<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/NCT03292471</url>
  </required_header>
  <id_info>
    <org_study_id>B2566-P</org_study_id>
    <secondary_id>I21RX002566-01A1</secondary_id>
    <nct_id>NCT03292471</nct_id>
  </id_info>
  <brief_title>Effects of rTMS on Brain Activation in Aphasia</brief_title>
  <official_title>Immediate and Cumulative Effects of rTMS on Brain Activation in Chronic Aphasia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will investigate the use of repetitive transcranial magnetic stimulation (rTMS), a&#xD;
      non-invasive brain stimulation method, to improve word-finding abilities in Veterans and&#xD;
      non-Veterans with chronic language problems following stroke (aphasia). Improving&#xD;
      word-finding is important because word-finding difficulties are among the most common and&#xD;
      debilitating consequences of aphasia. Although rTMS has shown promise as a treatment&#xD;
      approach, not all individuals with aphasia show the same level of benefit. Specifically, this&#xD;
      study will use functional magnetic resonance imaging (fMRI) to examine whether the likelihood&#xD;
      of improved word-finding abilities following rTMS depends on pre-intervention&#xD;
      language-related brain activity and will examine changes in brain activity in response to&#xD;
      stimulation. A better understanding of how and for whom rTMS works will 1) help to identify&#xD;
      the best candidates for rTMS treatment, 2) optimize rTMS treatment protocols to improve&#xD;
      patient outcomes, and 3) improve the investigators' understanding of how the brain&#xD;
      re-organizes language functions following stroke.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aphasia, an acquired communication disorder, is a common consequence of left-hemisphere&#xD;
      stroke. Persisting, or chronic, aphasia negatively impacts not only interpersonal&#xD;
      communication but participation in activities of daily living, independence, and autonomy. It&#xD;
      is also associated with higher rates of depression and lower quality of life. Therefore,&#xD;
      examining factors and treatments that result in the best possible recovery of language&#xD;
      function for individuals with chronic aphasia is of paramount importance.&#xD;
&#xD;
      An intervention approach that has shown promise in early-phase research on treatment of&#xD;
      chronic aphasia is repetitive transcranial magnetic stimulation (rTMS). rTMS is a&#xD;
      non-invasive brain stimulation technique that can be used to focally modulate activity in&#xD;
      targeted brain regions. Studies have shown that multiple sessions of 1Hz inhibitory rTMS&#xD;
      applied to the right hemisphere Pars Triangularis (PTr) of people with chronic aphasia&#xD;
      results in improved naming abilities. These improvements accrue over time, and may persist&#xD;
      even after rTMS has ended. It has been proposed that rTMS induces this improvement by&#xD;
      reducing the disruptive influence of compensatory activity in the right hemisphere PTr,&#xD;
      allowing for recruitment of more efficient left hemisphere peri-lesional brain areas.&#xD;
      However, existing neuroimaging evidence to support this hypothesis is insufficient.&#xD;
&#xD;
      The goal of the proposed study is to investigate the neurological mechanisms underlying the&#xD;
      effect of rTMS on naming performance in chronic aphasia. This will extend existing knowledge&#xD;
      regarding hemispheric contributions to language recovery following stroke and elucidate how&#xD;
      rTMS-induced neuroplasticity can be co-opted to encourage optimal reorganization. The study&#xD;
      will also investigate a potential source of individual response variability to rTMS, one&#xD;
      which can inform both candidate selection and optimal stimulation parameters. Sixteen&#xD;
      participants will be enrolled, yielding a significantly larger sample size than previous&#xD;
      studies that have examined changes in functional brain activation in response to rTMS (n = 1,&#xD;
      2).&#xD;
&#xD;
      All participants will receive a sequence of 1200 pulses of 1 Hz rTMS to right hemisphere PTr&#xD;
      across 10 daily sessions. Half of the participants will also receive a 6 Hz rTMS excitatory&#xD;
      priming pulse sequence immediately prior to the 1 Hz sequence. This priming sequence ensures&#xD;
      a consistent inhibitory response to the subsequent 1Hz rTMS and will permit an examination of&#xD;
      state-dependent individual response variability.&#xD;
&#xD;
      To evaluate the effect of rTMS over time, participants will undergo functional magnetic&#xD;
      resonance (fMRI) scans at four time points: prior to initiation of rTMS (&quot;baseline&quot;),&#xD;
      immediately following the first rTMS session (&quot;post-rTMS&quot;), following the conclusion of the&#xD;
      rTMS series (&quot;post-treatment&quot;) and at a 2-month follow-up visit. During the scans,&#xD;
      participants will be asked to name pictures, and both patterns of regional naming-related&#xD;
      activation and effective connectivity (directional causal influence between activated brain&#xD;
      regions) will be evaluated at each time point. In addition, naming performance will be&#xD;
      measured via standardized assessments at baseline, post-treatment, and follow-up.&#xD;
