xml: <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/NCT06017765</url>
    </required_header>
    <id_info>
      <org_study_id>22-0245</org_study_id>
      <secondary_id>2022-A02603-40</secondary_id>
      <nct_id>NCT06017765</nct_id>
    </id_info>
    <brief_title>Coping After Loss Through Mindfulness in Adults With Prolonged Grief Disorder</brief_title>
    <acronym>CALM-NiPS</acronym>
    <official_title>Coping After Loss Through Mindfulness Training in Grieving Adults With Prolonged Grief Disorder - A Neuroimaging Pilot Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University Hospital, Caen</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Northeastern University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Cyceron</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Université de Caen Normandie</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University Hospital, Caen</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>
        The goal of this clinical trial is to pilot the effectiveness of an 8-week standardized&#xD;
        Mindfulness Training program to decrease the psychiatric and somatic symptoms of prolonged&#xD;
        grief disorder (PGD) and to examine changes in physiological and neuroimaging biomarkers of&#xD;
        bereavement-related stress reactivity that are associated with Mindfulness Training in&#xD;
        grieving adult patients (men and women, aged 18-60) who are diagnosed with PGD.&#xD;
  &#xD;
        The main questions it aims to answer are:&#xD;
  &#xD;
          1. What is the effectiveness of Mindfulness Training to lower PGD symptom severity?&#xD;
  &#xD;
          2. What is the effectiveness of Mindfulness Training on physiological and neuroimaging&#xD;
             biomarkers of stress reactivity?&#xD;
  &#xD;
          3. What are the potential mechanisms of treatment change of Mindfulness Training?&#xD;
  &#xD;
        Participants will be:&#xD;
  &#xD;
          -  randomly assigned to immediately receiving an 8-week Mindfulness Training program or&#xD;
             after a 12-week waitlist.&#xD;
  &#xD;
          -  assessed for psychiatric and somatic symptoms and for physiological responses during a&#xD;
             baseline, midpoint and endpoint visit, and at a one-month follow-up visit.&#xD;
  &#xD;
          -  assessed for functional neuroimaging biomarkers of bereavement-related and general&#xD;
             stress reactivity at the baseline and endpoint visits using a script-driven imagery task&#xD;
             (which induces bereavement-related stress reactivity during an imagery of a personal&#xD;
             situation related to the death compared to imagery of a neutral personal situation), and&#xD;
             loud tones stress task (which induces general stress reactivity).&#xD;
  &#xD;
        Researchers will compare the Mindfulness Training group (which consists of patients with PGD&#xD;
        who will receive the Mindfulness Training immediately) with the waitlist control group (which&#xD;
        consists of patients with PGD who are waiting on a waitlist to receive the training after the&#xD;
        Mindfulness Training group) to investigate if they differ in PGD symptom severity as well as&#xD;
        physiological and neuroimaging biomarkers of stress reactivity.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Bereavement is a major life stressor that triggers a stress response that can last months or&#xD;
        years after the death of a loved one. This condition of persisting grief response called&#xD;
        Prolonged Grief Disorder (PGD) has been recently included in the World Health Organization&#xD;
        (WHO) International Classification of Diseases, and the fifth text-revised version of the&#xD;
        Diagnostic and Statistical Manual of Mental Disorders (DSM-5TR). A core symptom of PGD is the&#xD;
        heightened reactivity to reminders of the death. This stress response, if exaggerated and&#xD;
        persisting, is associated with increased risk for mental health problems including suicide,&#xD;
        as well as somatic problems such as cardiac adverse events. To date, no efficacious&#xD;
        intervention for reducing a bereavement-related stress response exist to prevent the negative&#xD;
        health outcomes of adults who lost a loved one. Mindfulness Training has shown efficacy to&#xD;
        decrease the general stress reactivity, as was shown in healthy individuals and in anxiety&#xD;
        disorders, supposedly by improving emotional regulation. Therefore, it has the potential to&#xD;
        successfully target bereavement-related stress-reactivity in grievers, as supported by our&#xD;
        pilot data. However, it is unknown whether mindfulness meditation may also decrease&#xD;
        bereavement-specific stress reactivity, one of the core symptoms of PGD. Furthermore, little&#xD;
        is known about the neurobiological changes that underlie the decrease in stress reactivity&#xD;
        that results from mindfulness training.&#xD;
  &#xD;
        The present proposal is the first ever clinical trial to pilot the effectiveness of an 8-week&#xD;
        Mindfulness Training to decrease psychiatric and somatic symptoms of PGD in adult patients,&#xD;
        as well as to pilot changes in physiological and neuroimaging biomarkers of&#xD;
        bereavement-related stress reactivity that are associated with Mindfulness Training using a&#xD;
        script-driven imagery task (which induces bereavement-related stress reactivity during an&#xD;
        imagery of a personal situation related to the death compared to imagery of a neutral&#xD;
        personal situation), and loud tones stress task (which induces general stress reactivity). As&#xD;
        PGD is a newly recognized psychiatric condition, there are very limited data available about&#xD;
        its pathophysiology and neurobiology, and in particular how treatments can intervene on it.&#xD;
        Although mind-body interventions such as Mindfulness Training have recently shown to be&#xD;
        effective for stress-related conditions, limited data are available about their mechanisms of&#xD;
        actions. Our proposal is the first to examine trauma-related emotional regulation neural&#xD;
        circuits implicated in the effects of Mindfulness Training on pathological grief reactions.&#xD;
  &#xD;
          1. OBJECTIVES:&#xD;
  &#xD;
             This study aims to examine the effects of an 8-week standardized Mindfulness Training&#xD;
             program on PGD symptom severity and stress reactivity, as well as to elucidate the&#xD;
             neural mechanism of these effects, in grieving adult patients who are diagnosed with&#xD;
             PGD.&#xD;
  &#xD;
             The specific aims of this study are:&#xD;
  &#xD;
               -  PRIMARY AIM Aim 1. Examine the efficacy of Mindfulness Training to decrease PGD&#xD;
                  symptom severity (primary outcome) in a group of patients with PGD who will&#xD;
                  immediately receive the training versus the waitlist control group consisting of&#xD;
                  patients with PGD who are waiting on a waitlist to receive the training after the&#xD;
                  Mindfulness Training group.&#xD;
  &#xD;
               -  SECONDARY AIMS Aim 2. Examine the efficacy of Mindfulness Training on physiological&#xD;
                  and neuroimaging biomarkers of bereavement-related and general stress reactivity in&#xD;
                  a group of patients with PGD who will immediately receive the training versus the&#xD;
                  waitlist control group.&#xD;
  &#xD;
             Aim 3. Examine potential mechanisms of action of treatment change of Mindfulness&#xD;
             Training in a group of patients with PGD who will immediately receive the training&#xD;
             versus the waitlist control group.&#xD;
  &#xD;
          2. METHODS:&#xD;
  &#xD;
             The investigators conduct a pilot randomized wait-list controlled trial of an 8-week&#xD;
             standardized Mindfulness Training program for PGD and examine its effects on&#xD;
             physiological and neural correlates of bereavement-related and general stress&#xD;
             reactivity. N=30 adults with PGD are included who will be randomly assigned (1:1 group&#xD;
             randomization) to immediately receiving an 8-week Mindfulness Training program&#xD;
             (experimental group), adapted from the Stress Management and Resiliency Training -&#xD;
             SMART, versus after a 12-week waitlist (control group). During a baseline, midpoint,&#xD;
             endpoint, and one-month follow-up visit, participants are assessed for psychiatric and&#xD;
             somatic symptoms using several questionnaires. In addition, at the baseline and endpoint&#xD;
             visit, the investigators will perform functional magnetic resonance imaging (fMRI) to&#xD;
             assess functional neuroimaging biomarkers (brain activity and functional connectivity)&#xD;
             of bereavement-related and general stress reactivity while collecting physiological&#xD;
             responses (heart rate and skin conductance), using a script-driven imagery task&#xD;
             (inducing bereavement-related stress reactivity during imagery of a personal situation&#xD;
