<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/NCT02980484</url>
  </required_header>
  <id_info>
    <org_study_id>201603051</org_study_id>
    <nct_id>NCT02980484</nct_id>
  </id_info>
  <brief_title>fMRI-neuronavigated rTMS for the Treatment of Major Depression Associated With TBI</brief_title>
  <official_title>fMRI-neuronavigated Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depression Associated With Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot study aims to investigate the efficacy of fMRI-targeted repetitive transcranial&#xD;
      magnetic stimulation (rTMS) in treatment of major depression associated with traumatic brain&#xD;
      injury (TBI). Half of patients will receive active treatment, while the other will receive a&#xD;
      sham treatment with the option of receiving open-label active treatment afterwards.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      rTMS is an FDA-approved treatment for major depressive disorder, but its utility has not yet&#xD;
      been investigated for major depression associated with traumatic brain injury.&#xD;
&#xD;
      This will be a prospective double-blind randomized sham-controlled crossover study. Patients&#xD;
      in the treatment group will receive 20 sessions of high-frequency rTMS over the left&#xD;
      dorsolateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC. The DLPFC&#xD;
      will be identified as target by using individual subject-level resting state network&#xD;
      estimation (Hacker et al, 2013). Patients in the control group will receive 20 sham&#xD;
      treatments designed to be visibly indistinguishable from active treatment, and will&#xD;
      subsequently have the option to be crossed over to receive active treatment with the&#xD;
      aforementioned protocol. A subgroup of patients in each group will receive more detailed&#xD;
      diffusion imaging (diffusion tensor and diffusion kurtosis imaging) and resting state fMRI&#xD;
      scans before and after the treatment in order to assess for changes in white matter integrity&#xD;
      and functional connectivity associated with the treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Investigators left the institution for unrelated reasons&#xD;
  </why_stopped>
  <start_date>August 2016</start_date>
  <completion_date type="Actual">August 2017</completion_date>
  <primary_completion_date type="Actual">August 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Randomized double-blind sham-controlled trial with an optional open-label crossover extension for subjects randomized to sham group.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement in depressive symptoms</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>This will be measured as the mean percentage change in baseline scores on Montgomery-Asberg Depression Rating Scale (MADRS) before treatment and immediately after the 4-week treatment period.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in resting-state fMRI and DTI findings</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>MRI imaging will be conducted to assess resting-state functional connectivity using functional magnetic resonance imaging (fMRI). More detailed structural (DTI) and functional (fMRI) imaging will be measured in a subgroup of patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in NIH Toolbox Cognitive, Emotional, and Quality of Life batteries</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>The NIH Toolbox Cognitive battery will be used to determine change in cognitive symptoms with treatment. Emotional battery and TBI-QoL scales will be used to determine change in general neuropsychiatric symptom burden.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in temperament and character</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>Will administer the 140-question Temperament and Character Inventory (TCI-R140) before and after treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response and remission rates in depressive symptoms</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>Percentage of subjects achieving response (&gt;50% improvement in MADRS) and remission (final MADRS score &lt;7) before treatment and immediately after the 4-week treatment period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in headache scales</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>Mean percentage improvement in HIT-6 headache scores</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in tinnitus score</measure>
    <time_frame>Difference between pre-treatment (baseline) and post-treatment (4 weeks)</time_frame>
    <description>Mean percentage improvement in tinnitus severity score and mini-Tinnitus Questionnaire scores</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Major Depressive Disorder</condition>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Active rTMS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive a full course of 20 rTMS treatments over 20 consecutive weekdays as described above.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham/crossover rTMS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Rather than receiving active treatment, subjects will receive sham treatment designed to be indistinguishable from active treatment to the patient. After completion of the sham course, patients will have the option to receive open-label active treatment at no cost.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Active</intervention_name>
    <description>Repetitive transcranial magnetic stimulation (rTMS) will be applied to the left dorsolateral prefrontal cortex (DLPFC) (4000 pulses, 10 Hz, 5-sec trains, 25-sec inter-train interval) followed by the right DLPFC (1000 pulses, 1 Hz frequency, single train). The DLPFC will be identified using individual subject-level resting-state network estimation (Hacker et al, 2013). Each treatment will be completed over the course of 1 hour, and each subject will receive a total of 20 treatments over the course of 20 consecutive weekdays.</description>
    <arm_group_label>Active rTMS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Sham</intervention_name>
    <description>Treatment that looks and feels similar to active rTMS will be administered as a sham treatment.</description>
    <arm_group_label>Sham/crossover rTMS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Adults age 18 to 65&#xD;
&#xD;
          -  History of traumatic brain injury (TBI) at least two weeks prior to study initiation&#xD;
&#xD;
          -  Presence of an active major depressive episode as defined by DSM-5 criteria, including&#xD;
             depression secondary to traumatic brain injury&#xD;
&#xD;
          -  Baseline score of 10 or greater on Montgomery-Asberg Depression Rating Scale (MADRS)&#xD;
&#xD;
          -  Failure of at least one prior antidepressant trial after the traumatic brain injury&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
        History of:&#xD;
&#xD;
          -  Moderate or severe substance use disorder in the past six months as defined by DSM-5&#xD;
             criteria, with the exception of cannabis and nicotine use disorders.&#xD;
&#xD;
          -  Dementia, as defined by treating neurologist&#xD;
&#xD;
          -  Moderate or severe autism spectrum disorder&#xD;
&#xD;
          -  Bipolar disorder&#xD;
&#xD;
