<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/NCT03796936</url>
  </required_header>
  <id_info>
    <org_study_id>WRNMMC-2018-0201</org_study_id>
    <nct_id>NCT03796936</nct_id>
  </id_info>
  <brief_title>3MDR to Treat PTSD With mTBI (3MDR)</brief_title>
  <acronym>3MDR</acronym>
  <official_title>Clinical Trial of 3MDR to Treat PTSD With mTBI, With and Without Eye Movement (3MDR)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Walter Reed National Military Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Uniformed Services University of the Health Sciences</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Walter Reed National Military Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background and Purpose: Posttraumatic stress disorder (PTSD) and mild traumatic brain injury&#xD;
      (mTBI) are persistent and frequently comorbid complications of recent combat. There is no&#xD;
      proven treatment for mTBI, and standard treatments for PTSD frequently achieve only&#xD;
      transient, modest impact. Motion-assisted, Multi-modular Memory Desensitization and&#xD;
      Reconsolidation (3MDR) is a novel treatment for PTSD combining aspects of virtual reality&#xD;
      exposure therapy (VRET) and Eye Movement Desensitization and Reprocessing (EMDR), within the&#xD;
      Computer Assisted Rehabilitation Environment (CAREN). The added benefit of the eye movement&#xD;
      (EM) component of EMDR is controversial; the purpose of this pilot study is therefore to: 1)&#xD;
      obtain an initial estimate of the efficacy of 3MDR in service members with comorbid PTSD and&#xD;
      mTBI, and 2) determine the impact of EM on treatment response. The investigators hypothesize&#xD;
      that 3MDR will significantly improve symptom severity, both with and without EM.&#xD;
&#xD;
      Population: Participants will be active or retired service members with a history of mTBI who&#xD;
      meet criteria for probable PTSD on the PCL5. It is anticipated that participants will be&#xD;
      recruited through the Center for Neuroscience and Regenerative Medicine (CNRM) Recruitment&#xD;
      Core and the National Intrepid Center of Excellence (NICoE).&#xD;
&#xD;
      Design type and procedures: This is a pilot, controlled clinical trial in which all 20&#xD;
      participants with comorbid PTSD and mTBI receive 10 sessions (3 preparatory, 6 3MDR&#xD;
      treatment, and 1 conclusion), but will be randomized to either include EM (EM+) or not (EM-).&#xD;
      In the preparatory sessions, the therapist will help each participant select 2 songs and 14&#xD;
      pictures to be used in their treatment sessions. The therapist will help the participant rate&#xD;
      the pictures from least to most impactful. Each 3MDR treatment session will start by playing&#xD;
      the first song, to bring them back to the time of their trauma. This will be done while the&#xD;
      participant walks on the CAREN's embedded treadmill through the 3MDR virtual environment (VE)&#xD;
      projected onto the system's curved screen. This is followed by a display of one of their&#xD;
      pictures, a manifestation of their trauma, which they directly face and walk down a hallway&#xD;
      toward, until the picture looms before them. The therapist, standing next to the participant&#xD;
      along the treadmill's edge, will query the participant about what the picture means to them,&#xD;
      how it makes them feel, etc., while the CAREN operator superimposes key words (said by the&#xD;
      participant) over the picture, which the therapist later asks the participant to read aloud.&#xD;
      Then, for ~60 seconds, the EM+ group will see a red ball &quot;bounce&quot; across the screen in front&#xD;
      of the picture, and a number appears on the ball as it touches the screen's edge. The&#xD;
      participant will be asked to recite each number aloud. This element is absent for EM-&#xD;
      participants. All participants repeats these procedures for 5-7 pictures in each 3MDR&#xD;
      treatment session; the pictures used will be agreed upon by therapist and participant,&#xD;
      targeting more impactful pictures, whether repeats or new, in later sessions. The pictures&#xD;
      are followed by playing the second song, chosen to bring the participant back to present day.&#xD;
      The participant will walk at a comfortable pace throughout the session, with each session&#xD;
      lasting typically ~60 minutes. The primary outcome measure will be change in PCL-5 score from&#xD;
      pre- to post-intervention, with additional measures at 3 and 6 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a pilot prospective, randomized, interventional controlled clinical trial. Our study&#xD;
      at the NICoE site will specifically target active or retired SMs who are OIF/OEF/OND veterans&#xD;
      of any age and either gender who meet criteria for PTSD and have a lifetime history of mTBI.&#xD;
      Comorbid PTSD and mTBI is highly prevalent in SMs and veterans of the recent wars in&#xD;
      Afghanistan and Iraq, and having both diagnoses is associated with significantly greater&#xD;
      symptom severity than either PTSD or mTBI alone (Brenner et al., 2010). TBI, the great&#xD;
      majority of which is mTBI, is one of the most challenging, significant, and costly problems&#xD;
      facing the DoD, and inhibiting readiness, whether in times of war or peace. Currently, no&#xD;
      therapy has yet been proven efficacious in reducing persistent symptoms after TBI. Many&#xD;
      patients with PTSD, particularly when it is combat-related, still suffer from substantial&#xD;
      residual symptoms even after undergoing evidence-based psychotherapy (Watts et al., 2013;&#xD;
      Bradley et al., 2001; Bison et al., 2007) and many even maintain their PTSD diagnosis&#xD;
      (Steenkamp et al., 2015). The novel elements of 3MDR may prove to be particularly beneficial&#xD;
      for those with both PTSD and a history of mTBI. If our approach is proven effective, there&#xD;
      will be a sizeable population for whom this treatment could be provided, translating into&#xD;
      both individual and DoD-wide benefit. Both TBI and PTSD have become signature wounds of the&#xD;
      wars in Iraq and Afghanistan and pose significant health concerns for many military&#xD;
      personnel. Currently, no intervention has yet been proven efficacious in reducing long-term&#xD;
      symptoms of TBI. Furthermore, individuals with PTSD often have persistent symptoms even after&#xD;
      completing validated treatments.&#xD;
&#xD;
      The proposed research has the potential to have a significant positive impact on the care of&#xD;
      individuals with both PTSD and mTBI. As previously stated, 3MDR combines emotional exposure,&#xD;
      dual-task processing, attenuation of working memory resources, and physical activity.&#xD;
      Physical activity may be particularly beneficial in enhancing blood flow to the brain and&#xD;
      facilitating production of beneficial factors such as brain-derived neurotrophic factor&#xD;
      (BDNF). In addition, participants have the opportunity to demonstrate to themselves that they&#xD;
      can actively overcome their avoidance by approaching and walking toward, or deliberately&#xD;
      confronting, representations of their own traumatic memories. This approach may be&#xD;
      particularly useful or of interest to veterans and SMs, who are accustomed to being&#xD;
      physically active, may be less inclined to turn to pharmacotherapy than others with PTSD, and&#xD;
      also have had high dropout rates and greater resistance to established, more traditional&#xD;
      therapies. This relatively short treatment approach could have tremendous implications for&#xD;
      improvement in symptoms as well as quality of life in individuals with PTSD and mTBI. Prior&#xD;
      to any other study procedures, written informed consent will be obtained from each&#xD;
      participant by the principal investigator (PI) or another study staff member trained by the&#xD;
      PI to obtain informed consent. The PI will then complete a medical history and a series of&#xD;
      questionnaires, to include a review of inclusion and exclusion criteria, to ensure that each&#xD;
      participant is eligible to be enrolled in the study. A random number table will be used to&#xD;
      randomly assign participants to either the eye movement (EM+) or no eye movement (EM-) group.&#xD;
&#xD;
      Table 1&#xD;
&#xD;
      Weeks Months 0&#xD;
&#xD;
      1 2 3 4 5 6 7 8 9 10 3 6 Consent X&#xD;
&#xD;
      3MDR Preparatory Sessions&#xD;
&#xD;
      X X X&#xD;
&#xD;
      3MDR CAREN Sessions&#xD;
&#xD;
      X X X X X X&#xD;
&#xD;
      Wrap-up Session&#xD;
&#xD;
      X&#xD;
&#xD;
      Post-Therapy Follow-Up&#xD;
&#xD;
      X X&#xD;
&#xD;
      Intervention All participants will complete 10 treatment sessions (three preparatory&#xD;
      sessions, six 3MDR sessions and one concluding session; see Table 1), led by a therapist who&#xD;
      has been completed training in the conduct of this form of therapy, with the only difference&#xD;
      between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement&#xD;
      component. Dr. Eric Vermetten, head of research at the Military Mental Health unit of the&#xD;
      Netherlands Ministry of Defense, and one of the developers of the 3MDR system, will conduct&#xD;
      the training of all study therapists, will ensure that they are fully prepared to carry out&#xD;
      the treatment protocol using the study manual he wrote, and he will provide regular&#xD;
      supervision for the study therapists throughout the conduct of the study.&#xD;
&#xD;
      Preparatory Session 1: Research personnel will explain the upcoming 3MDR therapy sessions.&#xD;
      Participants will be asked to identify 14 photographs, as well as two songs. The photographs&#xD;
      may be digital, hard copy, or downloaded from the internet, and should be related to or&#xD;