             related to the death versus imagery of a neutral personal situation), and loud tones&#xD;
             stress task (inducing general stress reactivity).&#xD;
  &#xD;
             Participants will not be blinded to the intervention condition. They will complete&#xD;
             self-report questionnaires and be assessed by blinded Independent Evaluators, who will&#xD;
             not be involved in the Mindfulness Training sessions, at the baseline (week 0), midpoint&#xD;
             (week 4), endpoint (week 8), and follow-up visit (week 12). Participants will be&#xD;
             instructed to keep their evaluators blinded to the randomization. Blinded Independent&#xD;
             Evaluators will be clinical psychologists who are fully trained in the different&#xD;
             measures.&#xD;
  &#xD;
          3. HYPOTHESES:&#xD;
  &#xD;
               1. Hypothesis 1. It is hypothesized that adult patients with PGD who are assigned to&#xD;
                  immediate Mindfulness Training will exhibit significantly greater improvements from&#xD;
                  the baseline to the endpoint visit (and the one-month follow-up visit), than the&#xD;
                  patients in the waitlist control group, concerning PGD symptom severity (primary&#xD;
                  outcome), PTSD symptom severity, depressive symptom severity, somatic complaints,&#xD;
                  and/or the ability to cope with stress, and global symptom improvement and&#xD;
                  severity.&#xD;
  &#xD;
               2. Hypothesis 2-a. It is hypothesized that adult patients with PGD who are assigned to&#xD;
                  immediate Mindfulness Training will exhibit significantly greater changes in&#xD;
                  physiological stress responses, as measured by skin conductance and heart rate,&#xD;
  &#xD;
                    -  for bereavement-related stress reactivity in response to the imagery of a&#xD;
                       personal situation related to the death (compared to imagery of a neutral&#xD;
                       personal situation, using a script-driven imagery task) from the baseline to&#xD;
                       the endpoint visit, than the patients in the waitlist control group.&#xD;
  &#xD;
                    -  for general stress reactivity in response (induced by the loud tones stress&#xD;
                       task) from the baseline to the endpoint visit, than the patients in the&#xD;
                       waitlist control group.&#xD;
  &#xD;
               3. Hypothesis 2-b. It is hypothesized that adult patients with PGD who are assigned to&#xD;
                  immediate Mindfulness Training will show significantly greater changes in&#xD;
                  blood-oxygen-level dependent (BOLD) signals in response to the imagery of a&#xD;
                  personal situation related to the death (compared to imagery of a neutral personal&#xD;
                  situation, using a script-driven imagery task) in brain regions that are implicated&#xD;
                  in emotion regulation and regulatory control at the endpoint visit, compared to the&#xD;
                  patients in the waitlist control group, including:&#xD;
  &#xD;
                    -  less BOLD activity in the amygdala,&#xD;
  &#xD;
                    -  more BOLD activity in the medial prefrontal cortex (consisting of the medial&#xD;
                       frontal gyrus and rostral anterior cingulate cortex),&#xD;
  &#xD;
                    -  more functional connectivity between the amygdala and the medial prefrontal&#xD;
                       cortex.&#xD;
  &#xD;
               4. Hypothesis 3-a. It is hypothesized that at the baseline visit, psychiatric and&#xD;
                  somatic symptom severity will be significantly correlated with the physiological&#xD;
                  and neuroimaging biomarkers of bereavement-related stress reactivity in response to&#xD;
                  the imagery of a personal situation related to the death (compared to imagery of a&#xD;
                  neutral personal situation).&#xD;
  &#xD;
               5. Hypothesis 3-b. It is hypothesized that greater reductions in psychiatric and&#xD;
                  somatic symptom severity between the baseline and endpoint visit, will be&#xD;
                  significantly correlated with greater decreases in physiological and neuroimaging&#xD;
                  biomarkers of bereavement-specific stress reactivity in response to the imagery of&#xD;
                  a personal situation related to the death (compared to imagery of a neutral&#xD;
                  personal situation).&#xD;
  &#xD;
               6. Hypothesis 3-c. It is hypothesized that changes in bereavement-related stress&#xD;
                  reactivity in response to the imagery of a personal situation related to the death&#xD;
                  (compared to imagery of a neutral personal situation) will mediate the effects of&#xD;
                  Mindfulness Training on the reductions in clinical symptom severity.&#xD;
  &#xD;
          4. PARTICIPATION:&#xD;
  &#xD;
             - All potential participants are asked to sign the informed consent form (approved by&#xD;
             the ethics committee) with a medical doctor/study clinician prior to participation and&#xD;
             are given as much time as needed to review the consent form. The consent form states&#xD;
             that participation is voluntary, that participants can refuse to answer any questions,&#xD;
             that they can withdraw from the research at any time, and that participation in no way&#xD;
             impacts their care. All participants must be beneficiaries of the social security&#xD;
             system.&#xD;
  &#xD;
          5. METHODOLOGY&#xD;
  &#xD;
               1. Power considerations:&#xD;
  &#xD;
                  Our primary analysis follows the intention-to-treat (ITT) principle to compare&#xD;
                  participants' outcomes according to their initial treatment assignment. The&#xD;
                  investigators restrict the ITT sample to randomized participants who attend at&#xD;
                  least one treatment session, including those who do not have analyzable&#xD;
                  neuroimaging and/or psychophysiological data. With N = 30 participants with usable&#xD;
                  data for aim 2, and alpha = 0.05 (2-tailed), there will be 80% power to detect a&#xD;
                  large d=1.1 difference.&#xD;
  &#xD;
               2. Dropout and study withdrawal:&#xD;
  &#xD;
             Participants may discontinue their participation if they wish, at any time and for any&#xD;
             reason, or upon the decision of the investigator.&#xD;
  &#xD;
             Premature study exits may be (a) progression of the study condition, (b) participants'&#xD;
             refusal to continue, (c) withdrawal of consent, (d) protocol violation requiring a study&#xD;
             exit, (e) unblinding, (f) by decision of the investigator, (g) by decision of the&#xD;
             sponsor, (h) participant non-compliance.&#xD;
  &#xD;
             At every assessment visit, and every 2 weeks during the active phase of the Mindfulness&#xD;
             Training, an investigator will assess symptom improvement and worsening, adverse events&#xD;
             (reviewed weekly by the Principal Investigator), and suicidal risk assessments&#xD;
             (monitored bi-weekly). Any participant at immediate risk, will be referred to a higher&#xD;
             level of care and discontinued from the study. A participant is also removed in case of&#xD;
             an intercurrent illness, or because they require a new drug or therapeutic method that&#xD;
             has demonstrated its efficacy in this indication (in this case, the withdrawal from the&#xD;
             trial will occur as soon as the new therapeutic agent is introduced).&#xD;
  &#xD;
             Any study withdrawal is documented and specified until the trial exit. The investigators&#xD;
             replace each early drop out (over enrollment). Missing data will be handled through&#xD;
             maximum likelihood estimation in the primary analysis models, using predictors of&#xD;
             missingness and drop-out. The investigators will conduct regular quality checks to&#xD;
             maintain data quality throughout. In case of uninterpretable data, they will recruit a&#xD;
             few additional participants to reach N=30 with analyzable neuroimaging and&#xD;
             psychophysiological data. The investigators anticipate to recruit n=35 total&#xD;
             participants to obtain N=30 participants with analyzable neuroimaging and&#xD;
             psychophysiological data (anticipated dropout = 20%).&#xD;
  &#xD;
          6. CONSIDERATIONS AND OBLIGATIONS:&#xD;
  &#xD;
               1. Standard Operating Procedures are created for all procedure which will address&#xD;
                  registry operations and analysis activities, such as patient recruitment, data&#xD;
                  collection, data management, data analysis, reporting for adverse events, and&#xD;
                  possible change management.&#xD;
  &#xD;
               2. Data are managed in a database administered by the sponsor, in accordance with the&#xD;
