Treatment of Pediatric Post-traumatic Stress Disorder With Memory Reactivation Under the Influence of Propranolol

Study Overview
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Brief Summary
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By age 18, roughly 8% of traumatized youth have met criteria for a diagnosis of PTSD, with numbers rising up to 40% in cases of sexual abuse and assault. To date there is no empirical support for the use of psychopharmacological interventions as treatment of pediatric PTSD. Trauma-focused psychotherapeutic/TFP approaches should be favored in childhood PTSD. However, when compared to active control conditions, TFP produced a mean effect size on child and adolescents population (g=0.83). Moreover, in therapies with a substantial exposure component, the intense and lengthy reexperiencing of the traumatic event results in a substantial proportion of participants dropping out. The reactivation of a previously consolidated memory can make it labile, subsequently requiring a re-stabilization of it called reconsolidation of the memory. Acting on these reconsolidation processes makes possible to interfere with the subsequent storage of this memory.

Detailed Description
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By age 18, roughly 8% of traumatized youth have met criteria for a diagnosis of PTSD, with numbers rising up to 40% in cases of sexual abuse and assault. To date there is no empirical support for the use of psychopharmacological interventions as treatment of pediatric PTSD. Trauma-focused psychotherapeutic/TFP approaches should be favored in childhood PTSD. However, when compared to active control conditions, TFP produced a mean effect size on child and adolescents population (g=0.83). Moreover, in therapies with a substantial exposure component, the intense and lengthy reexperiencing of the traumatic event results in a substantial proportion of participants dropping out. The reactivation of a previously consolidated memory can make it labile, subsequently requiring a re-stabilization of it called reconsolidation of the memory. Acting on these reconsolidation processes makes possible to interfere with the subsequent storage of this memory. The combination of the targeted reactivation of the traumatic memory and the intake of an agent that decreases the reconsolidation can thus disrupt the recall of unwanted memories and thus serve as a treatment for people suffering from traumatic memories, such as in PTSD. Since stimulation of β-noradrenergic receptors facilitates the consolidation of memories as well as their re-consolidation, an antagonist of these receptors, propranolol, has generated considerable interest as a treatment to alleviate emotional and traumatic memories in individuals with PTSD. In adults diagnosed with long-standing PTSD two 6-week, double-blind, placebocontrolled, randomised clinical trials, one in 60 subjects and the other in 67 have shown promising results. PTSD participants who actively recalled their traumatic event under the influence of propranolol once a week for up to 6 weeks showed a substantial decrease in symptom ratings compared with placebo. Thus, all of this data led the team to propose a comparable design study in children with PTSD

Official Title
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Treatment of Pediatric Post-traumatic Stress Disorder With Memory Reactivation Under the Influence of Propranolol: A Randomized Placebo-controlled Trial. PPP

Conditions
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PTSD

Intervention / Treatment
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* Drug: Propranolol Oral Product
* Drug: Placebo
* Other: memory reactivation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 7-12 years CPTS-RI total score ≥40 Primary diagnosis of PTSD (6 months or more after the traumatic event) Heart rate ≥ 55 bpm Systolic blood pressure ≥ 95 mm Hg Affiliation to a social security scheme Written consent signed by the parents/holders of parental authority and the investigator Acceptance of the protocol by the child-Child and Parents/Holders of parental authority fluent in French Exclusion Criteria: Age<7 years or ≥13 years Children whose parents have been deprived of their authority Contraindication to propranolol (cardiogenic shock, sinus bradycardia, hypotension (< fifth percentile oscillometric or <2SD) (Banker et al., 2016 - see APPENDIX 1), greater than first-degree heart block, heart failure, bronchial asthma and hypersensitivity to propranolol hydrochloride) Concurrent medication with possible interactions with propranolol (cf 8.2) Concurrent psychotropic drugs that have been shown to be effective in improving symptoms of PTSD (Antidepressants, atypical antipsychotics, mood stabilizers) Concurrent psychotherapy (>1 structured session/month declared by the clinician who follows the child) Current active psychosis, anorexia nervosa, bulimia nervosa, binge-eating disorder, attention-deficit hyperactivity disorder, autism spectrum disorder Children with psoriasis Children with a predisposition to hypoglycemia Obsessive-compulsive disorders Bipolar Disorders Mental retardation, Traumatic brain injury (loss of consciousness > 10 minutes) Currently treated with a bradycardic drug Concurrent participation to another interventional study Renal or Hepatic Impairment Pregnancy

