Clinical trial NCT06017765: Coping After Loss Through Mindfulness in Adults With Prolonged Grief Disorder
Official title: Coping After Loss Through Mindfulness Training in Grieving Adults With Prolonged Grief Disorder - A Neuroimaging Pilot Study
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Prolonged Grief Disorder
Keywords: Prolonged Grief Disorder
Bereavement
Mindfulness Training
Script-driven Imagery
Stress Reactivity
Neuroimaging
Lead sponsor: University Hospital, Caen
Sponsor class: OTHER
Collaborators: name: Northeastern University
name: Institut National de la Santé Et de la Recherche Médicale, France
name: Cyceron
name: Université de Caen Normandie
First posted: 2023-08-30
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Must have lost a loved one (spouse, romantic partner, parent, child, sibling, close friend)
* Must have a score \>29 on the Inventory of Complicated Grief (ICG)
* Clinical diagnosis of Prolonged Grief Disorder as assessed by the Structured Clinical Interview for Complicated Grief (SCI-CG)

Exclusion Criteria:

* History of a lifetime clinical diagnosis of schizophrenia
* History of a lifetime clinical diagnosis of bipolar disorder
* History of a lifetime clinical diagnosis of a psychotic disorder
* Current diagnosis of substance or alcohol use disorder within the past 12 months
* History of a neurologic disease, seizures, stroke or head injury resulting in prolonged loss of consciousness and/or neurological sequelae
* Current pregnancy as assessed by a urinary pregnancy test at screening during the Screening (week -4 until 0), Baseline (week 0) or Endpoint visit (week 8), or lack of use approved methods birth control for women of childbearing age
* Currently practice of mind-body techniques at least once a week (e.g., yoga) in the past 3 months
* Currently undergoing concomitant psychotherapy for grief (any psychotherapy)
* Left-handedness
* Current use of medications that would affect cerebral metabolism
* Any contraindications to Magnetic Resonance Imaging (MRI)
* Being under legal guardianship

Primary outcomes:
measure: Mean change in Prolonged Grief Disorder (PGD) symptom severity from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
Secondary outcomes:
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.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
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.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
measure: Mean change in Depression symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
measure: Mean change in somatic complaints from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
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.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
measure: Mean change in global symptom severity from the pre-intervention baseline to the post-intervention endpoint, and one-month follow-up visit.
timeFrame: Assessed during the pre-intervention baseline (week 0), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
measure: Mean change in global symptom improvement from the mid-intervention midpoint to the post-intervention endpoint, and one-month follow-up visit.
timeFrame: Assessed during the mid-intervention midpoint (week 4), post-intervention endpoint (week 8), and one-month follow-up visit (week 12).
measure: Mean change in skin conductance response rates to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
measure: Mean change in heart rate responses to bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
measure: Mean change in skin conductance response rates during general stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
measure: Mean change in heart rate responses to general stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
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.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
measure: Mean change in brain Functional Connectivity during bereavement-related stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
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.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
measure: Mean change in brain Functional Connectivity during general stress from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: Assessed during the pre-intervention baseline (week 0) and post-intervention endpoint visit (week 8).
Other outcomes:
measure: Characteristics of the death.
timeFrame: Assessed during the screening visit (week-4 until 0).
measure: The absence of diagnostic exclusion criteria and co-occurring Axis-I psychiatric disorders.
timeFrame: Assessed during the screening visit (week-4 until 0).
measure: Socio-demographic variables.
timeFrame: Assessed during the screening visit (week-4 until 0).
measure: Self-reports of mood and bereavement-related stress responses.
timeFrame: 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).
measure: Mean change in self-reports of mood and bereavement-related stress responses from the pre-intervention baseline to the post-intervention endpoint visit.
timeFrame: 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).
measure: Procedure-related time variables.
timeFrame: 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).
measure: Potential adverse events experienced by the participant.
timeFrame: 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).
measure: Suicidal risk experienced by the participant.
timeFrame: 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).
measure: Procedure-related comments
timeFrame: 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).
Locations:
city: Caen
country: France
facility: CHU de Caen et Université de Caen Normandie - Centre Esquirol Adult Psychiatry
state: Calvados
Study officials:
affiliation: CHU de Caen, Université de Caen Normandie, INSERM U1237, PhIND
name: Eric BUI, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: INSERM U1237, PhIND
name: Annick Haelewyn-Razafimandimby, Associate Pr
role: STUDY_DIRECTOR
affiliation: INSERM U1237, PhIND
name: Charlotte Hilberdink, Postdoc
role: STUDY_CHAIR
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