      reminiscent of the participant's traumatic experience. Each of the two songs are selected for&#xD;
      specific purposes and will be played in their entirety during each of the 3MDR sessions. The&#xD;
      first song is intended to bring them back to the time in which the trauma occurred; for&#xD;
      example, for a service member with combat-related PTSD, this might be a song that they&#xD;
      listened to a lot during their deployment. This will be played at the start of the 3MDR&#xD;
      session while the participant walks at a comfortable pace through a virtual environment,&#xD;
      before any of their pictures are displayed. The second song, on the other hand, is&#xD;
      specifically chosen in order to bring them back to the present time, to remind them they are&#xD;
      safe and are in the present moment.&#xD;
&#xD;
      Preparatory Session 2: The participant will share their photographs and music selections with&#xD;
      the therapist. If the participant has difficulty identifying a sufficient number of&#xD;
      appropriate photographs, the therapist will work with the participant during this session to&#xD;
      identify why they may not have been able to come up with a sufficient number, and to help&#xD;
      them find suitable options. This could include conducting online searches for publicly&#xD;
      available pictures, including such options as Google Maps images of the area in which their&#xD;
      trauma occurred. Sometimes, difficulty in the selection of pictures is a manifestation of the&#xD;
      avoidance of any reminders of the traumatic, which is a cardinal feature of PTSD. The&#xD;
      therapist may at this time explore the avoidance, if it is perceived to be a significant&#xD;
      factor, and help the participant to work through and overcome it to a sufficient degree to&#xD;
      identify suitable pictures to use in the treatment sessions. While the selection of songs&#xD;
      does not usually pose as significant a challenge, the therapist will also review the&#xD;
      participant's song selections, discuss why they were chosen, and try to ensure that the songs&#xD;
      selected are suitable to take the participant back to the trauma, and then bring them back to&#xD;
      the present and help them differentiate past from present, respectively. The therapist will&#xD;
      then guide the participant to arrange their photographs according to their subjective units&#xD;
      of distress (SUDS; Wolp,1969). The SUDS is a verbal self-report rating of subjective distress&#xD;
      on a scale from 0-10, with 0 indicating no distress, and 10 representing maximum distress.&#xD;
      The SUDS scale will be explained verbally to the participant and is not given via pencil and&#xD;
      paper format. This will be used to rank the pictures for use during 3MDR treatment.&#xD;
&#xD;
      Preparatory Session 3: Participants will be introduced to, and familiarized with, the CAREN&#xD;
      system (e.g., standing, shifting weight, and walking) located at the National Intrepid Center&#xD;
      of Excellence (NICoE). Participants will be fitted by the engineer with a safety harness that&#xD;
      will be worn for the entirety of each session that a participant is on the CAREN platform. In&#xD;
      this session, a series of introductory applications will be used to familiarize the&#xD;
      participant with the CAREN, which will take less than five minutes to perform. A short&#xD;
      practice 3MDR session with a non-affecting photograph (e.g., a flower) will be conducted.&#xD;
&#xD;
      3MDR Sessions 1-6: A 3MDR trained therapist, as well as a CAREN engineer, will be present at&#xD;
      every 3MDR therapy session.&#xD;
&#xD;
      Since sessions only include level treadmill walking, the platform will be disengaged with the&#xD;
      bridge extended, as opposed to being separated from the main floor and set up to enable&#xD;
      left-right and forward-backward shifts from the horizontal. This will minimize equipment&#xD;
      noise and facilitate the communication between the therapist and participant. For participant&#xD;
      monitoring and objective data collection, heart rate and kinematic data will be collected. A&#xD;
      chest strap heart rate monitor will be worn by the participant throughout the session (Polar&#xD;
      Electro Inc., Woodbury, NY; Zephyr Performance Systems, Annapolis, MD). Reflective motion&#xD;
      capture markers will be placed on the participant's head, torso, and legs to measure&#xD;
      biomechanics collected via motion capture cameras (Motion Analysis Inc., Santa Rosa, CA) that&#xD;
      surround the CAREN.&#xD;
&#xD;
      Participants will then be fitted with an adjustable safety harness that fits comfortably over&#xD;
      the shoulders. There is a risk of skin chafing if there is a lot of movement and the harness&#xD;
      is not fitted properly. Each participant will be asked if they are comfortable throughout the&#xD;
      study to mitigate this risk. The safety harness will be slipped into the safety support on&#xD;
      the CAREN, which allows the participant to walk freely on the treadmill, but it does not&#xD;
      allow them to walk off the platform. There is also a safety bar in front of the participant.&#xD;
      The therapist will stand next to the participant during the session, on the edge of the&#xD;
      platform but not on the treadmill. Up to seven pictures will be selected based on the&#xD;
      participant's SUDS scores and/or themes agreed upon for each session. Pictures may be&#xD;
      repeated during a session, reducing the number of pictures used for some sessions; this will&#xD;
      be at the discretion of the treating therapist.&#xD;
&#xD;
      Each session has three phases: warm-up, intervention, and cool-down. The participant's&#xD;
      preferred walking speed will be used to start the warm-up phase (2-5 min) and can be adjusted&#xD;
      as needed. During this phase, the participant will virtually walk along an outdoor pathway&#xD;
      toward a door while their chosen opening song plays to bring them back to a time of their&#xD;
      trigger, as verbal guidance from their therapist prepares them for the intervention phase.&#xD;
&#xD;
      The CAREN system will be operated by a Biomedical Engineer, Sarah Kruger, who has been&#xD;
      operating CAREN systems since 2007, and is certified by Motekforce Link. Motekforce Link is&#xD;
      the manufacturer of the CAREN system. Motekforce Link provides CAREN operators with training&#xD;
      and also verifies competencies required for system operation.&#xD;
&#xD;
      During utilization, the system is operated by a certified CAREN Operator and per protocol, at&#xD;
      no time will the system be operated with less than two staff members in the room.&#xD;
&#xD;
      System checks are run daily by the CAREN Operator. All equipment is calibrated and&#xD;
      maintained. Personnel from Motekforce Link visit annually to verify that everything is&#xD;
      working properly and make any changes that are necessary.&#xD;
&#xD;
      In the intervention phase (50-55 min), the participant passes through an initial hallway&#xD;
      leading to an open door that in turn leads them down a second hallway to approach their first&#xD;
      picture, while being guided by the therapist with regard to what to do at each stage. The&#xD;
      picture appears in the distance, but gradually becomes larger as they get closer to it, until&#xD;
      it fills their field of vision. As soon as the participant is able to see the picture&#xD;
      clearly, the therapist will request that they provide a detailed description of what the&#xD;
      picture represents to them, and will then go on to ask the participant about their related&#xD;
      memories and feelings. The therapist will verbally repeat key feelings and phrases that seem&#xD;
      to carry particular meaning and resonance for the participant, so the CAREN engineer can type&#xD;
      these words into the computer to have them appear superimposed over the picture (stage 1).&#xD;
&#xD;
      For those in the EM+ intervention group, the EM component will start after the participant&#xD;
      has confirmed there are no more new feelings or words to be identified with the picture, and&#xD;
      the therapist has asked the participant to read each of these words aloud, after which the&#xD;
      engineer will remove the words from the screen but retain the picture. At this point a red&#xD;
      ball will start at the left edge of the screen, and will move across the screen fairly&#xD;
      rapidly from left to right, and upon reaching the right edge of the screen, a 2-digit number&#xD;
      will appear superimposed on the red ball in white font (stage 2). The ball will then reverse&#xD;
      course, passing from right to left, and the number will change as the ball meets the opposite&#xD;
      edge of the screen. The ball will continue to move back and forth and the number will change&#xD;
      every time the ball meets either edge of the screen. The participant will be asked to track&#xD;
      the ball and call out the numbers displayed on the ball. After approximately 60 seconds, the&#xD;
      distractor stimulus (ball image) is removed and a SUDS score is reported by the participant&#xD;
      and recorded by the CAREN operator (stage 3). The participant will then walk out of the&#xD;
      virtual hallway and onto an outdoor pathway that will lead them to another set of hallways,&#xD;
      leading in turn to another picture, and the stages are repeated. There will be no exposure to&#xD;
      the distractor stimulus (red ball) for those in the EM- intervention group.&#xD;
&#xD;
      After the last picture, the final phase of treatment (cool-down) begins (2-5 min). The&#xD;
      session concludes with a piece of music, chosen by the participant to bring them back to the&#xD;
