<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/NCT04486586</url>
  </required_header>
  <id_info>
    <org_study_id>NA_00071337-2</org_study_id>
    <nct_id>NCT04486586</nct_id>
  </id_info>
  <brief_title>Effects of tDCS on Apraxia of Speech in Non-Fluent Primary Progressive Aphasia</brief_title>
  <official_title>Effects of Transcranial Direct Current Stimulation in Primary Progressive Aphasia (PPA)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johns Hopkins University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary progressive aphasia (PPA) is a neurodegenerative disease that affects first and&#xD;
      foremost language abilities. There are three different variants of PPA, each a relatively&#xD;
      distinct speech and language profile. For individuals with non-fluent variant PPA (nfvPPA), a&#xD;
      core symptom is apraxia of speech (AOS), which is defined as an oral motor speech disorder.&#xD;
      Such a disorder inhibits one's ability to translate speech plans into motor plans and results&#xD;
      in longer segmental durations and reduced rate of syllabic production.&#xD;
&#xD;
      This research project investigates the behavioral and neuromodulatory effects of transcranial&#xD;
      direct current stimulation (tDCS) during language therapy in participants with nfvPPA over&#xD;
      time. Anodal tDCS targeting the left inferior frontal gyrus (IFG) administered in combination&#xD;
      with language therapy is expected to be more beneficial when compared to language therapy&#xD;
      alone (sham). The investigators believe tDCS during language therapy will 1) improve language&#xD;
      performance or decrease rate of decline, 2) promote better-sustained effects at 2 weeks and 2&#xD;
      months post-treatment, and 3) produce generalization to untrained language items and some&#xD;
      other cognitive functions. Resting-state fMRI, diffusion tensor imaging (DTI), and volumetric&#xD;
      data are also collected to investigate changes in functional brain connectivity associated&#xD;
      with tDCS in individuals with PPA.&#xD;
&#xD;
      A better understanding of the therapeutic and neuromodulatory mechanisms of tDCS as an&#xD;
      adjunct to language therapy in nfvPPA may have a significant impact on the development of&#xD;
      effective therapies for PPA, and may offer insight into ways of impeding neurodegeneration&#xD;
      that may improve patients' quality of life, as well as extend patients' ability to work and&#xD;
      manage patients' affairs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A. Evaluation Tasks&#xD;
&#xD;
      Language Tasks:&#xD;
&#xD;
      Participants will be administered baseline language and cognitive tasks, including 1 or more&#xD;
      of the following, depending on participants' residual language and cognitive skills:&#xD;
&#xD;
      a) writing to dictation b) oral spelling c) oral and written naming of pictures d)&#xD;
      word-picture matching f) written and oral picture description g) digit span h) spatial span&#xD;
      i) verbal learning j) grammatical sentence production k) oral word repetition l) sentence&#xD;
      comprehension&#xD;
&#xD;
      Quality of Life questionnaires:&#xD;
&#xD;
      Participants will be administered standardized and non-standardized quality-of-life&#xD;
      questionnaires before, after, and at follow-up intervals of each experimental period. The&#xD;
      purpose of these questionnaires is to assess whether the proposed interventions have affected&#xD;
      participants' well-being and the general quality of participants' life.&#xD;
&#xD;
      B. AOS Intervention&#xD;
&#xD;
      Intervention involves oral word repetition of increasingly complex words. The goal is to&#xD;
      improve volitional control of participants' articulators in order to produce co-articulated,&#xD;
      intelligible speech, as well as improve prosody, voice quality, and speech fluency.&#xD;
&#xD;
      C. Assessment of Language Therapy Tasks:&#xD;
&#xD;
      Follow-up assessments will probe all sets of increasingly complex words targeted in&#xD;
      intervention and as well as word sets not targeted in intervention to assess near-transfer&#xD;
      generalization. Other language and cognitive tasks will be assessed for far-transfer&#xD;
      generalization. Differences in baseline measures in pre- and post-intervention accuracy for&#xD;
      word production for each patient will be evaluated using the following: percentages of total&#xD;
      number of words correct, arithmetic differences between percentage scores, and permutation&#xD;
      tests (Pearson's chi-square test; Fisher's exact test).&#xD;
&#xD;
      C. tDCS Methods:&#xD;
&#xD;
      Participants will take part in 10-15 consecutive training sessions (3-5 per week), separated&#xD;
      by 2 months. Anodal tDCS has typically been shown to up-regulate neuronal excitability and&#xD;
      produce enhancement of behavioral performance. A Soterix-CT device will be delivering current&#xD;