                  regulations in force. Data entry are performed by investigators at each center or&#xD;
                  any person on the task delegation list. A data dictionary is created that contains&#xD;
                  detailed descriptions of each variable used for data registry (e.g., information on&#xD;
                  variable source, normal (score) ranges). Data are identified only by participant&#xD;
                  codes, with all identifying information removed to protect confidentiality.&#xD;
                  Participant identity will not be revealed in any presentation or publication of&#xD;
                  results.&#xD;
  &#xD;
               3. In accordance with the French law, the participant may exercise their right to&#xD;
                  access and rectify data collected at any time. The participation of the person in&#xD;
                  the research as well as the modalities of the collection of his consent and the&#xD;
                  delivery of the information in order to collect it are specified in the&#xD;
                  participant's medical file. The sponsor will inform participants of the overall&#xD;
                  results of this research at the end of the study.&#xD;
  &#xD;
               4. Depending on level of risk and/or impact of the study defined by the sponsor, the&#xD;
                  data may be monitored randomly. In this case, a person mandated by the sponsor will&#xD;
                  monitor the data collected in the data collection booklet (verification from the&#xD;
                  patient's medical record). It is therefore the investigator's responsibility to&#xD;
                  give free access to all the medical records of the participants involved in the&#xD;
                  research (having signed a consent form).&#xD;
  &#xD;
               5. The investigator agrees to accept quality assurance audits by the sponsor or&#xD;
                  inspections by the health authorities.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Enrolling by invitation</overall_status>
    <start_date type="Anticipated">August 30, 2023</start_date>
    <completion_date type="Anticipated">January 31, 2024</completion_date>
    <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Crossover Assignment</intervention_model>
      <intervention_model_description>The study model is a pilot randomized waitlist controlled trial of an 8-session mindfulness training program (i.e., Stress Management and Resiliency Training, SMART program) delivered weekly for Prolonged Grief Disorder, either within 4 weeks (immediate) or after 12 weeks (waitlist). After participants have completed the baseline assessment (V0), they will be randomly assigned (1:1 randomization) to either the immediate mindfulness training group or the waitlist control group. The waitlist control group will wait for 12 weeks (when the immediate intervention group finished all study procedures, including the follow-up assessment) before receiving the mindfulness training, which is the same intervention as employed in the immediate intervention group.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Single (Outcomes Assessor)</masking>
      <masking_description>Participants will be assessed for psychiatric symptoms (primary objective) by blinded Independent Evaluators, who will not be involved in the mindfulness training sessions. Participants will be instructed to keep their evaluators blinded to the randomization. Blinded Independent Evaluators will be clinical psychologists who are fully trained in assessing the different measures.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Mean change in Prolonged Grief Disorder (PGD) symptom severity from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>PGD symptom severity is assessed by the Inventory of Complicated Grief (ICG) questionnaire.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Mean change in Prolonged Grief Disorder (PGD) symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>PGD symptom severity is assessed by the Structural Clinical Interview for Complicated Grief (SCI-CG).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in Posttraumatic Stress Disorder (PTSD) symptom severity in relation to the death, from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>PTSD symptom severity is assessed by the PTSD Checklist for DSM-5 (PCL-5).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in Depression symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>Depression symptom severity is assessed by the Quick Inventory of Depressive Symptomatology (QIDS-SR).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in somatic complaints from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>Somatic symptoms are assessed by the Medical Symptom Checklist (MSCL).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in the ability to cope with stress from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>Coping ability with stress is assessed by the Measure of Current Status (MOCS).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in global symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>Global symptom severity is assessed by the Clinical Global Impressions of Severity scale (CGI-S).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in global symptom improvement from the mid-intervention midpoint to the post-intervention endpoint, and one-month follow-up visit.</measure>
      <time_frame>Assessed during the mid-intervention midpoint (week 4), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).</time_frame>
      <description>Global symptom improvement is assessed by the Clinical Global Impressions of Improvement scale (CGI-I).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in skin conductance response rates to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Skin conductance response rates during the Script-Driven Imagery paradigm are measured as peripheral biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in heart rate responses to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Heart rate responses during the Script-Driven Imagery paradigm are measured as peripheral biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in skin conductance response rates during general stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Skin conductance response rates during the Loud Tones paradigm are measured as peripheral biomarkers of general stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in heart rate responses to general stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Heart rate responses during the Loud Tones paradigm are measured as peripheral biomarkers of general stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in Blood Oxygentation Level Dependent (BOLD brain activity) signals during bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Blood Oxygentation Level Dependent (BOLD brain activity) signals during a Script-Driven Imagery paradigm are measured as neural biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in brain Functional Connectivity during bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Brain Functional Connectivity during a Script-Driven Imagery paradigm are measured as neural biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in Blood Oxygentation Level Dependent (BOLD brain activity) signals during general stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Blood Oxygentation Level Dependent (brain activity) signals during a Loud Tones paradigm are measured as neural biomarkers of general stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Mean change in brain Functional Connectivity during general stress from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Brain Functional Connectivity during a Loud Tones paradigm are measured as neural biomarkers of general stress reactivity in the neuroimaging scanner.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Characteristics of the death.</measure>
      <time_frame>Assessed during the screening visit (week-4 until 0).</time_frame>
      <description>Charcteristics of the death are assessed as covariates and include the time since the loss, the type of death, the cause of death, and the relationship between the participant and the deceased.</description>
    </other_outcome>
    <other_outcome>
      <measure>The absence of diagnostic exclusion criteria and co-occurring Axis-I psychiatric disorders.</measure>
      <time_frame>Assessed during the screening visit (week-4 until 0).</time_frame>
      <description>Diagnoses is assessed by the Mini International Neuropsychiatric Interview (MINI).</description>
    </other_outcome>
    <other_outcome>
      <measure>Socio-demographic variables.</measure>
      <time_frame>Assessed during the screening visit (week-4 until 0).</time_frame>
      <description>Socio-demographic variables are assessed as potential Confounders for grief reactions and include age, sex, gender, socioeconomic status, educational level, racial and ethnic origins, menstrual cycle information, and handedness.</description>
    </other_outcome>
    <other_outcome>
      <measure>Self-reports of mood and bereavement-related stress responses.</measure>
      <time_frame>Assessed during each imagery phase of the Script-Driven Imagery paradigm during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).</time_frame>
