<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/NCT03827057</url>
  </required_header>
  <id_info>
    <org_study_id>CNRM-83-9763</org_study_id>
    <nct_id>NCT03827057</nct_id>
  </id_info>
  <brief_title>RECONsolidation of Traumatic Memories to ResOLve Post Traumatic Stress Disorder (RECONTROLPTSD)</brief_title>
  <acronym>RECONTROLPTSD</acronym>
  <official_title>RECONsolidation of Traumatic Memories to ResOLve Post Traumatic Stress Disorder (RECONTROLPTSD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Uniformed Services University of the Health Sciences</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Research and Recognition Project</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Uniformed Services University of the Health Sciences</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>
      Posttraumatic Stress Disorder (PTSD) is a common cause of morbidity in combat veterans, but&#xD;
      current treatments are often inadequate. Reconsolidation of Traumatic Memories (RTM) is a&#xD;
      novel treatment that seeks to alter key aspects of the target memory (e.g., color, clarity,&#xD;
      speed, distance, perspective) to make it less impactful, and reduce nightmares, flashbacks,&#xD;
      and other features of PTSD. The memory is reviewed in the context of an imaginal movie&#xD;
      theater, presenting a fast (~45 sec) black and white movie of the trauma memory, with further&#xD;
      adjustment as needed so the patient can comfortably watch it. Open and waitlist studies of&#xD;
      RTM have reported high response rates and rapid remission, setting the stage for this&#xD;
      randomized, controlled, single-blind trial comparing RTM versus prolonged exposure (PE), the&#xD;
      PTSD therapy with the strongest current evidence base.&#xD;
&#xD;
      The investigators hypothesize that RTM will be non-inferior to PE in reducing PTSD symptom&#xD;
      severity post-treatment and at 1-year follow up; will achieve faster remission, with fewer&#xD;
      dropouts; will improve cognitive function; and that epigenetic markers will correlate with&#xD;
      treatment response. The investigators will randomize 108 active or retired service members&#xD;
      (SMs) with PTSD to ≤10 sessions of RTM or PE, affording power to test our hypotheses while&#xD;
      allowing for ≤ 25% dropouts. The investigators will use an intent to treat analysis, and the&#xD;
      Clinician Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental&#xD;
      Disorders, 5th Edition, or DSM5 (CAPS-5), conducted by blinded assessors, will be the primary&#xD;
      outcome measure. Secondary measures of depression (PHQ-9), anxiety (GAD-7), sleep (PSQI), and&#xD;
      functional status (WHOQOL-100), will be assessed pre- and post-treatment, and at 2, 6, and 12&#xD;
      months. ANOVA will compare symptom severity over time within and between groups. The&#xD;
      investigators will track comorbid TBI, anticipating it will not adversely impact response.&#xD;
      More effective therapies for PTSD, with and without TBI, must be developed and evaluated. RTM&#xD;
      is safe and promising, but requires testing against evidence-based interventions in&#xD;
      well-designed randomized clinical trials (RCTs). The full study can be conducted either in&#xD;
      person or via secure video conferencing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective: The primary intent of this study is to determine whether Reconsolidation&#xD;
      of Traumatic Memories (RTM) achieves a greater and/or more rapid response than prolonged&#xD;
      exposure (PE) in the treatment of military service members with PTSD. This is an&#xD;
      interventional randomized controlled trial in which all participants will receive active&#xD;
      psychotherapy for PTSD, either what is currently considered the best-evidenced treatment,&#xD;
      prolonged exposure, or a novel approach, reconsolidation of traumatic memories, that the&#xD;
      investigators believe can achieve a higher response rate that will also prove more rapid and&#xD;
      more durable. Participants will be active duty, reserve or National Guard service members, or&#xD;
      former service members who were retired either medically or for length of service, who are&#xD;
      eligible for care in the Department of Defense Healthcare System. Our findings should be&#xD;
      generalizable to current and former military service members with PTSD.&#xD;
&#xD;
      Approach This is a randomized controlled trial, enrolling 108 SMs with active PTSD, to RTM&#xD;
      and PE, with up to 10 treatment sessions in each arm. The anticipated average enrollment rate&#xD;
      will be 2 new participants per week. Participants may be male and female adult (ages 18+)&#xD;
      participants who are active, reserve component, National Guard, or retired SMs; those with&#xD;
      active suicidal or homicidal ideation, or a history of a psychotic disorder, will be&#xD;