      at an intensity of 1-2 mA (estimated current density 0.04 mA/cm^2; estimated total charge&#xD;
      0.048 C/cm^2) for a maximum of 20 minutes in the tDCS groups and for a maximum of 30 seconds&#xD;
      in the Sham group. For both interventions (tDCS and Sham) the electrical current will be&#xD;
      increased in a ramp-like fashion at the onset of the stimulation eliciting a transient&#xD;
      tingling sensation on the scalp that usually disappears over seconds.&#xD;
&#xD;
      D. Imaging Methods:&#xD;
&#xD;
      Imaging will be performed at the beginning of enrollment, before and after each 12-to-15-day&#xD;
      tDCS treatment, and at follow-up intervals for up to 8 time points per individual on a 3T&#xD;
      Philips system, and will consist of resting-state fMRI (rsfMRI), MPRAGE, and diffusion tensor&#xD;
      imaging (DTI). Each scanning session will last approximately 1 hour.&#xD;
&#xD;
      E. Statistical Analyses:&#xD;
&#xD;
      In the within-subject crossover protocol, each participant will be administered two&#xD;
      experimental conditions: IFG tDCS+language (tDCS intervention) and IFG sham+language (sham&#xD;
      treatment). All analyses, behavioral and imaging, will be under the oversight of the study&#xD;
      statisticians.&#xD;
&#xD;
      F. Study duration and number of study visits required of research participants.&#xD;
&#xD;
      Before any intervention, participants will be randomly assigned to either sham or tDCS&#xD;
      experimental conditions. After 1-3 weeks of tDCS application (3-5 sessions in a week, 10-15&#xD;
      sessions per stimulation site) there will be an interval of approximately 2 months and then&#xD;
      the investigators will implement the other two tDCS conditions in a within-subject cross-over&#xD;
      design. Participants will be followed-up at 2-week and 2-month follow-up intervals.&#xD;
&#xD;
      G. Blinding, including justification for blinding or not blinding the trial, if applicable.&#xD;
&#xD;
      Participants will be blinded to the application of anodal or sham tDCS. To achieve blinding,&#xD;
      all participants will be fitted with the tDCS electrodes placed over the left inferior&#xD;
      frontal gyrus (IFG). The Soterix-CT device will be used for double-blinding purposes.&#xD;
&#xD;
      H. Justification of why participants will not receive routine care or will have current&#xD;
      therapy stopped&#xD;
&#xD;
      Participation in this study will not disrupt any current care or therapy.&#xD;
&#xD;
      I. Justification for inclusion of a placebo or non-treatment group&#xD;
&#xD;
      All participants will undergo active and sham conditions, thus serving as participants' own&#xD;
      control.&#xD;
&#xD;
      J. Definition of treatment failure or participant removal criteria&#xD;
&#xD;
      Participants will be removed from the study if participants are unable to comply with task&#xD;
      instructions or tolerate the tDCS procedure.&#xD;
&#xD;
      K. Description of what happens to participants receiving therapy when study ends or if a&#xD;
      participant's participation in the study ends prematurely&#xD;
&#xD;
      When the study ends participants will continue to receive management with participants'&#xD;
      neurologist as usual. If a patient's participation in the study ends prematurely s/he will&#xD;
      still receive care as before. In sum, termination of the study or termination of&#xD;
      participation in it will not affect regular therapy he or she may be receiving.&#xD;
&#xD;
      L. Qualification of investigators:&#xD;
&#xD;
      The principal investigator (PI) and co-investigators have extensive research and clinical&#xD;
      experience with all study tasks: behavioral language therapy (including AOS intervention).&#xD;
      The investigators have already published tDCS studies showing positive results in spelling.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 2013</start_date>
  <completion_date type="Anticipated">April 2025</completion_date>
  <primary_completion_date type="Anticipated">April 2025</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in segmental duration of vowels of trained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Duration of vowels for trained words (practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in segmental duration of vowels of untrained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Duration of vowels for untrained words (not practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in segmental duration of consonants of trained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Duration of consonants for trained words (practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in segmental duration of consonants of untrained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Duration of consonants for untrained words (not practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in speech fluency on trained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Speech fluency will be measured on trained words (practiced in therapy) using the mean log of sound duration collected via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Lower log duration indicates faster speech production. A decrease in sound duration is considered a benefit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in speech fluency on untrained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Speech fluency will be measured on untrained words (not practiced in therapy) using the mean log of sound duration collected via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Lower log duration indicates faster speech production. A decrease in sound duration is considered a benefit.