      <description>Self-report mood and bereavement-related stress responses measured on 8-point Likert scales (range 0 &quot;none&quot; - 8 &quot;a great deal&quot;) are assessed for vividness, valence related to control/dominance, happiness/pleasure, and excitement/ arousal of their imagery, as well as feelings of sadness, anger, fear, disgust, surprise, guilt, emotional pain and yearning for the deceased during each imagery phase of the Script-Driven Imagery paradigm in the neuroimaging scanner to check that the paradigm elicited the intended emotions.</description>
    </other_outcome>
    <other_outcome>
      <measure>Mean change in self-reports of mood and bereavement-related stress responses from the pre-intervention baseline to the post-intervention endpoint visit.</measure>
      <time_frame>Assessed during each imagery phase of the Script-Driven Imagery paradigm, and from the pre-intervention baseline (week 0) to post-intervention endpoint visit (week 8).</time_frame>
      <description>Self-report mood and bereavement-related stress responses measured on 8-point Likert scales (range 0 &quot;none&quot; - 8 &quot;a great deal&quot;) are assessed for vividness, valence related to control/dominance, happiness/pleasure, and excitement/ arousal of their imagery, as well as feelings of sadness, anger, fear, disgust, surprise, guilt, emotional pain and yearning for the deceased during each imagery phase of the Script-Driven Imagery paradigm in the neuroimaging scanner.</description>
    </other_outcome>
    <other_outcome>
      <measure>Procedure-related time variables.</measure>
      <time_frame>Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).</time_frame>
      <description>Procedure-related time variables are assessed as potential potential covariates and include time of arrival and end time during assessment visits.</description>
    </other_outcome>
    <other_outcome>
      <measure>Potential adverse events experienced by the participant.</measure>
      <time_frame>Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).</time_frame>
      <description>Potential adverse events are assessed as safety check-in assessment using the Adverse Events Monitoring Form.</description>
    </other_outcome>
    <other_outcome>
      <measure>Suicidal risk experienced by the participant.</measure>
      <time_frame>Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).</time_frame>
      <description>Suicidal risk is assessed as safety check-in assessment and will include the severity of a patient's suicidal ideation using the Clinician Suicide Assessment Checklist (CSAS).</description>
    </other_outcome>
    <other_outcome>
      <measure>Procedure-related comments</measure>
      <time_frame>Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).</time_frame>
      <description>Procedure-related comments are assessed as any important notes or comments about the research procedures.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">30</enrollment>
    <condition>Prolonged Grief Disorder</condition>
    <arm_group>
      <arm_group_label>Immediate Meditation Training group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The Immediate Meditation Training group will immediately receive 8 weekly sessions of Mindfulness Training within 4 weeks after the Baseline visit (V0, during which participants are randomized).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Waitlist Control group</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>The Waitlist Control group will receive the Mindfulness Training after a waiting time of 12 weeks. Participants in this group will not receive any type of intervention before this and will wait till the Immediate Meditation Training group finished all assessment visits (including the follow-up visit in week 12 (V3)).</description>
    </arm_group>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Meditation Training</intervention_name>
      <description>The Meditation Training consists of 8 weekly sessions of Mindfulness Training and is adapted from the group-based Stress Management and Resiliency Training - Relaxation Response Resiliency Program, SMART-3RP. This training is structured around the following four goals:&#xD;
  Education about stress response&#xD;
  Elicitation of the Relaxation Response through Mindfulness Training&#xD;
  Creating adaptive perspectives&#xD;
  Coping strategiest.</description>
      <arm_group_label>Immediate Meditation Training group</arm_group_label>
      <other_name>Mindfulness Training</other_name>
      <other_name>SMART</other_name>
    </intervention>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Waitlist</intervention_name>
      <description>The waitlist consists of a waiting time of 12 weeks during which participants will nog receive any type of intervention.</description>
      <arm_group_label>Waitlist Control group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Must have lost a loved one (spouse, romantic partner, parent, child, sibling, close&#xD;
               friend)&#xD;
  &#xD;
            -  Must have a score &gt;29 on the Inventory of Complicated Grief (ICG)&#xD;
  &#xD;
            -  Clinical diagnosis of Prolonged Grief Disorder as assessed by the Structured Clinical&#xD;
               Interview for Complicated Grief (SCI-CG)&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  History of a lifetime clinical diagnosis of schizophrenia&#xD;
  &#xD;
            -  History of a lifetime clinical diagnosis of bipolar disorder&#xD;
  &#xD;
            -  History of a lifetime clinical diagnosis of a psychotic disorder&#xD;
  &#xD;
            -  Current diagnosis of substance or alcohol use disorder within the past 12 months&#xD;
  &#xD;
            -  History of a neurologic disease, seizures, stroke or head injury resulting in&#xD;
               prolonged loss of consciousness and/or neurological sequelae&#xD;
  &#xD;
            -  Current pregnancy as assessed by a urinary pregnancy test at screening during the&#xD;
               Screening (week -4 until 0), Baseline (week 0) or Endpoint visit (week 8), or lack of&#xD;
               use approved methods birth control for women of childbearing age&#xD;
  &#xD;
            -  Currently practice of mind-body techniques at least once a week (e.g., yoga) in the&#xD;
               past 3 months&#xD;
  &#xD;
            -  Currently undergoing concomitant psychotherapy for grief (any psychotherapy)&#xD;
  &#xD;
            -  Left-handedness&#xD;
  &#xD;
            -  Current use of medications that would affect cerebral metabolism&#xD;
  &#xD;
            -  Any contraindications to Magnetic Resonance Imaging (MRI)&#xD;
  &#xD;
            -  Being under legal guardianship&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>60 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Eric BUI, Professor</last_name>
      <role>Principal Investigator</role>
      <affiliation>CHU de Caen, Université de Caen Normandie, INSERM U1237, PhIND</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Annick Haelewyn-Razafimandimby, Associate Pr</last_name>
      <role>Study Director</role>
      <affiliation>INSERM U1237, PhIND</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Charlotte Hilberdink, Postdoc</last_name>
      <role>Study Chair</role>
      <affiliation>INSERM U1237, PhIND</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>CHU de Caen et Université de Caen Normandie - Centre Esquirol Adult Psychiatry</name>
        <address>
          <city>Caen</city>
          <state>Calvados</state>
          <zip>14000</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <link>
      <url>https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp</url>
      <description>Weathers, F., B. Litz, T. Keane, P. Palmieri, B. Marx and P. Schnurr (2013). The PTSD Checklist for DSM-5 (PCL-5). Scale available from the National Center for PTSD.</description>
    </link>
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    <verification_date>April 2023</verification_date>
    <study_first_submitted>July 20, 2023</study_first_submitted>
    <study_first_submitted_qc>August 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 30, 2023</study_first_posted>
    <last_update_submitted>August 28, 2023</last_update_submitted>
    <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 30, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Prolonged Grief Disorder</keyword>
    <keyword>Bereavement</keyword>
    <keyword>Mindfulness Training</keyword>
    <keyword>Script-driven Imagery</keyword>
    <keyword>Stress Reactivity</keyword>
    <keyword>Neuroimaging</keyword>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06017765
  org study id: 22-0245
  secondary id: 2022-A02603-40
  nct id: NCT06017765
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this clinical trial is to pilot the effectiveness of an 8-week standardized
        Mindfulness Training program to decrease the psychiatric and somatic symptoms of prolonged
        grief disorder (PGD) and to examine changes in physiological and neuroimaging biomarkers of
        bereavement-related stress reactivity that are associated with Mindfulness Training in
        grieving adult patients (men and women, aged 18-60) who are diagnosed with PGD.
  