      excluded. Participants may have a history of lifetime mild or moderate traumatic brain injury&#xD;
      (TBI), or no TBI history, but no lifetime history of severe TBI. Given that most participants&#xD;
      are expected to be referred from the Center for Neuroscience and Regenerative Medicine&#xD;
      (CNRM)'s Military Recruitment Protocol, it is anticipated that the great majority will have&#xD;
      comorbid mild TBI (mTBI). All participants will also complete a total of 5 assessment visits:&#xD;
      at baseline, immediately after the course of treatment, and at 2, 6 and 12 months. The&#xD;
      baseline visit will begin with the completion of informed consent, followed by the&#xD;
      administration of a series of questionnaires, a detailed neurocognitive assessment, and a&#xD;
      blood draw; serial assessment will occur throughout the intervention period and for 12 months&#xD;
      of follow-up. Participants will be randomly assigned to PE or RTM using a random number&#xD;
      generator in MS Excel or other program to generate a random sequence of 108 zeroes and ones&#xD;
      as a list. Subjects will be assigned to the treatment arms from that list: all zeros will be&#xD;
      assigned to RTM and ones to PE.&#xD;
&#xD;
      Hypotheses: Military service members with PTSD who are randomized to Reconsolidation of&#xD;
      Traumatic Memories (RTM) therapy will be significantly more likely to achieve PTSD resolution&#xD;
      than those randomized to Prolonged Exposure (PE) therapy, measured by the&#xD;
      Clinician-Administered PTSD Scale for DSM5 (CAPS-5, by expert assessors blinded to treatment&#xD;
      group assignment). The investigators also anticipate that RTM will achieve a response more&#xD;
      rapidly, and will prove more durable. Among the secondary measures that will correlate with&#xD;
      response to therapy are measures of depression, anxiety, sleep quality, and overall&#xD;
      functional status. Primary Aim: Compare response rates of PTSD to RTM vs. PE, defined by&#xD;
      remission of diagnosis on the CAPS-5, using a 2-tailed t-test, from baseline to&#xD;
      post-intervention. The investigators will also utilize repeated measures ANOVA to compare&#xD;
      CAPS-5 scores at baseline, post-intervention, and at 2-, 6-, and 12-month follow up within&#xD;
      groups. In addition to this primary measure, the investigators will also use independent&#xD;
      sample t-tests to document the efficacy of randomization by comparing the two groups'&#xD;
      baseline CAPS-5 total scores, along with PCL5, PHQ-9, NSI, GAD-7, PSQI, WHOQOL-10, number of&#xD;
      TBIs, and all other demographic variables.&#xD;
&#xD;
      Secondary Aim 1: Corroborate impact on PTSD symptom severity by measuring changes in CAPS-5&#xD;
      and PCL5, respectively, from baseline to post-treatment for RTM and PE, using a 2-tailed&#xD;
      t-test. The investigators will then use repeated measures ANOVA to compare within and between&#xD;
      group changes in the CAPS-5 at baseline, post-treatment, 2-, 6-, and 12-month follow-up for&#xD;
      the CAPS-5, and these as well as scores obtained prior to treatment sessions 2, 4, 6, 8 and&#xD;
      10 for the PCL5.&#xD;
&#xD;
      Secondary Aim 2: Compare rapidity of improvement in PTSD symptom severity between RTM and PE,&#xD;
      measured by PCL5 scores at baseline, prior to treatment sessions 2, 4, 6, 8 and 10, and&#xD;
      post-treatment, using a log-rank test to compare Kaplan-Meier curves for two groups.&#xD;
&#xD;
      Secondary Aim 3: Compare the durability of response to treatment, with the primary measure&#xD;
      being the percentage meeting criteria for PTSD on the CAPS-5, at post-treatment, and at 2-,&#xD;
      6-, and 12-month follow-ups, using repeated measures ANOVA between the two groups. The&#xD;
      investigators will also determine whether this is corroborated by symptom severity reduction&#xD;
      by comparing the CAPS-5 and PCL5 scores at these time points, again using repeated measures&#xD;
      ANOVA.&#xD;
&#xD;
      Secondary Aim 4: Compare the impact of RTM and PE upon comorbid conditions by using ANOVA&#xD;
      with Bonferroni adjustment for multiple comparisons, to compare scores at baseline,&#xD;
      post-treatment, and each of the follow-up time-points, on postconcussive symptoms (NSl),&#xD;
      depression (PHQ-9), anxiety (GAD-7), sleep (PSQI), and functional status (WHOQOL-100).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 12, 2019</start_date>
  <completion_date type="Anticipated">March 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2023</primary_completion_date>
  <phase>Phase 2/Phase 3</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 an interventional randomized controlled trial in which participants have an equal chance of receiving either the current best-evidenced PTSD treatment, prolonged exposure, or a novel approach, reconsolidation of traumatic memories, that has the potential to achieve a more rapid, durable and greater overall response rate.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Care Provider, Outcomes Assessor)</masking>