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in prosody/intonation of trained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Prosody/intonation for trained words (practiced in therapy) will be measured using mean fundamental frequency (F0), which is frequency at which vocal folds vibrate in voiced sounds. Such measurements will come from acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Consistency over time is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in prosody/intonation of untrained words</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Prosody/intonation for untrained words (not practiced in therapy) will be measured using mean fundamental frequency (f0), which is frequency at which vocal folds vibrate in voiced sounds. Such measurements will come from acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Consistency over time is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>The 40-item Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery of various sub-tests will be used to assess argument structure comprehension and production. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in verbal fluency task score</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Verbal fluency tasks (semantic and letter fluency) involve generating as many words as possible in one minute. Scoring will be based on number of words generated per minute. The investigators will compute the raw score of items correct and subsequently the percent difference between before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in semantic content of connected speech</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Using the Cookie Theft image from the Boston Diagnostic Aphasia Examination (BDAE) and the Circus image from the Apraxia Battery for Adults (ABA) investigators will obtain representative language samples as participants describe the images. The investigators will compute the raw score of items (semantics) correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oral naming Boston Naming Test score</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>The Boston Naming Test is a widely used picture naming test that detects lexical retrieval deficits in the oral modality. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Accuracy in oral naming of actions will be assessed using HANA. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in digit span forward score</measure>
    <time_frame>Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention</time_frame>
    <description>Digit span forward involves the recall of a series of single digits (sets of 1-8 digits) in the same order the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in digit span backward score</measure>
    <time_frame>Before intervention, immediately after intervention, 1 month post intervention and 3 months post intervention</time_frame>
    <description>Digit span backward involves the recall of a series of single digits (sets of 1-8 digits) in the reverse order than the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in volumetric measurements of select brain regions</measure>
    <time_frame>Before intervention, immediately after intervention and 3 months post intervention</time_frame>
    <description>Using Magnetization-Prepared Rapid Gradient-Echo (MPRAGE) Magnetic Resonance Imaging (MRI) investigators will perform volumetric measurements of select brain regions. Measurements will be collected in millimeters cubed (mm^3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in anisotropy of white matter tracts of select brain regions</measure>
    <time_frame>Before intervention, immediately after intervention and 3 months post intervention</time_frame>
    <description>Using Diffusion Weighted/Diffusion Tensor Imaging (DWI/DTI) investigators will estimate the anisotropy of the brain's white matter tracts on the brain regions of concern.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in location of white matter tracts of select brain regions</measure>
    <time_frame>Before intervention, immediately after intervention and 3 months post intervention</time_frame>
    <description>Using Diffusion Weighted/Diffusion Tensor Imaging (DWI/DTI) investigators will estimate the location of the brain's white matter tracts on the regions of concern.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Primary Progressive Aphasia</condition>