      present time, typically a current favorite song of theirs. This music will be used to assist&#xD;
      the participant in returning back to the present moment, while the therapist simultaneously&#xD;
      provides them with positive feedback regarding their performance during the session, with a&#xD;
      goal of achieving a significantly reduced SUDS score, which is reassessed at the end of the&#xD;
      song.&#xD;
&#xD;
      Following the session, the CAREN operator will remove the safety harness from the&#xD;
      participant. Participants will also be able to stop the session at any time if they feel ill&#xD;
      or any motion sickness. A therapist-led discussion (approximately 15 minutes) with the&#xD;
      participant will then occur in a private room; open questions will be used to elicit how the&#xD;
      session was for the participant, and to discuss the purpose of re-experiencing to the&#xD;
      participant in this setting. Notes made by the therapist will be stored, identified by study&#xD;
      code and session number only, stored in password-protected files on a CAC-requiring computer.&#xD;
      The study therapist will ensure the participant has completely returned to the present&#xD;
      moment, has a reduced SUDS, and has ideally been able to attach a positive meaning to the&#xD;
      3MDR session. Participants will be asked to write their experiences and reflections down&#xD;
      following each session in a diary format. All sessions will be recorded and a report&#xD;
      summarizing the behavioral response to the intervention will be produced.&#xD;
&#xD;
      Concluding Session: Participants will provide their perception of how beneficial the&#xD;
      treatment was, and if the current state of their symptoms will be discussed, with a focus on&#xD;
      to what degree they have or have not improved compared to prior to their participation in the&#xD;
      study.&#xD;
&#xD;
      Participants will return to the laboratory to complete follow-up assessments at 3 and 6&#xD;
      months. If participants are unable to return to the laboratory (i.e., no longer in the area),&#xD;
      they will be contacted via phone, and the study questionnaires will be completed&#xD;
      telephonically.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 11, 2019</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a pilot, controlled clinical trial in which all 20 participants with comorbid PTSD and mTBI receive 10 sessions (3 preparatory, 6 3MDR treatment, and 1 conclusion), but will be randomized to either include eye movement, EM (EM+), or not (EM-).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in PTSD Checklist for DSM5 (PCL-5) score</measure>
    <time_frame>Post-intervention session 10, as well as 3 and 6 months later, compared to baseline</time_frame>
    <description>The well-validated PCL-5 will assess self-reported PTSD symptom severity; range 0-84, higher score represents greater severity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Neurobehavioral Symptom Inventory (NSI) score</measure>
    <time_frame>Post-intervention session, and 3 and 6 months later, compared to baseline</time_frame>
    <description>measure of postconcussive symptom severity; range 0-88, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Patient Health Questionnaire depression module (PHQ-9) score</measure>
    <time_frame>Post-intervention session 10, as well as pre-intervention session 7, and 3 and 6 months later, compared to baseline</time_frame>
    <description>measure of depression symptom severity; range 0-27, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Insomnia Severity Index (ISI) score</measure>
    <time_frame>Post-intervention session 10, as well as pre-intervention session 7, 3 and 6 months later, compared to baseline</time_frame>
    <description>measure of insomnia and sleep concerns; range 0-28, higher score represents greater severity</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Posttraumatic Stress Disorder</condition>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>3MDR With Eye Movement Component (EM+)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will complete 10 treatment sessions (3 preparatory, 6 3MDR and 1 concluding), led by a trained therapist, with the only difference between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement component. For those in the EM+ intervention group, the EM component starts after the participant has thoroughly discussed a picture with the therapist; a red ball starts at one edge of the screen, moves rapidly back and forth across it, and upon reaching either edge, a 2-digit number appears superimposed in white on the ball. The number changes every time the ball meets either edge. The participant is asked to track the ball and call out the displayed numbers.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3MDR Without Eye Movement Component (EM-)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All participants will complete 10 treatment sessions (three preparatory sessions, six 3MDR sessions and one concluding session; see Table 1), led by a therapist who has been completed training in the conduct of this form of therapy, with the only difference between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement component.There will be no exposure to the distractor stimulus (red ball) for those in the EM- intervention group.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Motion-assisted, Multi-modular Memory Desensitization and Reconsolidation (3MDR) Therapy</intervention_name>
    <description>a novel treatment for PTSD combining aspects of virtual reality exposure therapy (VRET) and Eye Movement Desensitization and Reprocessing (EMDR), within the Computer Assisted Rehabilitation Environment (CAREN)</description>
    <arm_group_label>3MDR With Eye Movement Component (EM+)</arm_group_label>
    <arm_group_label>3MDR Without Eye Movement Component (EM-)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Military service member or veteran&#xD;
&#xD;
          2. Diagnosis of probable PTSD, as manifest by a PCL-5 score of 34 or greater&#xD;
&#xD;
          3. History of mild traumatic injury (mTBI) at least 3 months prior, documented by the OSU&#xD;
             TBI-ID.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of moderate, severe, or penetrating TBI&#xD;
&#xD;
          2. History of a psychotic disorder, bipolar disorder, or active suicidal or homicidal&#xD;
             ideation&#xD;
&#xD;
          3. Use of benzodiazepines on a regular basis within the past 30 days.&#xD;
&#xD;
          4. Inability to walk continuously, at a normal pace, for up to 60 minutes&#xD;
&#xD;
          5. Inability to follow verbal command and/or observe safety precautions&#xD;
&#xD;
          6. Women who are pregnant, based on self-reported date of last menses&#xD;
&#xD;
          7. Does not demonstrate capacity for informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>we seek to enroll 50% male, 50% female participants</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Walter Reed National Military Medical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20889</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael J Roy, MD, MPH</last_name>
      <phone>301-295-9601</phone>
      <email>michael.roy@usuhs.edu</email>
    </contact>
    <contact_backup>
      <last_name>Paula Bellini, MA</last_name>
      <phone>301-295-5840</phone>
      <email>paula.bellini.ctr@usuhs.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>January 24, 2019</last_update_submitted>
  <last_update_submitted_qc>January 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Walter Reed National Military Medical Center</investigator_affiliation>
    <investigator_full_name>Michael Roy</investigator_full_name>
    <investigator_title>Professor of Medicine &amp; Director, Division of Military Internal Medicine</investigator_title>
  </responsible_party>
  <keyword>posttraumatic stress disorder</keyword>
  <keyword>traumatic brain injury</keyword>
  <keyword>virtual reality</keyword>
  <keyword>eye movement desensitization and reprocessing</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Stress Disorders, Traumatic</mesh_term>
    <mesh_term>Stress Disorders, Post-Traumatic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified data will be made available via the Federal Interagency TBI Registry (FITBIR) after the study has been completed and all links to personal identifying information have been destroyed.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Data will be made available after the completion of the study and destruction of links to personal identifying information, and then will be available indefinitely.</ipd_time_frame>
    <ipd_url>https://fitbir.nih.gov/</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03796936
org study id: WRNMMC-2018-0201
nct id: NCT03796936
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background and Purpose: Posttraumatic stress disorder (PTSD) and mild traumatic brain injury
      (mTBI) are persistent and frequently comorbid complications of recent combat. There is no
      proven treatment for mTBI, and standard treatments for PTSD frequently achieve only
      transient, modest impact. Motion-assisted, Multi-modular Memory Desensitization and
      Reconsolidation (3MDR) is a novel treatment for PTSD combining aspects of virtual reality
      exposure therapy (VRET) and Eye Movement Desensitization and Reprocessing (EMDR), within the
      Computer Assisted Rehabilitation Environment (CAREN). The added benefit of the eye movement
      (EM) component of EMDR is controversial; the purpose of this pilot study is therefore to: 1)
      obtain an initial estimate of the efficacy of 3MDR in service members with comorbid PTSD and
      mTBI, and 2) determine the impact of EM on treatment response. The investigators hypothesize
      that 3MDR will significantly improve symptom severity, both with and without EM.