    <masking_description>The CAPS-5, the gold standard for PTSD diagnosis, will be administered and scored at baseline to confirm the diagnosis, and subsequently as the primary outcome measure at 2, 6, and 12 months, by expert administrators who will be blinded to treatment arm.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Clinician Administered PTSD Symptom Scale for DSM5 (CAPS-5)</measure>
    <time_frame>week 10</time_frame>
    <description>the gold standard for PTSD diagnosis, a trained expert administrator scores PTSD symptom severity; range 0-80, higher score represents greater severity</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Patient Health Questionnaire (PHQ-9) Score</measure>
    <time_frame>week 10, and 2, 6 and 12 months later, compared to baseline</time_frame>
    <description>well-validated and widely used 9-item self-report measure of depression symptom severity, range 0-27, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in PTSD Checklist for DSM5 (PCL5) Score</measure>
    <time_frame>week 10, and 2, 6 and 12 months later, compared to baseline</time_frame>
    <description>a reliable 20-item screen for PTSD, in which each item is rated on a 5-point Likert scale, range 0-80, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pittsburgh Sleep Quality Index (PSQI) Score</measure>
    <time_frame>week 10, and 2, 6 and 12 months later, compared to baseline</time_frame>
    <description>a clinically validated 9-item assessment of sleep quality and sleep disturbances; range 0 to 21, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Neurobehavioral Symptom Inventory (NSI) Score</measure>
    <time_frame>week 10, and 2, 6 and 12 months later, compared to baseline</time_frame>
    <description>a reliable 22-item self-report measure assessing functional status and post concussive symptoms, range 0-88, higher score represents greater severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in World Health Organization Quality of Life Inventory (WHOQOL-100) Score</measure>
    <time_frame>week 10, and 2, 6 and 12 months later, compared to baseline</time_frame>
    <description>a reliable 100 item self-report inventory measuring overall quality of life in 8 dimensions; range 100 to 500, higher score represents greater severity</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">108</enrollment>
  <condition>Posttraumatic Stress Disorder</condition>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Reconsolidation of Traumatic Memories (RTM)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in each arm of the study will receive up to 10 90-minute manualized treatment sessions. RTM will follow a manual developed by the Research and Recognition Project, who will also train and supervise the therapists. It is anticipated that these treatments will most often be administered once per week for 10 weeks. To best meet participant needs, we will allow therapy in either arm to be &quot;massed&quot; in the pattern recently reported by Foa et al. for PE, with sessions separated by at least 24 hours over two weeks. This schedule has been used with both RTM and PE without hurting response rates, and may reduce drop-out rates. Participants who achieve remission of their PTSD before 10 sessions, measured by a PCL5 &lt;34, can decide with their therapist whether early cessation of therapy is appropriate.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prolonged Exposure (PE)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants in each arm of the study will receive up to 10 90-minute manualized treatment sessions. PE will follow a manual written by the Foa and colleagues, and the therapists will be trained by expert trainers from the Center for Deployment Psychology. It is anticipated that these treatments will most often be administered once per week for 10 weeks. To best meet participant needs, we will allow therapy in either arm to be &quot;massed&quot; in the pattern recently reported by Foa et al. for PE, with sessions separated by at least 24 hours over two weeks. This schedule has been used with both RTM and PE without hurting response rates, and may reduce drop-out rates. Participants who achieve remission of their PTSD before 10 sessions, measured by a PCL5 &lt;34, can decide with their therapist whether early cessation of therapy is appropriate.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Reconsolidation of Traumatic Memories (RTM)</intervention_name>