        The main questions it aims to answer are:
  
          1. What is the effectiveness of Mindfulness Training to lower PGD symptom severity?
  
          2. What is the effectiveness of Mindfulness Training on physiological and neuroimaging
             biomarkers of stress reactivity?
  
          3. What are the potential mechanisms of treatment change of Mindfulness Training?
  
        Participants will be:
  
          -  randomly assigned to immediately receiving an 8-week Mindfulness Training program or
             after a 12-week waitlist.
  
          -  assessed for psychiatric and somatic symptoms and for physiological responses during a
             baseline, midpoint and endpoint visit, and at a one-month follow-up visit.
  
          -  assessed for functional neuroimaging biomarkers of bereavement-related and general
             stress reactivity at the baseline and endpoint visits using a script-driven imagery task
             (which induces bereavement-related stress reactivity during an imagery of a personal
             situation related to the death compared to imagery of a neutral personal situation), and
             loud tones stress task (which induces general stress reactivity).
  
        Researchers will compare the Mindfulness Training group (which consists of patients with PGD
        who will receive the Mindfulness Training immediately) with the waitlist control group (which
        consists of patients with PGD who are waiting on a waitlist to receive the training after the
        Mindfulness Training group) to investigate if they differ in PGD symptom severity as well as
        physiological and neuroimaging biomarkers of stress reactivity.
  Bereavement is a major life stressor that triggers a stress response that can last months or
        years after the death of a loved one. This condition of persisting grief response called
        Prolonged Grief Disorder (PGD) has been recently included in the World Health Organization
        (WHO) International Classification of Diseases, and the fifth text-revised version of the
        Diagnostic and Statistical Manual of Mental Disorders (DSM-5TR). A core symptom of PGD is the
        heightened reactivity to reminders of the death. This stress response, if exaggerated and
        persisting, is associated with increased risk for mental health problems including suicide,
        as well as somatic problems such as cardiac adverse events. To date, no efficacious
        intervention for reducing a bereavement-related stress response exist to prevent the negative
        health outcomes of adults who lost a loved one. Mindfulness Training has shown efficacy to
        decrease the general stress reactivity, as was shown in healthy individuals and in anxiety
        disorders, supposedly by improving emotional regulation. Therefore, it has the potential to
        successfully target bereavement-related stress-reactivity in grievers, as supported by our
        pilot data. However, it is unknown whether mindfulness meditation may also decrease
        bereavement-specific stress reactivity, one of the core symptoms of PGD. Furthermore, little
        is known about the neurobiological changes that underlie the decrease in stress reactivity
        that results from mindfulness training.
  
        The present proposal is the first ever clinical trial to pilot the effectiveness of an 8-week
        Mindfulness Training to decrease psychiatric and somatic symptoms of PGD in adult patients,
        as well as to pilot changes in physiological and neuroimaging biomarkers of
        bereavement-related stress reactivity that are associated with Mindfulness Training using a
        script-driven imagery task (which induces bereavement-related stress reactivity during an
        imagery of a personal situation related to the death compared to imagery of a neutral
        personal situation), and loud tones stress task (which induces general stress reactivity). As
        PGD is a newly recognized psychiatric condition, there are very limited data available about
        its pathophysiology and neurobiology, and in particular how treatments can intervene on it.
        Although mind-body interventions such as Mindfulness Training have recently shown to be
        effective for stress-related conditions, limited data are available about their mechanisms of
        actions. Our proposal is the first to examine trauma-related emotional regulation neural
        circuits implicated in the effects of Mindfulness Training on pathological grief reactions.
  
          1. OBJECTIVES:
  
             This study aims to examine the effects of an 8-week standardized Mindfulness Training
             program on PGD symptom severity and stress reactivity, as well as to elucidate the
             neural mechanism of these effects, in grieving adult patients who are diagnosed with
             PGD.
  