  <arm_group>
    <arm_group_label>Active tDCS plus Speech-Language Therapy first</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Active tDCS will be applied at the beginning of 45 minutes speech-language therapy session and then participant will be switched to sham tDCS after a washout period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham plus Speech-Language Therapy first</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham will be applied at the beginning of 45 minutes speech-language therapy session and then participant will be switched to an active tDCS after a washout period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Active tDCS plus Speech-Language Therapy</intervention_name>
    <description>Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (inferior frontal gyrus). The stimulation will be delivered at an intensity of 2 mA (estimated current density 0.04 mA/cm^2; estimated total charge 0.048 C/cm^2) in a ramp-like fashion for a maximum of 20 minutes. Speech-language therapy will target apraxia of speech (AOS).</description>
    <arm_group_label>Active tDCS plus Speech-Language Therapy first</arm_group_label>
    <arm_group_label>Sham plus Speech-Language Therapy first</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham plus Speech-Language Therapy</intervention_name>
    <description>Speech-language therapy will be administered during sham stimulation. Current will be administered in a ramp-line fashion but after the ramping the intensity will drop to 0 mA. Speech-language therapy will target apraxia of speech (AOS).</description>
    <arm_group_label>Active tDCS plus Speech-Language Therapy first</arm_group_label>
    <arm_group_label>Sham plus Speech-Language Therapy first</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must be clinically diagnosed with nfvPPA or unclassifiable PPA. Diagnosis will be&#xD;
             based on neuropsychological testing, language testing (most commonly the Western&#xD;
             Aphasia Battery), MRI and clinical assessment.&#xD;
&#xD;
          -  Must be right-handed.&#xD;
&#xD;
          -  Must be speaker of English.&#xD;
&#xD;
          -  Must have at least 9th grade education.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncorrected visual or hearing impairment by self report.&#xD;
&#xD;
          -  Stroke/other premorbid neurological disorder affecting the brain.&#xD;
&#xD;
          -  Any other language-based learning disorder other than PPA.&#xD;
&#xD;
          -  Inability to follow directions for baseline tasks.&#xD;
&#xD;
          -  Western Aphasia Battery Aphasia Quotient (AQ) &lt;30 (indicating severe language&#xD;
             impairment).&#xD;
&#xD;
        Exclusion Criteria for MRI Participation:&#xD;
&#xD;
          -  Severe claustrophobia.&#xD;
&#xD;
          -  Cardiac pacemakers or ferromagnetic implants.&#xD;
&#xD;
          -  Pregnant women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kyrana Tsapkini, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kyrana Tsapkini, PhD</last_name>
    <phone>410-736-2940</phone>
    <email>tsapkini@jhmi.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kelly Williamson, MS</last_name>
    <email>kwill261@jh.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kyrana Tsapkini, PhD</last_name>
      <phone>410-736-2940</phone>
      <email>tsapkini@jhmi.edu</email>
    </contact>
    <contact_backup>
      <last_name>Olivia Herrmann, MS</last_name>
      <email>oherrma1@jh.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Argye Hillis, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2020</study_first_posted>
  <last_update_submitted>June 15, 2023</last_update_submitted>
  <last_update_submitted_qc>June 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>transcranial direct current stimulation (tDCS)</keyword>
  <keyword>neurodegeneration</keyword>
  <keyword>language therapy</keyword>
  <keyword>primary progressive aphasia (PPA)</keyword>
  <keyword>apraxia of speech (AOS)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aphasia</mesh_term>
    <mesh_term>Aphasia, Primary Progressive</mesh_term>
    <mesh_term>Pick Disease of the Brain</mesh_term>
    <mesh_term>Frontotemporal Dementia</mesh_term>
  </condition_browse>
  <!-- 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/NCT04486586
org study id: NA_00071337-2
nct id: NCT04486586
lead sponsor: 
is fda regulated drug: No
is fda regulated device: Yes
Primary progressive aphasia (PPA) is a neurodegenerative disease that affects first and
      foremost language abilities. There are three different variants of PPA, each a relatively
      distinct speech and language profile. For individuals with non-fluent variant PPA (nfvPPA), a
      core symptom is apraxia of speech (AOS), which is defined as an oral motor speech disorder.
      Such a disorder inhibits one's ability to translate speech plans into motor plans and results
      in longer segmental durations and reduced rate of syllabic production.