      Population: Participants will be active or retired service members with a history of mTBI who
      meet criteria for probable PTSD on the PCL5. It is anticipated that participants will be
      recruited through the Center for Neuroscience and Regenerative Medicine (CNRM) Recruitment
      Core and the National Intrepid Center of Excellence (NICoE).

      Design type and procedures: This is a pilot, controlled clinical trial in which all 20
      participants with comorbid PTSD and mTBI receive 10 sessions (3 preparatory, 6 3MDR
      treatment, and 1 conclusion), but will be randomized to either include EM (EM+) or not (EM-).
      In the preparatory sessions, the therapist will help each participant select 2 songs and 14
      pictures to be used in their treatment sessions. The therapist will help the participant rate
      the pictures from least to most impactful. Each 3MDR treatment session will start by playing
      the first song, to bring them back to the time of their trauma. This will be done while the
      participant walks on the CAREN's embedded treadmill through the 3MDR virtual environment (VE)
      projected onto the system's curved screen. This is followed by a display of one of their
      pictures, a manifestation of their trauma, which they directly face and walk down a hallway
      toward, until the picture looms before them. The therapist, standing next to the participant
      along the treadmill's edge, will query the participant about what the picture means to them,
      how it makes them feel, etc., while the CAREN operator superimposes key words (said by the
      participant) over the picture, which the therapist later asks the participant to read aloud.
      Then, for ~60 seconds, the EM+ group will see a red ball "bounce" across the screen in front
      of the picture, and a number appears on the ball as it touches the screen's edge. The
      participant will be asked to recite each number aloud. This element is absent for EM-
      participants. All participants repeats these procedures for 5-7 pictures in each 3MDR
      treatment session; the pictures used will be agreed upon by therapist and participant,
      targeting more impactful pictures, whether repeats or new, in later sessions. The pictures
      are followed by playing the second song, chosen to bring the participant back to present day.
      The participant will walk at a comfortable pace throughout the session, with each session
      lasting typically ~60 minutes. The primary outcome measure will be change in PCL-5 score from
      pre- to post-intervention, with additional measures at 3 and 6 months.
This is a pilot prospective, randomized, interventional controlled clinical trial. Our study
      at the NICoE site will specifically target active or retired SMs who are OIF/OEF/OND veterans
      of any age and either gender who meet criteria for PTSD and have a lifetime history of mTBI.
      Comorbid PTSD and mTBI is highly prevalent in SMs and veterans of the recent wars in
      Afghanistan and Iraq, and having both diagnoses is associated with significantly greater
      symptom severity than either PTSD or mTBI alone (Brenner et al., 2010). TBI, the great
      majority of which is mTBI, is one of the most challenging, significant, and costly problems
      facing the DoD, and inhibiting readiness, whether in times of war or peace. Currently, no
      therapy has yet been proven efficacious in reducing persistent symptoms after TBI. Many
      patients with PTSD, particularly when it is combat-related, still suffer from substantial
      residual symptoms even after undergoing evidence-based psychotherapy (Watts et al., 2013;
      Bradley et al., 2001; Bison et al., 2007) and many even maintain their PTSD diagnosis
      (Steenkamp et al., 2015). The novel elements of 3MDR may prove to be particularly beneficial
      for those with both PTSD and a history of mTBI. If our approach is proven effective, there
      will be a sizeable population for whom this treatment could be provided, translating into
      both individual and DoD-wide benefit. Both TBI and PTSD have become signature wounds of the
      wars in Iraq and Afghanistan and pose significant health concerns for many military
      personnel. Currently, no intervention has yet been proven efficacious in reducing long-term
      symptoms of TBI. Furthermore, individuals with PTSD often have persistent symptoms even after
      completing validated treatments.