&#xD;
      Changes in naming performance will be assessed over time, as a measure of rTMS effectiveness&#xD;
      overall and between groups (priming sequence vs no priming sequence). In addition, changes in&#xD;
      activation and effective connectivity will be correlated with naming improvement to assess&#xD;
      the relative effectiveness of right hemisphere recruitment compared to left hemisphere&#xD;
      peri-lesional recruitment. Overall increases in left hemisphere recruitment are hypothesized&#xD;
      to result in greater improvements. However, the magnitude of left hemisphere recruitment due&#xD;
      to rTMS is expected to depend on baseline levels of right hemisphere PTr activity.&#xD;
&#xD;
      Results from this study will significantly improve the investigator's understanding of the&#xD;
      effects of rTMS on stroke recovery. The results will also inform future studies evaluating&#xD;
      rTMS as an adjunct to behavioral speech-language intervention, augmenting therapeutic gains&#xD;
      from traditional aphasia treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2018</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Participants will be assigned to receive 10 sessions of inhibitory rTMS to right hemisphere pars triangularis (RH PTr), either preceded by a 6 Hz priming rTMS stimulation sequence or not.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Philadelphia Naming Test (PNT) Performance</measure>
    <time_frame>Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up</time_frame>
    <description>The Philadelphia Naming Test is a performance-based measure commonly used to assess naming (word production) ability among adults with aphasia. The minimum raw score is 0 and the maximum is 175 (higher scores reflect more accurate naming/better naming ability).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Comprehensive Aphasia Test (CAT) Performance</measure>
    <time_frame>Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up</time_frame>
    <description>The Comprehensive Aphasia Test is a performance-based measure of language processing across multiple language domains commonly used to assess language-processing ability among adults with aphasia. CAT mean modality T-Score (average of all language subscale T-scores of the Comprehensive Aphasia Test) is a measure of overall aphasia severity. A T-score of 50 reflects mean performance for the CAT normative sample of individuals with aphasia, with a standard deviation of 10 (higher scores reflect better performance/less severe aphasia).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Aphasia, Acquired</condition>
  <arm_group>
    <arm_group_label>Inhibitory only</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Inhibitory 1Hz rTMS will be applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Excitatory primed</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The inhibitory sequence described above will be preceded for each session by priming stimulation which will consist of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Magnetic Stimulation</intervention_name>
    <description>rTMS is a non-invasive brain stimulation technique in which a focal, time-varying magnetic field is applied to a specific brain area to induce neuronal depolarization. rTMS can be used to selectively target a given brain region with a resolution as focal as 0.5 cm3 .Typically, administering a slow (1 Hz) sequence of magnetic pulses via rTMS temporarily reduces cortical excitability in the targeted brain region.</description>
    <arm_group_label>Excitatory primed</arm_group_label>
    <arm_group_label>Inhibitory only</arm_group_label>
    <other_name>rTMS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aphasia due to unilateral left-hemisphere stroke&#xD;
&#xD;
          -  Greater than 6 months post aphasia onset&#xD;
&#xD;
          -  English as a first language&#xD;
&#xD;
          -  No contraindications to MRI or TMS including:&#xD;
&#xD;
               -  pregnancy&#xD;
&#xD;
               -  presence of ferromagnetic substances in the head with the exception of dental&#xD;
                  fillings, stents or aneurysm clips documented to be MRI compatible&#xD;
&#xD;
               -  presence of any implanted devices including cardiac pacemaker, implanted cardiac&#xD;
                  defibrillator, insulin pump, cochlear implant, or drug infusion device&#xD;
&#xD;
               -  history of epilepsy; use of medications that are known to lower seizure threshold&#xD;
&#xD;
               -  severe claustrophobia&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History for progressive neurological disease or premorbid language disorder&#xD;
&#xD;
          -  Presence of severe motor speech disorder&#xD;
&#xD;
          -  Drug or alcohol dependence, or significant mood or behavioral disorder that is not&#xD;
             currently stable or medically managed&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michelle L. Gravier, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15240</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 8, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <results_first_submitted>September 20, 2021</results_first_submitted>
  <results_first_submitted_qc>December 22, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">January 21, 2022</results_first_posted>