             The specific aims of this study are:
  
               -  PRIMARY AIM Aim 1. Examine the efficacy of Mindfulness Training to decrease PGD
                  symptom severity (primary outcome) in a group of patients with PGD who will
                  immediately receive the training versus the waitlist control group consisting of
                  patients with PGD who are waiting on a waitlist to receive the training after the
                  Mindfulness Training group.
  
               -  SECONDARY AIMS Aim 2. Examine the efficacy of Mindfulness Training on physiological
                  and neuroimaging biomarkers of bereavement-related and general stress reactivity in
                  a group of patients with PGD who will immediately receive the training versus the
                  waitlist control group.
  
             Aim 3. Examine potential mechanisms of action of treatment change of Mindfulness
             Training in a group of patients with PGD who will immediately receive the training
             versus the waitlist control group.
  
          2. METHODS:
  
             The investigators conduct a pilot randomized wait-list controlled trial of an 8-week
             standardized Mindfulness Training program for PGD and examine its effects on
             physiological and neural correlates of bereavement-related and general stress
             reactivity. N=30 adults with PGD are included who will be randomly assigned (1:1 group
             randomization) to immediately receiving an 8-week Mindfulness Training program
             (experimental group), adapted from the Stress Management and Resiliency Training -
             SMART, versus after a 12-week waitlist (control group). During a baseline, midpoint,
             endpoint, and one-month follow-up visit, participants are assessed for psychiatric and
             somatic symptoms using several questionnaires. In addition, at the baseline and endpoint
             visit, the investigators will perform functional magnetic resonance imaging (fMRI) to
             assess functional neuroimaging biomarkers (brain activity and functional connectivity)
             of bereavement-related and general stress reactivity while collecting physiological
             responses (heart rate and skin conductance), using a script-driven imagery task
             (inducing bereavement-related stress reactivity during imagery of a personal situation
             related to the death versus imagery of a neutral personal situation), and loud tones
             stress task (inducing general stress reactivity).
  
             Participants will not be blinded to the intervention condition. They will complete
             self-report questionnaires and be assessed by blinded Independent Evaluators, who will
             not be involved in the Mindfulness Training sessions, at the baseline (week 0), midpoint
             (week 4), endpoint (week 8), and follow-up visit (week 12). Participants will be
             instructed to keep their evaluators blinded to the randomization. Blinded Independent
             Evaluators will be clinical psychologists who are fully trained in the different
             measures.
  
          3. HYPOTHESES:
  
               1. Hypothesis 1. It is hypothesized that adult patients with PGD who are assigned to
                  immediate Mindfulness Training will exhibit significantly greater improvements from
                  the baseline to the endpoint visit (and the one-month follow-up visit), than the
                  patients in the waitlist control group, concerning PGD symptom severity (primary
                  outcome), PTSD symptom severity, depressive symptom severity, somatic complaints,
                  and/or the ability to cope with stress, and global symptom improvement and
                  severity.
  
               2. Hypothesis 2-a. It is hypothesized that adult patients with PGD who are assigned to
                  immediate Mindfulness Training will exhibit significantly greater changes in
                  physiological stress responses, as measured by skin conductance and heart rate,
  
                    -  for bereavement-related stress reactivity in response to the imagery of a
                       personal situation related to the death (compared to imagery of a neutral
                       personal situation, using a script-driven imagery task) from the baseline to
                       the endpoint visit, than the patients in the waitlist control group.
  
                    -  for general stress reactivity in response (induced by the loud tones stress
                       task) from the baseline to the endpoint visit, than the patients in the
                       waitlist control group.
  
               3. Hypothesis 2-b. It is hypothesized that adult patients with PGD who are assigned to
                  immediate Mindfulness Training will show significantly greater changes in
                  blood-oxygen-level dependent (BOLD) signals in response to the imagery of a
                  personal situation related to the death (compared to imagery of a neutral personal
                  situation, using a script-driven imagery task) in brain regions that are implicated
                  in emotion regulation and regulatory control at the endpoint visit, compared to the
                  patients in the waitlist control group, including:
  
                    -  less BOLD activity in the amygdala,
  
                    -  more BOLD activity in the medial prefrontal cortex (consisting of the medial
                       frontal gyrus and rostral anterior cingulate cortex),
  
                    -  more functional connectivity between the amygdala and the medial prefrontal
                       cortex.
  
               4. Hypothesis 3-a. It is hypothesized that at the baseline visit, psychiatric and
                  somatic symptom severity will be significantly correlated with the physiological
                  and neuroimaging biomarkers of bereavement-related stress reactivity in response to
                  the imagery of a personal situation related to the death (compared to imagery of a
                  neutral personal situation).
  
               5. Hypothesis 3-b. It is hypothesized that greater reductions in psychiatric and
                  somatic symptom severity between the baseline and endpoint visit, will be
                  significantly correlated with greater decreases in physiological and neuroimaging
                  biomarkers of bereavement-specific stress reactivity in response to the imagery of
                  a personal situation related to the death (compared to imagery of a neutral
                  personal situation).
  
               6. Hypothesis 3-c. It is hypothesized that changes in bereavement-related stress
                  reactivity in response to the imagery of a personal situation related to the death
                  (compared to imagery of a neutral personal situation) will mediate the effects of
                  Mindfulness Training on the reductions in clinical symptom severity.
  
          4. PARTICIPATION:
  
             - All potential participants are asked to sign the informed consent form (approved by
             the ethics committee) with a medical doctor/study clinician prior to participation and
             are given as much time as needed to review the consent form. The consent form states
             that participation is voluntary, that participants can refuse to answer any questions,
             that they can withdraw from the research at any time, and that participation in no way
             impacts their care. All participants must be beneficiaries of the social security
             system.
  
          5. METHODOLOGY
  
               1. Power considerations:
  
                  Our primary analysis follows the intention-to-treat (ITT) principle to compare
                  participants' outcomes according to their initial treatment assignment. The
                  investigators restrict the ITT sample to randomized participants who attend at
                  least one treatment session, including those who do not have analyzable
                  neuroimaging and/or psychophysiological data. With N = 30 participants with usable
                  data for aim 2, and alpha = 0.05 (2-tailed), there will be 80% power to detect a
                  large d=1.1 difference.
  
               2. Dropout and study withdrawal:
  
             Participants may discontinue their participation if they wish, at any time and for any
             reason, or upon the decision of the investigator.
  
             Premature study exits may be (a) progression of the study condition, (b) participants'
             refusal to continue, (c) withdrawal of consent, (d) protocol violation requiring a study
             exit, (e) unblinding, (f) by decision of the investigator, (g) by decision of the
             sponsor, (h) participant non-compliance.
  