    <description>RTM is a trauma-focused, but not cognitive behavioral, therapy: it involves brief exposure to the trauma memory, but does rely on conscious responses to correct the symptoms of PTSD. RTM was first used to treat phobias in the 1970s, and has more recently been refined to focus on reconsolidation to update long-term memories, reconfiguring the salience structure of the original memory, and incorporating those changes into the overall memory structure. Reconsolidation is a neural mechanism for updating long-term memory, inserting new information that contradicts an essential element of the memory, which makes it possible to change the emotional tone and salience of the memory. It is hypothesized that RTM can thereby achieve quicker, greater, and more durable responses than with &quot;traditional&quot; exposure therapies.</description>
    <arm_group_label>Reconsolidation of Traumatic Memories (RTM)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Prolonged Exposure (PE)</intervention_name>
    <description>PE is a trauma-focused cognitive behavioral therapy (TFCBT) that depends on exposure to the feared stimulus as a central effector of change, utilizing extinction, which theorizes that if a trigger that previously elicited a fear response is presented enough times without reinforcement, the response fades. Previous researchers have shown that extinction involves the creation of a new blocking memory which prevents expression of the original fear memory. While PE has more evidence to support its efficacy in PTSD than other approaches, and a majority achieve a clinical response (e.g., decrease in CAPS score of 10 or more), many do not achieve complete remission of symptoms, and the blocking memory may be fragile, so subsequent triggers may result in relapse.</description>
    <arm_group_label>Prolonged Exposure (PE)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Meets criteria for PTSD on the CAPS5, with past month nightmares or flashbacks.&#xD;
&#xD;
          2. Willing to be randomly assigned to one of the two interventions and to complete all&#xD;
             study measures.&#xD;
&#xD;
          3. Able to exhibit capacity to understand the informed consent process, by completion of&#xD;
             a corresponding series of questions&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        1. history of psychosis, bipolar disorder, or active suicidal or homicidal ideation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Michael Roy, MD, MPH</last_name>
    <phone>301-295-9601</phone>
    <email>michael.roy@usuhs.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Paula Bellini, MA</last_name>
    <phone>301-295-5840</phone>
    <email>paula.bellini.ctr@usuhs.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Uniformed Services University of Health Sciences (USUHS)</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20814</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paula Bellini, MA</last_name>
      <phone>301-412-8187</phone>
      <email>recontrol@usuhs.edu</email>
    </contact>
    <contact_backup>
      <last_name>Michael Roy, MD</last_name>
      <phone>301-295-9601</phone>
      <email>michael.roy@usuhs.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Michael J Roy, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 4, 2019</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>February 3, 2023</last_update_submitted>
  <last_update_submitted_qc>February 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>posttraumatic stress disorder</keyword>
  <keyword>traumatic brain injury</keyword>
  <keyword>cognitive behavioral therapy</keyword>
  <keyword>exposure therapy</keyword>
  <keyword>reconsolidation</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>Deidentified data will be entered into the Federal Interagency TBI Research Informatics System (FITBIR) through the CNRM after completion of the study and after all codes or links to personal identifying information have been destroyed.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>after study completion</ipd_time_frame>
    <ipd_access_criteria>Must have approved research protocol</ipd_access_criteria>
    <ipd_url>https://fitbir.nih.gov/</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 29, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/57/NCT03827057/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03827057
org study id: CNRM-83-9763
nct id: NCT03827057
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Posttraumatic Stress Disorder (PTSD) is a common cause of morbidity in combat veterans, but
      current treatments are often inadequate. Reconsolidation of Traumatic Memories (RTM) is a
      novel treatment that seeks to alter key aspects of the target memory (e.g., color, clarity,
      speed, distance, perspective) to make it less impactful, and reduce nightmares, flashbacks,
      and other features of PTSD. The memory is reviewed in the context of an imaginal movie
      theater, presenting a fast (~45 sec) black and white movie of the trauma memory, with further
      adjustment as needed so the patient can comfortably watch it. Open and waitlist studies of
      RTM have reported high response rates and rapid remission, setting the stage for this
      randomized, controlled, single-blind trial comparing RTM versus prolonged exposure (PE), the
      PTSD therapy with the strongest current evidence base.