  <last_update_submitted>December 16, 2022</last_update_submitted>
  <last_update_submitted_qc>December 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Aphasia</keyword>
  <keyword>Rehabilitation</keyword>
  <keyword>Stroke</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aphasia</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>March 6, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/71/NCT03292471/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 28, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/71/NCT03292471/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Prior to group assignment, participants completed the Comprehensive Aphasia Test to determine aphasia severity, as groups were pseudorandomized on this basis (groups were balanced for average aphasia severity). In addition, participants completed an MRI screener and medical records were reviewed to screen for the presence of contraindications to MRI and/or rTMS.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Inhibitory Only</title>
          <description>Inhibitory 1Hz rTMS was applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
        </group>
        <group group_id="P2">
          <title>Excitatory Primed</title>
          <description>The inhibitory sequence (1Hz rTMS was applied continuously for 1200 pulses) was preceded for each session by priming stimulation which consisted of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Inhibitory Only</title>
          <description>Inhibitory 1Hz rTMS was applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
        </group>
        <group group_id="B2">
          <title>Excitatory Primed</title>
          <description>The inhibitory sequence (1Hz rTMS was applied continuously for 1200 pulses) was preceded for each session by priming stimulation which will consist of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="16"/>
          </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="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </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="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                  </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="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <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="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Aphasia Severity (Comprehensive Aphasia Severity Mean Modality T-Score)</title>
          <description>CAT mean modality T-Score (average of all language subscale T-scores of the Comprehensive Aphasia Test) is a measure of overall aphasia severity. A T-score of 50 reflects mean performance for the CAT normative sample of individuals with aphasia, with a standard deviation of 10 (higher scores reflect better performance/less severe aphasia).</description>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53.56" spread="5.25"/>
                    <measurement group_id="B2" value="53.86" spread="4.29"/>
                    <measurement group_id="B3" value="53.64" spread="4.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Philadelphia Naming Test (PNT) Performance</title>
        <description>The Philadelphia Naming Test is a performance-based measure commonly used to assess naming (word production) ability among adults with aphasia. The minimum raw score is 0 and the maximum is 175 (higher scores reflect more accurate naming/better naming ability).</description>
        <time_frame>Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up</time_frame>
        <population>5 participants in each group were able to return for 2-month follow up testing</population>
        <group_list>
          <group group_id="O1">
            <title>Inhibitory Only</title>
            <description>Inhibitory 1Hz rTMS was applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
          </group>
          <group group_id="O2">
            <title>Excitatory Primed</title>
            <description>The inhibitory sequence (1Hz rTMS was applied continuously for 1200 pulses) was preceded for each session by priming stimulation which will consist of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Philadelphia Naming Test (PNT) Performance</title>
          <description>The Philadelphia Naming Test is a performance-based measure commonly used to assess naming (word production) ability among adults with aphasia. The minimum raw score is 0 and the maximum is 175 (higher scores reflect more accurate naming/better naming ability).</description>
          <population>5 participants in each group were able to return for 2-month follow up testing</population>
          <units>Score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="122.125" spread="27.18"/>
                    <measurement group_id="O2" value="130.875" spread="22.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132.5" spread="28.65"/>
                    <measurement group_id="O2" value="142.125" spread="16.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Follow-up</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="115.6" spread="21.85"/>