      This research project investigates the behavioral and neuromodulatory effects of transcranial
      direct current stimulation (tDCS) during language therapy in participants with nfvPPA over
      time. Anodal tDCS targeting the left inferior frontal gyrus (IFG) administered in combination
      with language therapy is expected to be more beneficial when compared to language therapy
      alone (sham). The investigators believe tDCS during language therapy will 1) improve language
      performance or decrease rate of decline, 2) promote better-sustained effects at 2 weeks and 2
      months post-treatment, and 3) produce generalization to untrained language items and some
      other cognitive functions. Resting-state fMRI, diffusion tensor imaging (DTI), and volumetric
      data are also collected to investigate changes in functional brain connectivity associated
      with tDCS in individuals with PPA.

      A better understanding of the therapeutic and neuromodulatory mechanisms of tDCS as an
      adjunct to language therapy in nfvPPA may have a significant impact on the development of
      effective therapies for PPA, and may offer insight into ways of impeding neurodegeneration
      that may improve patients' quality of life, as well as extend patients' ability to work and
      manage patients' affairs.
A. Evaluation Tasks

      Language Tasks:

      Participants will be administered baseline language and cognitive tasks, including 1 or more
      of the following, depending on participants' residual language and cognitive skills:

      a) writing to dictation b) oral spelling c) oral and written naming of pictures d)
      word-picture matching f) written and oral picture description g) digit span h) spatial span
      i) verbal learning j) grammatical sentence production k) oral word repetition l) sentence
      comprehension

      Quality of Life questionnaires:

      Participants will be administered standardized and non-standardized quality-of-life
      questionnaires before, after, and at follow-up intervals of each experimental period. The
      purpose of these questionnaires is to assess whether the proposed interventions have affected
      participants' well-being and the general quality of participants' life.

      B. AOS Intervention

      Intervention involves oral word repetition of increasingly complex words. The goal is to
      improve volitional control of participants' articulators in order to produce co-articulated,
      intelligible speech, as well as improve prosody, voice quality, and speech fluency.

      C. Assessment of Language Therapy Tasks:

      Follow-up assessments will probe all sets of increasingly complex words targeted in
      intervention and as well as word sets not targeted in intervention to assess near-transfer
      generalization. Other language and cognitive tasks will be assessed for far-transfer
      generalization. Differences in baseline measures in pre- and post-intervention accuracy for
      word production for each patient will be evaluated using the following: percentages of total
      number of words correct, arithmetic differences between percentage scores, and permutation
      tests (Pearson's chi-square test; Fisher's exact test).

      C. tDCS Methods:

      Participants will take part in 10-15 consecutive training sessions (3-5 per week), separated
      by 2 months. Anodal tDCS has typically been shown to up-regulate neuronal excitability and
      produce enhancement of behavioral performance. A Soterix-CT device will be delivering current
      at an intensity of 1-2 mA (estimated current density 0.04 mA/cm^2; estimated total charge
      0.048 C/cm^2) for a maximum of 20 minutes in the tDCS groups and for a maximum of 30 seconds
      in the Sham group. For both interventions (tDCS and Sham) the electrical current will be
      increased in a ramp-like fashion at the onset of the stimulation eliciting a transient
      tingling sensation on the scalp that usually disappears over seconds.

      D. Imaging Methods:

      Imaging will be performed at the beginning of enrollment, before and after each 12-to-15-day
      tDCS treatment, and at follow-up intervals for up to 8 time points per individual on a 3T
      Philips system, and will consist of resting-state fMRI (rsfMRI), MPRAGE, and diffusion tensor
      imaging (DTI). Each scanning session will last approximately 1 hour.