          -  Schizophrenia spectrum disorders&#xD;
&#xD;
        Current evidence of:&#xD;
&#xD;
          -  Substance-induced mood disorder&#xD;
&#xD;
          -  Active psychotic symptoms&#xD;
&#xD;
          -  Depression secondary to a general medical illness, with the exception of TBI&#xD;
&#xD;
          -  Dysphoria better explained by a baseline personality disorder than a major depressive&#xD;
             episode&#xD;
&#xD;
          -  Dysphoria better explained by a baseline anxiety disorder (including post-traumatic&#xD;
             stress disorder) rather than a major depressive episode&#xD;
&#xD;
          -  Active suicidal ideation&#xD;
&#xD;
        Contraindications to rTMS treatment:&#xD;
&#xD;
          -  Seizure disorder&#xD;
&#xD;
          -  Significantly elevated seizure risk, as determined by clinician assessment&#xD;
&#xD;
          -  TBI associated with elevated seizure risk, including penetrating injury and/or&#xD;
             cortical intraparenchymal hemorrhage&#xD;
&#xD;
          -  Presence of metallic objects within the head&#xD;
&#xD;
          -  Presence of an implanted neurostimulation device within the head&#xD;
&#xD;
        Contraindications to MRI&#xD;
&#xD;
          -  Severe claustrophobia&#xD;
&#xD;
          -  Severe pain/illness exacerbated by lying prone in the scanner&#xD;
&#xD;
          -  Presence of non-MRI compatible metal foreign bodies or implants&#xD;
&#xD;
          -  Weight in excess of 350 lbs&#xD;
&#xD;
          -  Shoulder width in excess of maximum tolerable width for scanner&#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>Shan H Siddiqi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>February 25, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>March 26, 2018</last_update_submitted>
  <last_update_submitted_qc>March 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>rTMS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified neuroimaging data will be submitted to FITBIR (Federal Interagency TBI Research)</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02980484
org study id: 201603051
nct id: NCT02980484
lead sponsor: 
has dmc: No
This pilot study aims to investigate the efficacy of fMRI-targeted repetitive transcranial
      magnetic stimulation (rTMS) in treatment of major depression associated with traumatic brain
      injury (TBI). Half of patients will receive active treatment, while the other will receive a
      sham treatment with the option of receiving open-label active treatment afterwards.
rTMS is an FDA-approved treatment for major depressive disorder, but its utility has not yet
      been investigated for major depression associated with traumatic brain injury.

      This will be a prospective double-blind randomized sham-controlled crossover study. Patients
      in the treatment group will receive 20 sessions of high-frequency rTMS over the left
      dorsolateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC. The DLPFC
      will be identified as target by using individual subject-level resting state network
      estimation (Hacker et al, 2013). Patients in the control group will receive 20 sham
      treatments designed to be visibly indistinguishable from active treatment, and will
      subsequently have the option to be crossed over to receive active treatment with the
      aforementioned protocol. A subgroup of patients in each group will receive more detailed
      diffusion imaging (diffusion tensor and diffusion kurtosis imaging) and resting state fMRI
      scans before and after the treatment in order to assess for changes in white matter integrity
      and functional connectivity associated with the treatment.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Randomized double-blind sham-controlled trial with an optional open-label crossover extension for subjects randomized to sham group.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Improvement in depressive symptoms
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: This will be measured as the mean percentage change in baseline scores on Montgomery-Asberg Depression Rating Scale (MADRS) before treatment and immediately after the 4-week treatment period.
measure: Changes in resting-state fMRI and DTI findings
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: MRI imaging will be conducted to assess resting-state functional connectivity using functional magnetic resonance imaging (fMRI). More detailed structural (DTI) and functional (fMRI) imaging will be measured in a subgroup of patients.
measure: Changes in NIH Toolbox Cognitive, Emotional, and Quality of Life batteries
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: The NIH Toolbox Cognitive battery will be used to determine change in cognitive symptoms with treatment. Emotional battery and TBI-QoL scales will be used to determine change in general neuropsychiatric symptom burden.
measure: Changes in temperament and character
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: Will administer the 140-question Temperament and Character Inventory (TCI-R140) before and after treatment.
measure: Response and remission rates in depressive symptoms
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: Percentage of subjects achieving response (>50% improvement in MADRS) and remission (final MADRS score <7) before treatment and immediately after the 4-week treatment period.
measure: Changes in headache scales
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: Mean percentage improvement in HIT-6 headache scores
measure: Changes in tinnitus score
time frame: Difference between pre-treatment (baseline) and post-treatment (4 weeks)
description: Mean percentage improvement in tinnitus severity score and mini-Tinnitus Questionnaire scores
arm group label: Active rTMS
arm group type: Experimental
description: Subjects will receive a full course of 20 rTMS treatments over 20 consecutive weekdays as described above.
arm group label: Sham/crossover rTMS
arm group type: Sham Comparator
description: Rather than receiving active treatment, subjects will receive sham treatment designed to be indistinguishable from active treatment to the patient. After completion of the sham course, patients will have the option to receive open-label active treatment at no cost.
intervention type: Procedure
intervention name: Active
description: Repetitive transcranial magnetic stimulation (rTMS) will be applied to the left dorsolateral prefrontal cortex (DLPFC) (4000 pulses, 10 Hz, 5-sec trains, 25-sec inter-train interval) followed by the right DLPFC (1000 pulses, 1 Hz frequency, single train). The DLPFC will be identified using individual subject-level resting-state network estimation (Hacker et al, 2013). Each treatment will be completed over the course of 1 hour, and each subject will receive a total of 20 treatments over the course of 20 consecutive weekdays.
arm group label: Active rTMS
intervention type: Procedure
intervention name: Sham
description: Treatment that looks and feels similar to active rTMS will be administered as a sham treatment.
arm group label: Sham/crossover rTMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Shan H Siddiqi, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
sharing ipd: Yes
ipd description: De-identified neuroimaging data will be submitted to FITBIR (Federal Interagency TBI Research)