                    <measurement group_id="O2" value="133.6" spread="26.84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Baysian Multivariate Analysis of Variance</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Dependent variable: PNT T-score Fixed Effects: Group Assignment (A = Standard, B= Priming), Time point (Pre-treatment, Post-treatment) Random Effects: Participant (intercept and slope) Priors for slope and intercept were set as t-distributions (PNT raw score converted to T-score scale with m = 50, sd = 10 based on sample estimates from Fergadiotis, Hula, &amp; Kellough, 2015)</non_inferiority_desc>
            <param_type>Highest Density Interval of Posterior Di</param_type>
            <param_value>.284</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.07</ci_lower_limit>
            <ci_upper_limit>2.92</ci_upper_limit>
            <estimate_desc>Direction of comparison: Group A (Standard Protocol) and post-treatment timepoint were set as reference values</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Baysian Multivariate Analysis of Variance</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Dependent variable: PNT T-score Fixed Effects: Group Assignment (A = Standard, B= Priming), Time point (Pre-treatment, Follow-up) Random Effects: Participant (intercept and slope) Priors for slope and intercept were set as t-distributions (PNT raw score converted to T-score scale with m = 50, sd = 10 based on sample estimates from Fergadiotis, Hula, &amp; Kellough, 2015)</non_inferiority_desc>
            <param_type>Highest Density Interval of Posterior Di</param_type>
            <param_value>.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.38</ci_lower_limit>
            <ci_upper_limit>2.46</ci_upper_limit>
            <estimate_desc>Direction of comparison: Group A (Standard Protocol) and follow-up (2 months post-treatment) timepoint were set as reference values</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Comprehensive Aphasia Test (CAT) Performance</title>
        <description>The Comprehensive Aphasia Test is a performance-based measure of language processing across multiple language domains commonly used to assess language-processing ability among adults with aphasia. CAT mean modality T-Score (average of all language subscale T-scores of the Comprehensive Aphasia Test) is a measure of overall aphasia severity. A T-score of 50 reflects mean performance for the CAT normative sample of individuals with aphasia, with a standard deviation of 10 (higher scores reflect better performance/less severe aphasia).</description>
        <time_frame>Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up</time_frame>
        <population>5 participants in each group were able to return for follow-up testing</population>
        <group_list>
          <group group_id="O1">
            <title>Inhibitory Only</title>
            <description>Inhibitory 1Hz rTMS was applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
          </group>
          <group group_id="O2">
            <title>Excitatory Primed</title>
            <description>The inhibitory sequence (1Hz rTMS was applied continuously for 1200 pulses) was preceded for each session by priming stimulation which will consist of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Comprehensive Aphasia Test (CAT) Performance</title>
          <description>The Comprehensive Aphasia Test is a performance-based measure of language processing across multiple language domains commonly used to assess language-processing ability among adults with aphasia. CAT mean modality T-Score (average of all language subscale T-scores of the Comprehensive Aphasia Test) is a measure of overall aphasia severity. A T-score of 50 reflects mean performance for the CAT normative sample of individuals with aphasia, with a standard deviation of 10 (higher scores reflect better performance/less severe aphasia).</description>
          <population>5 participants in each group were able to return for follow-up testing</population>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.56" spread="5.25"/>
                    <measurement group_id="O2" value="53.875" spread="4.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.54" spread="5.45"/>
                    <measurement group_id="O2" value="55.71" spread="4.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Follow-up</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.5" spread="4.04"/>
                    <measurement group_id="O2" value="56.7" spread="5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Baysian Multivariate Analysis of Variance</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Dependent variable: CAT Mean-modality T-score Fixed Effects: Group Assignment (A = Standard, B= Priming), Time point (Entry, Exit) Random Effects: Participant (intercept and slope) Priors for slope and intercept were set as t-distributions</non_inferiority_desc>
            <param_type>Highest Density Interval of Posterior Di</param_type>
            <param_value>.997</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.0719</ci_lower_limit>
            <ci_upper_limit>2.25</ci_upper_limit>
            <estimate_desc>Direction of comparison: Group A (Standard Protocol) and post-treatment timepoint were set as reference values</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Baysian Multivariate Analysis of Variance</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Dependent variable: CAT Mean-modality T-score Fixed Effects: Group Assignment (A = Standard, B= Priming), Time-point (Pre-treatment, Post-treatment) Random Effects: Participant (intercept and slope) Priors for slope and intercept were set as t-distributions</non_inferiority_desc>