      The proposed research has the potential to have a significant positive impact on the care of
      individuals with both PTSD and mTBI. As previously stated, 3MDR combines emotional exposure,
      dual-task processing, attenuation of working memory resources, and physical activity.
      Physical activity may be particularly beneficial in enhancing blood flow to the brain and
      facilitating production of beneficial factors such as brain-derived neurotrophic factor
      (BDNF). In addition, participants have the opportunity to demonstrate to themselves that they
      can actively overcome their avoidance by approaching and walking toward, or deliberately
      confronting, representations of their own traumatic memories. This approach may be
      particularly useful or of interest to veterans and SMs, who are accustomed to being
      physically active, may be less inclined to turn to pharmacotherapy than others with PTSD, and
      also have had high dropout rates and greater resistance to established, more traditional
      therapies. This relatively short treatment approach could have tremendous implications for
      improvement in symptoms as well as quality of life in individuals with PTSD and mTBI. Prior
      to any other study procedures, written informed consent will be obtained from each
      participant by the principal investigator (PI) or another study staff member trained by the
      PI to obtain informed consent. The PI will then complete a medical history and a series of
      questionnaires, to include a review of inclusion and exclusion criteria, to ensure that each
      participant is eligible to be enrolled in the study. A random number table will be used to
      randomly assign participants to either the eye movement (EM+) or no eye movement (EM-) group.

