Repetitive Transcranial Magnetic Stimulation Plus Reactivation Therapy Efficacy on PTSD Symptom Severity in Resistant PTSD

Study Overview
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Brief Summary
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A French multicenter randomized and double blinded shamed controlled study recruiting patients who present resistant PTSD. The aim of this trial is to assess the efficacy of cerebral modulation by rTMS with simultaneous reactivation of traumatic memory on the PTSD symptoms at M1.

Detailed Description
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Detailed Description : PTSD is considered as one of the top 10 public health concerns. Most patients with PTSD receive pharmacologic treatment and traumatic reactivation therapy. However, to date, the optimal treatment alternatives for non-responders PTSD patients are unknown. Functionally, the metabolic activity of the prefrontal-amygdala cortex circuit in PTSD is significantly altered. Repetitive Transcranial Magnetic Stimulation (rTMS) provides focused, non-invasive stimulation of cortical areas of the central nervous system and could correct cortical defective activation of the prefrontal cortex seen in PTSD Patient (FDA has already approved rTMS for depression and acoustic-verbal hallucinations treatment). Pairing rTMS with cues relevant to the trauma may be a novel approach to treat PTSD patient. The study will enroll 102 subjects with resistant PTSD. After screening and inclusion phase, the treatment phase with 12 sessions of rTMS and simultaneous reactivation of traumatic memory or sham rTMS and simultaneous reactivation of traumatic memory will be performed (3 to 4 weeks). Antidepressant treatment will be maintained. The follow up phase consist of 3 visits at M1, M3 and M6 to follow the evolution of the PTSD symptoms.

Official Title
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Repetitive Transcranial Magnetic Stimulation Plus Reactivation Therapy Efficacy on PTSD Symptom Severity in Resistant PTSD, a Randomized Double Blind Sham Controlled Trial (TraumaStim)

Conditions
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Post Traumatic Stress Disorder

Intervention / Treatment
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* Procedure: Repetitive Transcranial Magnetic Stimulation (rTMS)
* Procedure: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged between 18 and 65 years. Presenting a PTSD according to DSM-5 criteria Patient with persistent symptoms (PCL-5>40) after a 6 weeks treatment with labelled antidepressant for PTSD (paroxetine or sertraline) Patient with health insurance (AME excepted) Signed written inform consent Exclusion Criteria : Contraindication for rTMS: History of epilepsy or seizure Cochlear implants Cardiac pacemaker or intracardiac lines, or metal in the body Patient has already had a rTMS session and/or Electroconvulsive therapy (ECT) and/or Transcranial direct current stimulation (tDCS) Ongoing PTSD-oriented cognitive-behavioral therapy Lifetime psychotic or bipolar disorder or antisocial personality or borderline personality Brain injury defined by medical report (including cortical and subcortical atrophy, dementia, stroke, transient ischemic attack and head trauma) Current substance dependence (including alcohol, excluding tobacco); Acute suicidal ideation No adequate mastering of the French language or no ability to consent Pregnancy (confirmed by a urine test beta-HCG) or breast feeding or absence of birth control Patient under legal protection measure and or deprived of freedom Participation in any other interventional study or in the exclusion period any other interventional study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rTMS with simultaneous reactivation of traumatic memory in resistant PTSD<br>rTMS with simultaneous reactivation of traumatic memory in resistant PTSD during 12 sessions (3 to 4 weeks) | Procedure: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* rTMS with simultaneous reactivation of traumatic memory will be performed 3 to 4 times a week for 3 to 4 weeks through 12 sessions. A traumatic script will be prepared by the patient at the inclusion visit, which will be used to reactivate the traumatic memory after every rTMS or sham rTMS sessions.<br>|
| Placebo Comparator: sham rTMS and simultaneous reactivation of traumatic memory in resistant PTSD<br>sham rTMS and simultaneous reactivation of traumatic memory in resistant PTSD during 12 sessions (3 to 4 weeks) | Procedure: Placebo<br>* sham rTMS with simultaneous reactivation of traumatic memory will be performed 3 to 4 times a week for 3 to 4 weeks through 12 sessions. A traumatic script will be prepared by the patient at the inclusion visit, which will be used to reactivate the traumatic memory after every rTMS or sham rTMS sessions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PTSD severity score measured at M1 after 12 sessions of rTMS or sham rTMS and simultaneous reactivation of traumatic memory | CAPS-5 total severity score at M1 post treatment will be compared between groups (cerebral modulation by rTMS with simultaneous reactivation of traumatic memory VS sham rTMS with simultaneous reactivation of traumatic memory) | Month 1 after 12 sessions of rTMS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PTSD severity scores at M3 and M6 measured with CAPS-5 | The different dimensions of PTSD (assess by CAPS-5): Severity, repetition, avoidance, neurovegetative activation at M3 and M6 post treatment | At inclusion (v1), Month 3 and Month 6 post treatment | 
| The severity of PTSD assessed by PCL-5 at each visit. | PTSD severity score measured with the PTSD Checklist (PCL-S self-questionnaire) at once a during TMS sessions, M1, M3 and M6 post treatment | at once a during TMS sessions, Month1, Month 3 and Month 6 post treatment. | 
| Dissociative symptoms severity scores (1) | Dissociative symptoms severity score measured with the Clinician Administered Dissociative States Scale (CADSS) | at inclusion (V1), up to 4 weeks (V13) (end of treatment), Month 1, Month 3, Month 6 post treatment | 
| Dissociative symptoms severity scores (2) | The Multidimensional Assessment of Interoceptive Awareness (MAIA) | at inclusion (V1), up to 4 weeks (V13) (end of treatment), Month 1, Month 3, Month 6 post treatment | 
| Dissociative symptoms severity scores (3) | The Dissociative Experiences Scale (DES) | at inclusion (V1), up to 4 weeks (V13) (end of treatment), Month 1, Month 3, Month 6 post treatment | 
| The severity scores of the dimensions of anxiety at V13 (end of treatment), M1, M3, M6 post treatment. | The severity scores of the dimensions of anxiety measured with HAM-A at V13 (end of treatment), M1, M3 and M6. | Up to 4 weeks (V13) (end of treatment), Month 1, Month 3, Month 6 post treatment. | 
| Symptoms of depression at V13 (end of treatment), M1, M3, M6 post treatment. | The severity scores of the dimensions of depression measured with HAM-D at V13 (end of treatment), M1, M3 and M6. | at V13 (end of treatment), Month 1, Month 3, Month 6 post treatment. | 
| Evolution of social cognition at M3 post treatment. | Evolution of social cognition at M3 post treatment by a neuropsychologist | at Month 3 post treatment | 
| Quality of life | Quality of life evolution post treatment and M6 assessed by WHOQOL EuroQol Health Measure | post treatment and Month 6 | 
| Quality of life | Quality of life evolution post treatment and M6 assessed by EQ-5D-5L | post treatment and Month 6 | 
| Proportion of adverse events during the active treatment phase and during the follow-up | Number and description of adverse events during the active treatment phase and during the follow-up | through study completion, up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stress Disorders, Traumatic Stress Disorders, Post-Traumatic Trauma and Stressor Related Disorders, Mental Disorders