      E. Statistical Analyses:

      In the within-subject crossover protocol, each participant will be administered two
      experimental conditions: IFG tDCS+language (tDCS intervention) and IFG sham+language (sham
      treatment). All analyses, behavioral and imaging, will be under the oversight of the study
      statisticians.

      F. Study duration and number of study visits required of research participants.

      Before any intervention, participants will be randomly assigned to either sham or tDCS
      experimental conditions. After 1-3 weeks of tDCS application (3-5 sessions in a week, 10-15
      sessions per stimulation site) there will be an interval of approximately 2 months and then
      the investigators will implement the other two tDCS conditions in a within-subject cross-over
      design. Participants will be followed-up at 2-week and 2-month follow-up intervals.

      G. Blinding, including justification for blinding or not blinding the trial, if applicable.

      Participants will be blinded to the application of anodal or sham tDCS. To achieve blinding,
      all participants will be fitted with the tDCS electrodes placed over the left inferior
      frontal gyrus (IFG). The Soterix-CT device will be used for double-blinding purposes.

      H. Justification of why participants will not receive routine care or will have current
      therapy stopped

      Participation in this study will not disrupt any current care or therapy.

      I. Justification for inclusion of a placebo or non-treatment group

      All participants will undergo active and sham conditions, thus serving as participants' own
      control.

      J. Definition of treatment failure or participant removal criteria

      Participants will be removed from the study if participants are unable to comply with task
      instructions or tolerate the tDCS procedure.

      K. Description of what happens to participants receiving therapy when study ends or if a
      participant's participation in the study ends prematurely

      When the study ends participants will continue to receive management with participants'
      neurologist as usual. If a patient's participation in the study ends prematurely s/he will
      still receive care as before. In sum, termination of the study or termination of
      participation in it will not affect regular therapy he or she may be receiving.