      The investigators hypothesize that RTM will be non-inferior to PE in reducing PTSD symptom
      severity post-treatment and at 1-year follow up; will achieve faster remission, with fewer
      dropouts; will improve cognitive function; and that epigenetic markers will correlate with
      treatment response. The investigators will randomize 108 active or retired service members
      (SMs) with PTSD to ≤10 sessions of RTM or PE, affording power to test our hypotheses while
      allowing for ≤ 25% dropouts. The investigators will use an intent to treat analysis, and the
      Clinician Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental
      Disorders, 5th Edition, or DSM5 (CAPS-5), conducted by blinded assessors, will be the primary
      outcome measure. Secondary measures of depression (PHQ-9), anxiety (GAD-7), sleep (PSQI), and
      functional status (WHOQOL-100), will be assessed pre- and post-treatment, and at 2, 6, and 12
      months. ANOVA will compare symptom severity over time within and between groups. The
      investigators will track comorbid TBI, anticipating it will not adversely impact response.
      More effective therapies for PTSD, with and without TBI, must be developed and evaluated. RTM
      is safe and promising, but requires testing against evidence-based interventions in
      well-designed randomized clinical trials (RCTs). The full study can be conducted either in
      person or via secure video conferencing.
Primary Objective: The primary intent of this study is to determine whether Reconsolidation
      of Traumatic Memories (RTM) achieves a greater and/or more rapid response than prolonged
      exposure (PE) in the treatment of military service members with PTSD. This is an
      interventional randomized controlled trial in which all participants will receive active
      psychotherapy for PTSD, either what is currently considered the best-evidenced treatment,
      prolonged exposure, or a novel approach, reconsolidation of traumatic memories, that the
      investigators believe can achieve a higher response rate that will also prove more rapid and
      more durable. Participants will be active duty, reserve or National Guard service members, or
      former service members who were retired either medically or for length of service, who are
      eligible for care in the Department of Defense Healthcare System. Our findings should be
      generalizable to current and former military service members with PTSD.

      Approach This is a randomized controlled trial, enrolling 108 SMs with active PTSD, to RTM
      and PE, with up to 10 treatment sessions in each arm. The anticipated average enrollment rate
      will be 2 new participants per week. Participants may be male and female adult (ages 18+)
      participants who are active, reserve component, National Guard, or retired SMs; those with
      active suicidal or homicidal ideation, or a history of a psychotic disorder, will be
      excluded. Participants may have a history of lifetime mild or moderate traumatic brain injury
      (TBI), or no TBI history, but no lifetime history of severe TBI. Given that most participants
      are expected to be referred from the Center for Neuroscience and Regenerative Medicine
      (CNRM)'s Military Recruitment Protocol, it is anticipated that the great majority will have
      comorbid mild TBI (mTBI). All participants will also complete a total of 5 assessment visits:
      at baseline, immediately after the course of treatment, and at 2, 6 and 12 months. The
      baseline visit will begin with the completion of informed consent, followed by the
      administration of a series of questionnaires, a detailed neurocognitive assessment, and a
      blood draw; serial assessment will occur throughout the intervention period and for 12 months
      of follow-up. Participants will be randomly assigned to PE or RTM using a random number
      generator in MS Excel or other program to generate a random sequence of 108 zeroes and ones
      as a list. Subjects will be assigned to the treatment arms from that list: all zeros will be
      assigned to RTM and ones to PE.

