Oral Word
      Association Test (Letter Fluency) are administered. Patients are given 60 seconds to name as
      many words as possible within a given semantic category, and in two separate trials, patients
      are given 60 seconds to generate as many words as possible that begin with a given letter.
      The total number of words from the three trials is the outcome measure.

      Tower of London (Reasoning and Problem Solving). Patients look at two pictures
      simultaneously. Each picture shows 3 different-colored balls arranged on 3 pegs, with the
      balls in a unique arrangement in each picture. The patients are told about the rules in the
      task and are asked to provide the least number of times the balls in one picture would have
      to be moved to make the arrangement of balls identical to that of the other, opposing
      picture. There are two alternate forms.

      Symbol Coding (Attention and Processing Speed). As quickly as possible, patients write
      numerals 1-9 as matches to symbols on a response sheet for 90 seconds.

      Each of the six measures are compared to a healthy control sample to create z-scores, and a
      composite score is calculated by summing these z-scores and calculating a z-score of that
      sum. The composite score has high test-retest reliability in patients with schizophrenia and
      healthy controls (ICCs > .80).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Brief Assessment of Cognition (BACS) Composite T Score
time frame: 30 minutes
description: Performance on tasks included in the Brief Assessment of Cognition in Schizophrenia (BACS) battery, task performed and results recorded on IPAD. The mean change from baseline in total cognitive score on the BACS was calculated as a weighted average of T-scores (normalized for age) from BACS subtests including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Semantic Fluency, Letter Fluency, and Tower of London. The minimum and maximum values possible for this composite T-score of the change from baseline were -131 and 131, respectively. Higher values (positive changes from baseline) indicate better performance.
measure: Change in Gamma and Theta Oscillations as Measured by EEG
time frame: one session, approximately 30 minutes
arm group label: Theta Burst Stimulation Arm
arm group type: Other
description: This is a pilot open label study.
intervention type: Device
intervention name: Theta Burst Stimulation
description: Transcranial magnetic stimulation with theta burst stimulation
arm group label: Theta Burst Stimulation Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Gopalkumar Rakesh, MD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
citation: Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, Fenton WS, Frese F, Goldberg TE, Heaton RK, Keefe RS, Kern RS, Kraemer H, Stover E, Weinberger DR, Zalcman S, Marder SR. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004 Sep 1;56(5):301-7. doi: 10.1016/j.biopsych.2004.06.023.
PMID: 15336511
citation: Keefe RS, Fox KH, Harvey PD, Cucchiaro J, Siu C, Loebel A. Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res. 2011 Feb;125(2-3):161-8. doi: 10.1016/j.schres.2010.09.015. Epub 2010 Dec 31.
PMID: 21075600
citation: Young JW, Geyer MA. Developing treatments for cognitive deficits in schizophrenia: the challenge of translation. J Psychopharmacol. 2015 Feb;29(2):178-96. doi: 10.1177/0269881114555252. Epub 2014 Dec 16.
PMID: 25516372
citation: Barr MS, Farzan F, Arenovich T, Chen R, Fitzgerald PB, Daskalakis ZJ. The effect of repetitive transcranial magnetic stimulation on gamma oscillatory activity in schizophrenia. PLoS One. 2011;6(7):e22627. doi: 10.1371/journal.pone.0022627. Epub 2011 Jul 27.
PMID: 21818354
citation: Farzan F, Barr MS, Sun Y, Fitzgerald PB, Daskalakis ZJ. Transcranial magnetic stimulation on the modulation of gamma oscillations in schizophrenia. Ann N Y Acad Sci. 2012 Aug;1265:25-35. doi: 10.1111/j.1749-6632.2012.06543.x. Epub 2012 Jul 23.
PMID: 22823464
citation: Hasan A, Brinkmann C, Strube W, Palm U, Malchow B, Rothwell JC, Falkai P, Wobrock T. Investigations of motor-cortex cortical plasticity following facilitatory and inhibitory transcranial theta-burst stimulation in schizophrenia: a proof-of-concept study. J Psychiatr Res. 2015 Feb;61:196-204. doi: 10.1016/j.jpsychires.2014.12.006. Epub 2014 Dec 19. Erratum In: J Psychiatr Res. 2016 Sep;80:1-2.
PMID: 25555304
citation: Tikka SK, Nizamie SH, Venkatesh Babu GM, Aggarwal N, Das AK, Goyal N. Safety and Efficacy of Adjunctive Theta Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study. J ECT. 2017 Mar;33(1):43-51. doi: 10.1097/YCT.0000000000000343.
PMID: 27428476
citation: Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, Seidman LJ, Schmahmann JD, Pascual-Leone A. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010 Dec;124(1-3):91-100. doi: 10.1016/j.schres.2010.08.015.
PMID: 20817483
citation: Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015 Jun 15;77(12):1031-40. doi: 10.1016/j.biopsych.2015.03.010. Epub 2015 Mar 17.
PMID: 25863358
citation: Barr MS, Farzan F, Rusjan PM, Chen R, Fitzgerald PB, Daskalakis ZJ. Potentiation of gamma oscillatory activity through repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex. Neuropsychopharmacology. 2009 Oct;34(11):2359-67. doi: 10.1038/npp.2009.79. Epub 2009 Jul 15.
PMID: 19606086
citation: Keefe RS, Poe M, Walker TM, Harvey PD. The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome. J Clin Exp Neuropsychol. 2006 Feb;28(2):260-9. doi: 10.1080/13803390500360539.
PMID: 16484097
responsible party type: Sponsor
mesh term: Schizophrenia
mesh term: Psychotic Disorders
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 