            <param_type>Highest Density Interval of Posterior Di</param_type>
            <param_value>.443</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.596</ci_lower_limit>
            <ci_upper_limit>1.58</ci_upper_limit>
            <estimate_desc>Direction of comparison: Group A (Standard Protocol) and follow-up (2 months post-treatment) timepoint were set as reference values</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Approximately 3 months</time_frame>
      <desc>An adverse event reporting form was completed at each assessment and treatment visit</desc>
      <group_list>
        <group group_id="E1">
          <title>Inhibitory Only</title>
          <description>Inhibitory 1Hz rTMS was applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).</description>
        </group>
        <group group_id="E2">
          <title>Excitatory Primed</title>
          <description>The inhibitory sequence (1Hz rTMS was applied continuously for 1200 pulses) was preceded for each session by priming stimulation which consisted of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Mild Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="8"/>
              </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>
    <limitations_and_caveats>Unable to collect all planned functional MRI data due to technical difficulties/scanner out of service.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Michelle Gravier</name_or_title>
      <organization>VA Pittsburgh/California State University, East Bay</organization>
      <phone>510 885-3215</phone>
      <email>michelle.gravier@csueastbay.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/NCT03292471
org study id: B2566-P
secondary id: I21RX002566-01A1
nct id: NCT03292471
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
is us export: No
This study will investigate the use of repetitive transcranial magnetic stimulation (rTMS), a
      non-invasive brain stimulation method, to improve word-finding abilities in Veterans and
      non-Veterans with chronic language problems following stroke (aphasia). Improving
      word-finding is important because word-finding difficulties are among the most common and
      debilitating consequences of aphasia. Although rTMS has shown promise as a treatment
      approach, not all individuals with aphasia show the same level of benefit. Specifically, this
      study will use functional magnetic resonance imaging (fMRI) to examine whether the likelihood
      of improved word-finding abilities following rTMS depends on pre-intervention
      language-related brain activity and will examine changes in brain activity in response to
      stimulation. A better understanding of how and for whom rTMS works will 1) help to identify
      the best candidates for rTMS treatment, 2) optimize rTMS treatment protocols to improve
      patient outcomes, and 3) improve the investigators' understanding of how the brain
      re-organizes language functions following stroke.
Aphasia, an acquired communication disorder, is a common consequence of left-hemisphere
      stroke. Persisting, or chronic, aphasia negatively impacts not only interpersonal
      communication but participation in activities of daily living, independence, and autonomy. It
      is also associated with higher rates of depression and lower quality of life. Therefore,
      examining factors and treatments that result in the best possible recovery of language
      function for individuals with chronic aphasia is of paramount importance.

      An intervention approach that has shown promise in early-phase research on treatment of
      chronic aphasia is repetitive transcranial magnetic stimulation (rTMS). rTMS is a
      non-invasive brain stimulation technique that can be used to focally modulate activity in
      targeted brain regions. Studies have shown that multiple sessions of 1Hz inhibitory rTMS
      applied to the right hemisphere Pars Triangularis (PTr) of people with chronic aphasia
      results in improved naming abilities. These improvements accrue over time, and may persist
      even after rTMS has ended. It has been proposed that rTMS induces this improvement by
      reducing the disruptive influence of compensatory activity in the right hemisphere PTr,
      allowing for recruitment of more efficient left hemisphere peri-lesional brain areas.
      However, existing neuroimaging evidence to support this hypothesis is insufficient.

      The goal of the proposed study is to investigate the neurological mechanisms underlying the
      effect of rTMS on naming performance in chronic aphasia. This will extend existing knowledge
      regarding hemispheric contributions to language recovery following stroke and elucidate how
      rTMS-induced neuroplasticity can be co-opted to encourage optimal reorganization. The study
      will also investigate a potential source of individual response variability to rTMS, one
      which can inform both candidate selection and optimal stimulation parameters. Sixteen
      participants will be enrolled, yielding a significantly larger sample size than previous
      studies that have examined changes in functional brain activation in response to rTMS (n = 1,
      2).