             At every assessment visit, and every 2 weeks during the active phase of the Mindfulness
             Training, an investigator will assess symptom improvement and worsening, adverse events
             (reviewed weekly by the Principal Investigator), and suicidal risk assessments
             (monitored bi-weekly). Any participant at immediate risk, will be referred to a higher
             level of care and discontinued from the study. A participant is also removed in case of
             an intercurrent illness, or because they require a new drug or therapeutic method that
             has demonstrated its efficacy in this indication (in this case, the withdrawal from the
             trial will occur as soon as the new therapeutic agent is introduced).
  
             Any study withdrawal is documented and specified until the trial exit. The investigators
             replace each early drop out (over enrollment). Missing data will be handled through
             maximum likelihood estimation in the primary analysis models, using predictors of
             missingness and drop-out. The investigators will conduct regular quality checks to
             maintain data quality throughout. In case of uninterpretable data, they will recruit a
             few additional participants to reach N=30 with analyzable neuroimaging and
             psychophysiological data. The investigators anticipate to recruit n=35 total
             participants to obtain N=30 participants with analyzable neuroimaging and
             psychophysiological data (anticipated dropout = 20%).
  
          6. CONSIDERATIONS AND OBLIGATIONS:
  
               1. Standard Operating Procedures are created for all procedure which will address
                  registry operations and analysis activities, such as patient recruitment, data
                  collection, data management, data analysis, reporting for adverse events, and
                  possible change management.
  
               2. Data are managed in a database administered by the sponsor, in accordance with the
                  regulations in force. Data entry are performed by investigators at each center or
                  any person on the task delegation list. A data dictionary is created that contains
                  detailed descriptions of each variable used for data registry (e.g., information on
                  variable source, normal (score) ranges). Data are identified only by participant
                  codes, with all identifying information removed to protect confidentiality.
                  Participant identity will not be revealed in any presentation or publication of
                  results.
  
               3. In accordance with the French law, the participant may exercise their right to
                  access and rectify data collected at any time. The participation of the person in
                  the research as well as the modalities of the collection of his consent and the
                  delivery of the information in order to collect it are specified in the
                  participant's medical file. The sponsor will inform participants of the overall
                  results of this research at the end of the study.
  
               4. Depending on level of risk and/or impact of the study defined by the sponsor, the
                  data may be monitored randomly. In this case, a person mandated by the sponsor will
                  monitor the data collected in the data collection booklet (verification from the
                  patient's medical record). It is therefore the investigator's responsibility to
                  give free access to all the medical records of the participants involved in the
                  research (having signed a consent form).
  