      Table 1

      Weeks Months 0

      1 2 3 4 5 6 7 8 9 10 3 6 Consent X

      3MDR Preparatory Sessions

      X X X

      3MDR CAREN Sessions

      X X X X X X

      Wrap-up Session

      X

      Post-Therapy Follow-Up

      X X

      Intervention All participants will complete 10 treatment sessions (three preparatory
      sessions, six 3MDR sessions and one concluding session; see Table 1), led by a therapist who
      has been completed training in the conduct of this form of therapy, with the only difference
      between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement
      component. Dr. Eric Vermetten, head of research at the Military Mental Health unit of the
      Netherlands Ministry of Defense, and one of the developers of the 3MDR system, will conduct
      the training of all study therapists, will ensure that they are fully prepared to carry out
      the treatment protocol using the study manual he wrote, and he will provide regular
      supervision for the study therapists throughout the conduct of the study.

      Preparatory Session 1: Research personnel will explain the upcoming 3MDR therapy sessions.
      Participants will be asked to identify 14 photographs, as well as two songs. The photographs
      may be digital, hard copy, or downloaded from the internet, and should be related to or
      reminiscent of the participant's traumatic experience. Each of the two songs are selected for
      specific purposes and will be played in their entirety during each of the 3MDR sessions. The
      first song is intended to bring them back to the time in which the trauma occurred; for
      example, for a service member with combat-related PTSD, this might be a song that they
      listened to a lot during their deployment. This will be played at the start of the 3MDR
      session while the participant walks at a comfortable pace through a virtual environment,
      before any of their pictures are displayed. The second song, on the other hand, is
      specifically chosen in order to bring them back to the present time, to remind them they are
      safe and are in the present moment.