      Hypotheses: Military service members with PTSD who are randomized to Reconsolidation of
      Traumatic Memories (RTM) therapy will be significantly more likely to achieve PTSD resolution
      than those randomized to Prolonged Exposure (PE) therapy, measured by the
      Clinician-Administered PTSD Scale for DSM5 (CAPS-5, by expert assessors blinded to treatment
      group assignment). The investigators also anticipate that RTM will achieve a response more
      rapidly, and will prove more durable. Among the secondary measures that will correlate with
      response to therapy are measures of depression, anxiety, sleep quality, and overall
      functional status. Primary Aim: Compare response rates of PTSD to RTM vs. PE, defined by
      remission of diagnosis on the CAPS-5, using a 2-tailed t-test, from baseline to
      post-intervention. The investigators will also utilize repeated measures ANOVA to compare
      CAPS-5 scores at baseline, post-intervention, and at 2-, 6-, and 12-month follow up within
      groups. In addition to this primary measure, the investigators will also use independent
      sample t-tests to document the efficacy of randomization by comparing the two groups'
      baseline CAPS-5 total scores, along with PCL5, PHQ-9, NSI, GAD-7, PSQI, WHOQOL-10, number of
      TBIs, and all other demographic variables.

      Secondary Aim 1: Corroborate impact on PTSD symptom severity by measuring changes in CAPS-5
      and PCL5, respectively, from baseline to post-treatment for RTM and PE, using a 2-tailed
      t-test. The investigators will then use repeated measures ANOVA to compare within and between
      group changes in the CAPS-5 at baseline, post-treatment, 2-, 6-, and 12-month follow-up for
      the CAPS-5, and these as well as scores obtained prior to treatment sessions 2, 4, 6, 8 and
      10 for the PCL5.

      Secondary Aim 2: Compare rapidity of improvement in PTSD symptom severity between RTM and PE,
      measured by PCL5 scores at baseline, prior to treatment sessions 2, 4, 6, 8 and 10, and
      post-treatment, using a log-rank test to compare Kaplan-Meier curves for two groups.

      Secondary Aim 3: Compare the durability of response to treatment, with the primary measure
      being the percentage meeting criteria for PTSD on the CAPS-5, at post-treatment, and at 2-,
      6-, and 12-month follow-ups, using repeated measures ANOVA between the two groups. The
      investigators will also determine whether this is corroborated by symptom severity reduction
      by comparing the CAPS-5 and PCL5 scores at these time points, again using repeated measures
      ANOVA.

      Secondary Aim 4: Compare the impact of RTM and PE upon comorbid conditions by using ANOVA
      with Bonferroni adjustment for multiple comparisons, to compare scores at baseline,
      post-treatment, and each of the follow-up time-points, on postconcussive symptoms (NSl),
      depression (PHQ-9), anxiety (GAD-7), sleep (PSQI), and functional status (WHOQOL-100).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is an interventional randomized controlled trial in which participants have an equal chance of receiving either the current best-evidenced PTSD treatment, prolonged exposure, or a novel approach, reconsolidation of traumatic memories, that has the potential to achieve a more rapid, durable and greater overall response rate.
primary purpose: Treatment
masking: Double (Care Provider, Outcomes Assessor)
masking description: The CAPS-5, the gold standard for PTSD diagnosis, will be administered and scored at baseline to confirm the diagnosis, and subsequently as the primary outcome measure at 2, 6, and 12 months, by expert administrators who will be blinded to treatment arm.