      L. Qualification of investigators:

      The principal investigator (PI) and co-investigators have extensive research and clinical
      experience with all study tasks: behavioral language therapy (including AOS intervention).
      The investigators have already published tDCS studies showing positive results in spelling.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
measure: Change in segmental duration of vowels of trained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Duration of vowels for trained words (practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.
measure: Change in segmental duration of vowels of untrained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Duration of vowels for untrained words (not practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.
measure: Change in segmental duration of consonants of trained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Duration of consonants for trained words (practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.
measure: Change in segmental duration of consonants of untrained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Duration of consonants for untrained words (not practiced in therapy) will be measured in milliseconds (ms) via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Decrease in duration is considered a benefit.
measure: Change in speech fluency on trained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Speech fluency will be measured on trained words (practiced in therapy) using the mean log of sound duration collected via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Lower log duration indicates faster speech production. A decrease in sound duration is considered a benefit.
measure: Change in speech fluency on untrained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Speech fluency will be measured on untrained words (not practiced in therapy) using the mean log of sound duration collected via acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Lower log duration indicates faster speech production. A decrease in sound duration is considered a benefit.
measure: Change in prosody/intonation of trained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Prosody/intonation for trained words (practiced in therapy) will be measured using mean fundamental frequency (F0), which is frequency at which vocal folds vibrate in voiced sounds. Such measurements will come from acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Consistency over time is considered a benefit.
measure: Change in prosody/intonation of untrained words
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Prosody/intonation for untrained words (not practiced in therapy) will be measured using mean fundamental frequency (f0), which is frequency at which vocal folds vibrate in voiced sounds. Such measurements will come from acoustic analyses. Investigators will compute the change in outcome over time: before intervention versus each time point after. Consistency over time is considered a benefit.
measure: Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: The 40-item Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery of various sub-tests will be used to assess argument structure comprehension and production. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in verbal fluency task score
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Verbal fluency tasks (semantic and letter fluency) involve generating as many words as possible in one minute. Scoring will be based on number of words generated per minute. The investigators will compute the raw score of items correct and subsequently the percent difference between before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in semantic content of connected speech
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Using the Cookie Theft image from the Boston Diagnostic Aphasia Examination (BDAE) and the Circus image from the Apraxia Battery for Adults (ABA) investigators will obtain representative language samples as participants describe the images. The investigators will compute the raw score of items (semantics) correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in oral naming Boston Naming Test score
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: The Boston Naming Test is a widely used picture naming test that detects lexical retrieval deficits in the oral modality. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Accuracy in oral naming of actions will be assessed using HANA. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in digit span forward score
time frame: Before intervention, immediately after intervention, 2 weeks post intervention and 2 months post intervention
description: Digit span forward involves the recall of a series of single digits (sets of 1-8 digits) in the same order the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in digit span backward score
time frame: Before intervention, immediately after intervention, 1 month post intervention and 3 months post intervention
description: Digit span backward involves the recall of a series of single digits (sets of 1-8 digits) in the reverse order than the digits were presented. Scoring will be based on the number of consecutive digits correctly recalled. The investigators will compute the change in outcome between the time point before intervention and each time point after. Increase in score is considered a benefit.
measure: Change in volumetric measurements of select brain regions
time frame: Before intervention, immediately after intervention and 3 months post intervention
description: Using Magnetization-Prepared Rapid Gradient-Echo (MPRAGE) Magnetic Resonance Imaging (MRI) investigators will perform volumetric measurements of select brain regions. Measurements will be collected in millimeters cubed (mm^3).
measure: Change in anisotropy of white matter tracts of select brain regions
time frame: Before intervention, immediately after intervention and 3 months post intervention
description: Using Diffusion Weighted/Diffusion Tensor Imaging (DWI/DTI) investigators will estimate the anisotropy of the brain's white matter tracts on the brain regions of concern.
measure: Change in location of white matter tracts of select brain regions
time frame: Before intervention, immediately after intervention and 3 months post intervention
description: Using Diffusion Weighted/Diffusion Tensor Imaging (DWI/DTI) investigators will estimate the location of the brain's white matter tracts on the regions of concern.
arm group label: Active tDCS plus Speech-Language Therapy first
arm group type: Experimental
description: Active tDCS will be applied at the beginning of 45 minutes speech-language therapy session and then participant will be switched to sham tDCS after a washout period.
arm group label: Sham plus Speech-Language Therapy first
arm group type: Sham Comparator
description: Sham will be applied at the beginning of 45 minutes speech-language therapy session and then participant will be switched to an active tDCS after a washout period.
intervention type: Device
intervention name: Active tDCS plus Speech-Language Therapy
description: Stimulation will be delivered by a battery-driven constant current stimulator. The electrical current will be administered to a pre-specified region of the brain (inferior frontal gyrus). The stimulation will be delivered at an intensity of 2 mA (estimated current density 0.04 mA/cm^2; estimated total charge 0.048 C/cm^2) in a ramp-like fashion for a maximum of 20 minutes. Speech-language therapy will target apraxia of speech (AOS).
arm group label: Active tDCS plus Speech-Language Therapy first
arm group label: Sham plus Speech-Language Therapy first
intervention type: Device
intervention name: Sham plus Speech-Language Therapy
description: Speech-language therapy will be administered during sham stimulation. Current will be administered in a ramp-line fashion but after the ramping the intensity will drop to 0 mA. Speech-language therapy will target apraxia of speech (AOS).
arm group label: Active tDCS plus Speech-Language Therapy first
arm group label: Sham plus Speech-Language Therapy first
criteria: 
gender: All
minimum age: 50 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kyrana Tsapkini, PhD
role: Principal Investigator
affiliation: Johns Hopkins University
last name: Kyrana Tsapkini, PhD
phone: 410-736-2940
email: tsapkini@jhmi.edu
last name: Kelly Williamson, MS
email: kwill261@jh.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Aphasia
mesh term: Aphasia, Primary Progressive
mesh term: Pick Disease of the Brain
mesh term: Frontotemporal Dementia