      Preparatory Session 2: The participant will share their photographs and music selections with
      the therapist. If the participant has difficulty identifying a sufficient number of
      appropriate photographs, the therapist will work with the participant during this session to
      identify why they may not have been able to come up with a sufficient number, and to help
      them find suitable options. This could include conducting online searches for publicly
      available pictures, including such options as Google Maps images of the area in which their
      trauma occurred. Sometimes, difficulty in the selection of pictures is a manifestation of the
      avoidance of any reminders of the traumatic, which is a cardinal feature of PTSD. The
      therapist may at this time explore the avoidance, if it is perceived to be a significant
      factor, and help the participant to work through and overcome it to a sufficient degree to
      identify suitable pictures to use in the treatment sessions. While the selection of songs
      does not usually pose as significant a challenge, the therapist will also review the
      participant's song selections, discuss why they were chosen, and try to ensure that the songs
      selected are suitable to take the participant back to the trauma, and then bring them back to
      the present and help them differentiate past from present, respectively. The therapist will
      then guide the participant to arrange their photographs according to their subjective units
      of distress (SUDS; Wolp,1969). The SUDS is a verbal self-report rating of subjective distress
      on a scale from 0-10, with 0 indicating no distress, and 10 representing maximum distress.
      The SUDS scale will be explained verbally to the participant and is not given via pencil and
      paper format. This will be used to rank the pictures for use during 3MDR treatment.

      Preparatory Session 3: Participants will be introduced to, and familiarized with, the CAREN
      system (e.g., standing, shifting weight, and walking) located at the National Intrepid Center
      of Excellence (NICoE). Participants will be fitted by the engineer with a safety harness that
      will be worn for the entirety of each session that a participant is on the CAREN platform. In
      this session, a series of introductory applications will be used to familiarize the
      participant with the CAREN, which will take less than five minutes to perform. A short
      practice 3MDR session with a non-affecting photograph (e.g., a flower) will be conducted.

      3MDR Sessions 1-6: A 3MDR trained therapist, as well as a CAREN engineer, will be present at
      every 3MDR therapy session.

      Since sessions only include level treadmill walking, the platform will be disengaged with the
      bridge extended, as opposed to being separated from the main floor and set up to enable
      left-right and forward-backward shifts from the horizontal. This will minimize equipment
      noise and facilitate the communication between the therapist and participant. For participant
      monitoring and objective data collection, heart rate and kinematic data will be collected. A
      chest strap heart rate monitor will be worn by the participant throughout the session (Polar
      Electro Inc., Woodbury, NY; Zephyr Performance Systems, Annapolis, MD). Reflective motion
      capture markers will be placed on the participant's head, torso, and legs to measure
      biomechanics collected via motion capture cameras (Motion Analysis Inc., Santa Rosa, CA) that
      surround the CAREN.

      Participants will then be fitted with an adjustable safety harness that fits comfortably over
      the shoulders. There is a risk of skin chafing if there is a lot of movement and the harness
      is not fitted properly. Each participant will be asked if they are comfortable throughout the
      study to mitigate this risk. The safety harness will be slipped into the safety support on
      the CAREN, which allows the participant to walk freely on the treadmill, but it does not
      allow them to walk off the platform. There is also a safety bar in front of the participant.
      The therapist will stand next to the participant during the session, on the edge of the
      platform but not on the treadmill. Up to seven pictures will be selected based on the
      participant's SUDS scores and/or themes agreed upon for each session. Pictures may be
      repeated during a session, reducing the number of pictures used for some sessions; this will
      be at the discretion of the treating therapist.

      Each session has three phases: warm-up, intervention, and cool-down. The participant's
      preferred walking speed will be used to start the warm-up phase (2-5 min) and can be adjusted
      as needed. During this phase, the participant will virtually walk along an outdoor pathway
      toward a door while their chosen opening song plays to bring them back to a time of their
      trigger, as verbal guidance from their therapist prepares them for the intervention phase.

      The CAREN system will be operated by a Biomedical Engineer, Sarah Kruger, who has been
      operating CAREN systems since 2007, and is certified by Motekforce Link. Motekforce Link is
      the manufacturer of the CAREN system. Motekforce Link provides CAREN operators with training
      and also verifies competencies required for system operation.

      During utilization, the system is operated by a certified CAREN Operator and per protocol, at
      no time will the system be operated with less than two staff members in the room.

      System checks are run daily by the CAREN Operator. All equipment is calibrated and
      maintained. Personnel from Motekforce Link visit annually to verify that everything is
      working properly and make any changes that are necessary.

      In the intervention phase (50-55 min), the participant passes through an initial hallway
      leading to an open door that in turn leads them down a second hallway to approach their first
      picture, while being guided by the therapist with regard to what to do at each stage. The
      picture appears in the distance, but gradually becomes larger as they get closer to it, until
      it fills their field of vision. As soon as the participant is able to see the picture
      clearly, the therapist will request that they provide a detailed description of what the
      picture represents to them, and will then go on to ask the participant about their related
      memories and feelings. The therapist will verbally repeat key feelings and phrases that seem
      to carry particular meaning and resonance for the participant, so the CAREN engineer can type
      these words into the computer to have them appear superimposed over the picture (stage 1).

      For those in the EM+ intervention group, the EM component will start after the participant
      has confirmed there are no more new feelings or words to be identified with the picture, and
      the therapist has asked the participant to read each of these words aloud, after which the
      engineer will remove the words from the screen but retain the picture. At this point a red
      ball will start at the left edge of the screen, and will move across the screen fairly
      rapidly from left to right, and upon reaching the right edge of the screen, a 2-digit number
      will appear superimposed on the red ball in white font (stage 2). The ball will then reverse
      course, passing from right to left, and the number will change as the ball meets the opposite
      edge of the screen. The ball will continue to move back and forth and the number will change
      every time the ball meets either edge of the screen. The participant will be asked to track
      the ball and call out the numbers displayed on the ball. After approximately 60 seconds, the
      distractor stimulus (ball image) is removed and a SUDS score is reported by the participant
      and recorded by the CAREN operator (stage 3). The participant will then walk out of the
      virtual hallway and onto an outdoor pathway that will lead them to another set of hallways,
      leading in turn to another picture, and the stages are repeated. There will be no exposure to
      the distractor stimulus (red ball) for those in the EM- intervention group.