measure: Clinician Administered PTSD Symptom Scale for DSM5 (CAPS-5)
time frame: week 10
description: the gold standard for PTSD diagnosis, a trained expert administrator scores PTSD symptom severity; range 0-80, higher score represents greater severity
measure: Change in Patient Health Questionnaire (PHQ-9) Score
time frame: week 10, and 2, 6 and 12 months later, compared to baseline
description: well-validated and widely used 9-item self-report measure of depression symptom severity, range 0-27, higher score represents greater severity
measure: Change in PTSD Checklist for DSM5 (PCL5) Score
time frame: week 10, and 2, 6 and 12 months later, compared to baseline
description: a reliable 20-item screen for PTSD, in which each item is rated on a 5-point Likert scale, range 0-80, higher score represents greater severity
measure: Change in Pittsburgh Sleep Quality Index (PSQI) Score
time frame: week 10, and 2, 6 and 12 months later, compared to baseline
description: a clinically validated 9-item assessment of sleep quality and sleep disturbances; range 0 to 21, higher score represents greater severity
measure: Change in Neurobehavioral Symptom Inventory (NSI) Score
time frame: week 10, and 2, 6 and 12 months later, compared to baseline
description: a reliable 22-item self-report measure assessing functional status and post concussive symptoms, range 0-88, higher score represents greater severity
measure: Change in World Health Organization Quality of Life Inventory (WHOQOL-100) Score
time frame: week 10, and 2, 6 and 12 months later, compared to baseline
description: a reliable 100 item self-report inventory measuring overall quality of life in 8 dimensions; range 100 to 500, higher score represents greater severity
arm group label: Reconsolidation of Traumatic Memories (RTM)
arm group type: Experimental
description: Participants in each arm of the study will receive up to 10 90-minute manualized treatment sessions. RTM will follow a manual developed by the Research and Recognition Project, who will also train and supervise the therapists. It is anticipated that these treatments will most often be administered once per week for 10 weeks. To best meet participant needs, we will allow therapy in either arm to be "massed" in the pattern recently reported by Foa et al. for PE, with sessions separated by at least 24 hours over two weeks. This schedule has been used with both RTM and PE without hurting response rates, and may reduce drop-out rates. Participants who achieve remission of their PTSD before 10 sessions, measured by a PCL5 <34, can decide with their therapist whether early cessation of therapy is appropriate.
arm group label: Prolonged Exposure (PE)
arm group type: Active Comparator
description: Participants in each arm of the study will receive up to 10 90-minute manualized treatment sessions. PE will follow a manual written by the Foa and colleagues, and the therapists will be trained by expert trainers from the Center for Deployment Psychology. It is anticipated that these treatments will most often be administered once per week for 10 weeks. To best meet participant needs, we will allow therapy in either arm to be "massed" in the pattern recently reported by Foa et al. for PE, with sessions separated by at least 24 hours over two weeks. This schedule has been used with both RTM and PE without hurting response rates, and may reduce drop-out rates. Participants who achieve remission of their PTSD before 10 sessions, measured by a PCL5 <34, can decide with their therapist whether early cessation of therapy is appropriate.
intervention type: Behavioral
intervention name: Reconsolidation of Traumatic Memories (RTM)
description: RTM is a trauma-focused, but not cognitive behavioral, therapy: it involves brief exposure to the trauma memory, but does rely on conscious responses to correct the symptoms of PTSD. RTM was first used to treat phobias in the 1970s, and has more recently been refined to focus on reconsolidation to update long-term memories, reconfiguring the salience structure of the original memory, and incorporating those changes into the overall memory structure. Reconsolidation is a neural mechanism for updating long-term memory, inserting new information that contradicts an essential element of the memory, which makes it possible to change the emotional tone and salience of the memory. It is hypothesized that RTM can thereby achieve quicker, greater, and more durable responses than with "traditional" exposure therapies.
arm group label: Reconsolidation of Traumatic Memories (RTM)
intervention type: Behavioral
intervention name: Prolonged Exposure (PE)
description: PE is a trauma-focused cognitive behavioral therapy (TFCBT) that depends on exposure to the feared stimulus as a central effector of change, utilizing extinction, which theorizes that if a trigger that previously elicited a fear response is presented enough times without reinforcement, the response fades. Previous researchers have shown that extinction involves the creation of a new blocking memory which prevents expression of the original fear memory. While PE has more evidence to support its efficacy in PTSD than other approaches, and a majority achieve a clinical response (e.g., decrease in CAPS score of 10 or more), many do not achieve complete remission of symptoms, and the blocking memory may be fragile, so subsequent triggers may result in relapse.
arm group label: Prolonged Exposure (PE)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Roy, MD, MPH
phone: 301-295-9601
email: michael.roy@usuhs.edu
last name: Paula Bellini, MA
phone: 301-295-5840
email: paula.bellini.ctr@usuhs.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
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: Deidentified data will be entered into the Federal Interagency TBI Research Informatics System (FITBIR) through the CNRM after completion of the study and after all codes or links to personal identifying information have been destroyed.
ipd info type: Clinical Study Report (CSR)
ipd time frame: after study completion
ipd access criteria: Must have approved research protocol
ipd url: https://fitbir.nih.gov/
provided document: 