      All participants will receive a sequence of 1200 pulses of 1 Hz rTMS to right hemisphere PTr
      across 10 daily sessions. Half of the participants will also receive a 6 Hz rTMS excitatory
      priming pulse sequence immediately prior to the 1 Hz sequence. This priming sequence ensures
      a consistent inhibitory response to the subsequent 1Hz rTMS and will permit an examination of
      state-dependent individual response variability.

      To evaluate the effect of rTMS over time, participants will undergo functional magnetic
      resonance (fMRI) scans at four time points: prior to initiation of rTMS ("baseline"),
      immediately following the first rTMS session ("post-rTMS"), following the conclusion of the
      rTMS series ("post-treatment") and at a 2-month follow-up visit. During the scans,
      participants will be asked to name pictures, and both patterns of regional naming-related
      activation and effective connectivity (directional causal influence between activated brain
      regions) will be evaluated at each time point. In addition, naming performance will be
      measured via standardized assessments at baseline, post-treatment, and follow-up.

      Changes in naming performance will be assessed over time, as a measure of rTMS effectiveness
      overall and between groups (priming sequence vs no priming sequence). In addition, changes in
      activation and effective connectivity will be correlated with naming improvement to assess
      the relative effectiveness of right hemisphere recruitment compared to left hemisphere
      peri-lesional recruitment. Overall increases in left hemisphere recruitment are hypothesized
      to result in greater improvements. However, the magnitude of left hemisphere recruitment due
      to rTMS is expected to depend on baseline levels of right hemisphere PTr activity.

      Results from this study will significantly improve the investigator's understanding of the
      effects of rTMS on stroke recovery. The results will also inform future studies evaluating
      rTMS as an adjunct to behavioral speech-language intervention, augmenting therapeutic gains
      from traditional aphasia treatment.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants will be assigned to receive 10 sessions of inhibitory rTMS to right hemisphere pars triangularis (RH PTr), either preceded by a 6 Hz priming rTMS stimulation sequence or not.
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Change in Philadelphia Naming Test (PNT) Performance
time frame: Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up
description: The Philadelphia Naming Test is a performance-based measure commonly used to assess naming (word production) ability among adults with aphasia. The minimum raw score is 0 and the maximum is 175 (higher scores reflect more accurate naming/better naming ability).
measure: Change in Comprehensive Aphasia Test (CAT) Performance
time frame: Pre- to post treatment (an average of 3 weeks), and at 2 month follow-up
description: The Comprehensive Aphasia Test is a performance-based measure of language processing across multiple language domains commonly used to assess language-processing ability among adults with aphasia. CAT mean modality T-Score (average of all language subscale T-scores of the Comprehensive Aphasia Test) is a measure of overall aphasia severity. A T-score of 50 reflects mean performance for the CAT normative sample of individuals with aphasia, with a standard deviation of 10 (higher scores reflect better performance/less severe aphasia).
arm group label: Inhibitory only
arm group type: Experimental
description: Inhibitory 1Hz rTMS will be applied continuously for 1200 pulses (20 minutes) 5 days per week across 2 weeks (10 sessions total).
arm group label: Excitatory primed
arm group type: Experimental
description: The inhibitory sequence described above will be preceded for each session by priming stimulation which will consist of intermittent 6-Hz rTMS applied in 5 second trains with 25 second intervals between trains for a total 600 pulses (10 minutes).
intervention type: Device
intervention name: Transcranial Magnetic Stimulation
description: rTMS is a non-invasive brain stimulation technique in which a focal, time-varying magnetic field is applied to a specific brain area to induce neuronal depolarization. rTMS can be used to selectively target a given brain region with a resolution as focal as 0.5 cm3 .Typically, administering a slow (1 Hz) sequence of magnetic pulses via rTMS temporarily reduces cortical excitability in the targeted brain region.
arm group label: Excitatory primed
arm group label: Inhibitory only
other name: rTMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michelle L. Gravier, PhD
role: Principal Investigator
affiliation: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
facility: 
country: United States
responsible party type: Sponsor
mesh term: Aphasia
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Unable to collect all planned functional MRI data due to technical difficulties/scanner out of service.
point of contact: 