               5. The investigator agrees to accept quality assurance audits by the sponsor or
                  inspections by the health authorities.
  allocation: Randomized
  intervention model: Crossover Assignment
  intervention model description: The study model is a pilot randomized waitlist controlled trial of an 8-session mindfulness training program (i.e., Stress Management and Resiliency Training, SMART program) delivered weekly for Prolonged Grief Disorder, either within 4 weeks (immediate) or after 12 weeks (waitlist). After participants have completed the baseline assessment (V0), they will be randomly assigned (1:1 randomization) to either the immediate mindfulness training group or the waitlist control group. The waitlist control group will wait for 12 weeks (when the immediate intervention group finished all study procedures, including the follow-up assessment) before receiving the mindfulness training, which is the same intervention as employed in the immediate intervention group.
  primary purpose: Treatment
  masking: Single (Outcomes Assessor)
  masking description: Participants will be assessed for psychiatric symptoms (primary objective) by blinded Independent Evaluators, who will not be involved in the mindfulness training sessions. Participants will be instructed to keep their evaluators blinded to the randomization. Blinded Independent Evaluators will be clinical psychologists who are fully trained in assessing the different measures.
  measure: Mean change in Prolonged Grief Disorder (PGD) symptom severity from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: PGD symptom severity is assessed by the Inventory of Complicated Grief (ICG) questionnaire.
  measure: Mean change in Prolonged Grief Disorder (PGD) symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: PGD symptom severity is assessed by the Structural Clinical Interview for Complicated Grief (SCI-CG).
  measure: Mean change in Posttraumatic Stress Disorder (PTSD) symptom severity in relation to the death, from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: PTSD symptom severity is assessed by the PTSD Checklist for DSM-5 (PCL-5).
  measure: Mean change in Depression symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: Depression symptom severity is assessed by the Quick Inventory of Depressive Symptomatology (QIDS-SR).
  measure: Mean change in somatic complaints from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: Somatic symptoms are assessed by the Medical Symptom Checklist (MSCL).
  measure: Mean change in the ability to cope with stress from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: Coping ability with stress is assessed by the Measure of Current Status (MOCS).
  measure: Mean change in global symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: Global symptom severity is assessed by the Clinical Global Impressions of Severity scale (CGI-S).
  measure: Mean change in global symptom improvement from the mid-intervention midpoint to the post-intervention endpoint, and one-month follow-up visit.
  time frame: Assessed during the mid-intervention midpoint (week 4), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
  description: Global symptom improvement is assessed by the Clinical Global Impressions of Improvement scale (CGI-I).
  measure: Mean change in skin conductance response rates to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Skin conductance response rates during the Script-Driven Imagery paradigm are measured as peripheral biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.
  measure: Mean change in heart rate responses to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Heart rate responses during the Script-Driven Imagery paradigm are measured as peripheral biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.
  measure: Mean change in skin conductance response rates during general stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Skin conductance response rates during the Loud Tones paradigm are measured as peripheral biomarkers of general stress reactivity in the neuroimaging scanner.
  measure: Mean change in heart rate responses to general stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Heart rate responses during the Loud Tones paradigm are measured as peripheral biomarkers of general stress reactivity in the neuroimaging scanner.
  measure: Mean change in Blood Oxygentation Level Dependent (BOLD brain activity) signals during bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Blood Oxygentation Level Dependent (BOLD brain activity) signals during a Script-Driven Imagery paradigm are measured as neural biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.
  measure: Mean change in brain Functional Connectivity during bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Brain Functional Connectivity during a Script-Driven Imagery paradigm are measured as neural biomarkers of bereavement-related stress reactivity in the neuroimaging scanner.
  measure: Mean change in Blood Oxygentation Level Dependent (BOLD brain activity) signals during general stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Blood Oxygentation Level Dependent (brain activity) signals during a Loud Tones paradigm are measured as neural biomarkers of general stress reactivity in the neuroimaging scanner.
  measure: Mean change in brain Functional Connectivity during general stress from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Brain Functional Connectivity during a Loud Tones paradigm are measured as neural biomarkers of general stress reactivity in the neuroimaging scanner.
  measure: Characteristics of the death.
  time frame: Assessed during the screening visit (week-4 until 0).
  description: Charcteristics of the death are assessed as covariates and include the time since the loss, the type of death, the cause of death, and the relationship between the participant and the deceased.
  measure: The absence of diagnostic exclusion criteria and co-occurring Axis-I psychiatric disorders.
  time frame: Assessed during the screening visit (week-4 until 0).
  description: Diagnoses is assessed by the Mini International Neuropsychiatric Interview (MINI).
  measure: Socio-demographic variables.
  time frame: Assessed during the screening visit (week-4 until 0).
  description: Socio-demographic variables are assessed as potential Confounders for grief reactions and include age, sex, gender, socioeconomic status, educational level, racial and ethnic origins, menstrual cycle information, and handedness.
  measure: Self-reports of mood and bereavement-related stress responses.
  time frame: Assessed during each imagery phase of the Script-Driven Imagery paradigm during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
  description: Self-report mood and bereavement-related stress responses measured on 8-point Likert scales (range 0 "none" - 8 "a great deal") are assessed for vividness, valence related to control/dominance, happiness/pleasure, and excitement/ arousal of their imagery, as well as feelings of sadness, anger, fear, disgust, surprise, guilt, emotional pain and yearning for the deceased during each imagery phase of the Script-Driven Imagery paradigm in the neuroimaging scanner to check that the paradigm elicited the intended emotions.
  measure: Mean change in self-reports of mood and bereavement-related stress responses from the pre-intervention baseline to the post-intervention endpoint visit.
  time frame: Assessed during each imagery phase of the Script-Driven Imagery paradigm, and from the pre-intervention baseline (week 0) to post-intervention endpoint visit (week 8).
  description: Self-report mood and bereavement-related stress responses measured on 8-point Likert scales (range 0 "none" - 8 "a great deal") are assessed for vividness, valence related to control/dominance, happiness/pleasure, and excitement/ arousal of their imagery, as well as feelings of sadness, anger, fear, disgust, surprise, guilt, emotional pain and yearning for the deceased during each imagery phase of the Script-Driven Imagery paradigm in the neuroimaging scanner.
  measure: Procedure-related time variables.
  time frame: Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).
  description: Procedure-related time variables are assessed as potential potential covariates and include time of arrival and end time during assessment visits.
  measure: Potential adverse events experienced by the participant.
  time frame: Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).
  description: Potential adverse events are assessed as safety check-in assessment using the Adverse Events Monitoring Form.
  measure: Suicidal risk experienced by the participant.
  time frame: Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).
  description: Suicidal risk is assessed as safety check-in assessment and will include the severity of a patient's suicidal ideation using the Clinician Suicide Assessment Checklist (CSAS).
  measure: Procedure-related comments
  time frame: Assessed during the screening visit (week -4 until 0), baseline visit (week 0), midpoint visit (week 4), endpoint visit (week 8), follow-up visit (week 12), and 2-weekly safety checks (week 2, week 6).
  description: Procedure-related comments are assessed as any important notes or comments about the research procedures.
  arm group label: Immediate Meditation Training group
  arm group type: Experimental
  description: The Immediate Meditation Training group will immediately receive 8 weekly sessions of Mindfulness Training within 4 weeks after the Baseline visit (V0, during which participants are randomized).
  arm group label: Waitlist Control group
  arm group type: Other
  description: The Waitlist Control group will receive the Mindfulness Training after a waiting time of 12 weeks. Participants in this group will not receive any type of intervention before this and will wait till the Immediate Meditation Training group finished all assessment visits (including the follow-up visit in week 12 (V3)).
  intervention type: Behavioral
  intervention name: Meditation Training
  description: The Meditation Training consists of 8 weekly sessions of Mindfulness Training and is adapted from the group-based Stress Management and Resiliency Training - Relaxation Response Resiliency Program, SMART-3RP. This training is structured around the following four goals:
  Education about stress response
  Elicitation of the Relaxation Response through Mindfulness Training
  Creating adaptive perspectives
  Coping strategiest.
  arm group label: Immediate Meditation Training group
  other name: Mindfulness Training
  other name: SMART
  intervention type: Behavioral
  intervention name: Waitlist
  description: The waitlist consists of a waiting time of 12 weeks during which participants will nog receive any type of intervention.
  arm group label: Waitlist Control group
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 60 Years
  healthy volunteers: No
  last name: Eric BUI, Professor
  role: Principal Investigator
  affiliation: CHU de Caen, Université de Caen Normandie, INSERM U1237, PhIND
  last name: Annick Haelewyn-Razafimandimby, Associate Pr
  role: Study Director
  affiliation: INSERM U1237, PhIND
  last name: Charlotte Hilberdink, Postdoc
  role: Study Chair
  affiliation: INSERM U1237, PhIND
  facility: 
  country: France
  url: https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp
  description: Weathers, F., B. Litz, T. Keane, P. Palmieri, B. Marx and P. Schnurr (2013). The PTSD Checklist for DSM-5 (PCL-5). Scale available from the National Center for PTSD.
  citation: Benson H, Greenwood MM, Klemchuk H. The relaxation response: psychophysiologic aspects and clinical applications. Int J Psychiatry Med. 1975;6(1-2):87-98. doi: 10.2190/376W-E4MT-QM6Q-H0UM.
  PMID: 773864
  citation: Borysenko, J. (1988). Minding the Body Mending the Mind. New York, Bantam.
  citation: Bowlby, J. (1980). Attachment and loss, volume 3: loss; sadness and depression.
  citation: Bui E, Mauro C, Robinaugh DJ, Skritskaya NA, Wang Y, Gribbin C, Ghesquiere A, Horenstein A, Duan N, Reynolds C, Zisook S, Simon NM, Shear MK. THE STRUCTURED CLINICAL INTERVIEW FOR COMPLICATED GRIEF: RELIABILITY, VALIDITY, AND EXPLORATORY FACTOR ANALYSIS. Depress Anxiety. 2015 Jul;32(7):485-92. doi: 10.1002/da.22385. Epub 2015 Jun 9.
  PMID: 26061724
  citation: Bui E, Blackburn AM, Brenner LH, Laifer LM, Park ER, Fricchione GL, Sylvia LG. Military and Veteran Caregivers' Perspectives of Stressors and a Mind-Body Program. Issues Ment Health Nurs. 2018 Oct;39(10):850-857. doi: 10.1080/01612840.2018.1485796. Epub 2018 Sep 13.
  PMID: 30212258
  citation: Eric Bui, Ilana Ander & Clara Jaussaud. (2021). Grief in the time of COVID-19: An editorial, International Journal of Mental Health, 50:1, 1-3, DOI: 10.1080/00207411.2020.1870847
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