      After the last picture, the final phase of treatment (cool-down) begins (2-5 min). The
      session concludes with a piece of music, chosen by the participant to bring them back to the
      present time, typically a current favorite song of theirs. This music will be used to assist
      the participant in returning back to the present moment, while the therapist simultaneously
      provides them with positive feedback regarding their performance during the session, with a
      goal of achieving a significantly reduced SUDS score, which is reassessed at the end of the
      song.

      Following the session, the CAREN operator will remove the safety harness from the
      participant. Participants will also be able to stop the session at any time if they feel ill
      or any motion sickness. A therapist-led discussion (approximately 15 minutes) with the
      participant will then occur in a private room; open questions will be used to elicit how the
      session was for the participant, and to discuss the purpose of re-experiencing to the
      participant in this setting. Notes made by the therapist will be stored, identified by study
      code and session number only, stored in password-protected files on a CAC-requiring computer.
      The study therapist will ensure the participant has completely returned to the present
      moment, has a reduced SUDS, and has ideally been able to attach a positive meaning to the
      3MDR session. Participants will be asked to write their experiences and reflections down
      following each session in a diary format. All sessions will be recorded and a report
      summarizing the behavioral response to the intervention will be produced.

      Concluding Session: Participants will provide their perception of how beneficial the
      treatment was, and if the current state of their symptoms will be discussed, with a focus on
      to what degree they have or have not improved compared to prior to their participation in the
      study.

      Participants will return to the laboratory to complete follow-up assessments at 3 and 6
      months. If participants are unable to return to the laboratory (i.e., no longer in the area),
      they will be contacted via phone, and the study questionnaires will be completed
      telephonically.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a pilot, controlled clinical trial in which all 20 participants with comorbid PTSD and mTBI receive 10 sessions (3 preparatory, 6 3MDR treatment, and 1 conclusion), but will be randomized to either include eye movement, EM (EM+), or not (EM-).
primary purpose: Treatment
masking: None (Open Label)
measure: Change in PTSD Checklist for DSM5 (PCL-5) score
time frame: Post-intervention session 10, as well as 3 and 6 months later, compared to baseline
description: The well-validated PCL-5 will assess self-reported PTSD symptom severity; range 0-84, higher score represents greater severity.
measure: Change in Neurobehavioral Symptom Inventory (NSI) score
time frame: Post-intervention session, and 3 and 6 months later, compared to baseline
description: measure of postconcussive symptom severity; range 0-88, higher score represents greater severity
measure: Change in Patient Health Questionnaire depression module (PHQ-9) score
time frame: Post-intervention session 10, as well as pre-intervention session 7, and 3 and 6 months later, compared to baseline
description: measure of depression symptom severity; range 0-27, higher score represents greater severity
measure: Change in Insomnia Severity Index (ISI) score
time frame: Post-intervention session 10, as well as pre-intervention session 7, 3 and 6 months later, compared to baseline
description: measure of insomnia and sleep concerns; range 0-28, higher score represents greater severity
arm group label: 3MDR With Eye Movement Component (EM+)
arm group type: Experimental
description: All participants will complete 10 treatment sessions (3 preparatory, 6 3MDR and 1 concluding), led by a trained therapist, with the only difference between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement component. For those in the EM+ intervention group, the EM component starts after the participant has thoroughly discussed a picture with the therapist; a red ball starts at one edge of the screen, moves rapidly back and forth across it, and upon reaching either edge, a 2-digit number appears superimposed in white on the ball. The number changes every time the ball meets either edge. The participant is asked to track the ball and call out the displayed numbers.
arm group label: 3MDR Without Eye Movement Component (EM-)
arm group type: Active Comparator
description: All participants will complete 10 treatment sessions (three preparatory sessions, six 3MDR sessions and one concluding session; see Table 1), led by a therapist who has been completed training in the conduct of this form of therapy, with the only difference between the intervention groups being the presence (EM+) or absence (EM-) of the eye movement component.There will be no exposure to the distractor stimulus (red ball) for those in the EM- intervention group.
intervention type: Behavioral
intervention name: Motion-assisted, Multi-modular Memory Desensitization and Reconsolidation (3MDR) Therapy
description: a novel treatment for PTSD combining aspects of virtual reality exposure therapy (VRET) and Eye Movement Desensitization and Reprocessing (EMDR), within the Computer Assisted Rehabilitation Environment (CAREN)
arm group label: 3MDR With Eye Movement Component (EM+)
arm group label: 3MDR Without Eye Movement Component (EM-)
criteria: 
gender: All
gender based: Yes
gender description: we seek to enroll 50% male, 50% female participants
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Walter Reed National Military Medical Center
investigator full name: Michael Roy
investigator title: Professor of Medicine & Director, Division of Military Internal Medicine
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Stress Disorders, Traumatic
mesh term: Stress Disorders, Post-Traumatic
sharing ipd: Yes
ipd description: De-identified data will be made available via the Federal Interagency TBI Registry (FITBIR) after the study has been completed and all links to personal identifying information have been destroyed.
ipd info type: Clinical Study Report (CSR)
ipd time frame: Data will be made available after the completion of the study and destruction of links to personal identifying information, and then will be available indefinitely.
ipd url: https://fitbir.nih.gov/