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 12 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propranolol<br>Patient will receive oral propranolol | Drug: Propranolol Oral Product<br>* Child will receive oral propranolol (syrup). The dose of propranolol will increase gradually over the first 3 treatment sessions in order to assess tolerance.<br>* Other names: Propranolol;Other: memory reactivation<br>* 90 minutes after the propranolol take, a trained psychologist will ask the child to recount his trauma.<br>|
| Placebo Comparator: Placebo<br>Patient will receive oral placebo | Drug: Placebo<br>* Child will receive oral placebo (syrup). The dose of placebo will increase gradually over the first 3 treatment sessions in order to match propranolol intervention.<br>Other: memory reactivation<br>* 90 minutes after the propranolol take, a trained psychologist will ask the child to recount his trauma.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child Post-Traumatic Stress Reaction Index/CPTS-RI | The main evaluation criterion will be the difference between the Child Post-Traumatic Stress Reaction Index/CPTS-RI total score administered at week 8 and week 0. The CPTS-RI is a scale comprised of 20 Likert-type items, intended for children from 6 to 16 years, which evaluates the symptoms of PTSD after exposure to various traumatic events. Each item frequency is rated on a 5-point scale, from never (=0) to almost always (=4). The global score consists of the sum of the 20 items and ranges from 0 to 80, with higher scores indicating higher PTSD symptom severity. The time required for completion of the scale is 15-20 min. A total score of 12-24 is associated with a mild level of PTSD, from 25-39 with a moderate level, from 40-59 with a severe level, and ≥60 with a very severe level. | week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child Post-Traumatic Stress Reaction - Week 32 Index/CPTS-RI | The difference between the Child Post-Traumatic Stress Reaction Index/CPTS-RI total score at week 32 and week 8 . The CPTS-RI is a scale comprised of 20 Likert-type items, intended for children from 6 to 16 years, which evaluates the symptoms of PTSD after exposure to various traumatic events. Each item frequency is rated on a 5-point scale, from never (=0) to almost always (=4). The global score consists of the sum of the 20 items and ranges from 0 to 80, with higher scores indicating higher PTSD symptom severity. The time required for completion of the scale is 15-20 min. A total score of 12-24 is associated with a mild level of PTSD, from 25-39 with a moderate level, from 40-59 with a severe level, and ≥60 with a very severe level. | week 32 | 
| Child Post-Traumatic Stress Reaction - Week 60 Index/CPTS-RI | The difference between the Child Post-Traumatic Stress Reaction Index/CPTS-RI total score administered at week 60 and week 8. The CPTS-RI is a scale comprised of 20 Likert-type items, intended for children from 6 to 16 years, which evaluates the symptoms of PTSD after exposure to various traumatic events. Each item frequency is rated on a 5-point scale, from never (=0) to almost always (=4). The global score consists of the sum of the 20 items and ranges from 0 to 80, with higher scores indicating higher PTSD symptom severity. The time required for completion of the scale is 15-20 min. A total score of 12-24 is associated with a mild level of PTSD, from 25-39 with a moderate level, from 40-59 with a severe level, and ≥60 with a very severe level. | week 60 | 
| Child PTSD Checklist-Child version/CPC-C total score | The difference between the Child PTSD Checklist-Child version/CPC-C total score administered at week 8 and week 0 on items 14-34. The CPC-C includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-C 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 8 | 
| Child PTSD Checklist-Child version/CPC-C total score - Week 32 | The difference between the Child PTSD Checklist-Child version/CPC-C total score administered at week 8 and week 32 on items 14-34. The CPC-C includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-C 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 32 | 
| Child PTSD Checklist-Child version/CPC-C total score - Week 60 | The difference between the Child PTSD Checklist-Child version/CPC-C total score administered at week 8 and week 60 on items 14-34. The CPC-C includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-C 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 60 | 
| Child PTSD Checklist-Parent version/CPC-P total score - Week 32 | The difference between the Child PTSD Checklist-Parent version/CPC-P total score administered at week 8 and week 32 on items 14-34 (PTSD symptom items). The CPC-P includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-P, 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 32 | 
| Child PTSD Checklist-Parent version/CPC-P total score - Week 60 | The difference between the Child PTSD Checklist-Parent version/CPC-P total score administered at week 8 and week 60 on items 14-34 (PTSD symptom items). The CPC-P includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-P, 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 60 | 
| Child PTSD Checklist-Parent version/CPC-P total score | The difference between the Child PTSD Checklist-Parent version/CPC-P total score administered at week 8 and week 0 on items 14-34 (PTSD symptom items). The CPC-P includes a traumatic events page, 21 PTSD symptoms and 6 items of functional impairment. It is free in the public domain. For scoring the CPC-P, 7-18 years (Version May 23, 2014.), the Traumatic Events page (items 1-13) is important to include before administering the symptom portion. Items 14-34 are PTSD symptom items. | Week 8 | 
| Kiddie-SADS-Present and Lifetime Version DSM-5/K-SADS-PL-DSM5 | The percentage of children without a current diagnosis of PTSD assessing with Kiddie-SADS-Present and Lifetime Version DSM-5/K-SADS-PL-DSM5. The K-SADS-PL-DSM5 (November 2016) is a semi-structured diagnostic interview designed to collect information from the child or adolescent as well as their parents or other informants. | week 8 | 
| Current diagnosis of PTSD at Week 32 | The percentage of children without a current diagnosis of PTSD assessing with Kiddie-SADS-Present and Lifetime Version DSM-5/K-SADS-PL-DSM5. The K-SADS-PL-DSM5 (November 2016) is a semi-structured diagnostic interview designed to collect information from the child or adolescent as well as their parents or other informants. | week 32 | 
| Children Depression Inventory/CDI total score | The difference between the Children Depression Inventory/CDI total score administered at week 8 and week 0. The CDI is comprised of 27 items assessing self-reported symptoms of depression in children and adolescents 7-17 years of age. | week 8 | 
| Children Depression Inventory/CDI total score - Week 32 | The difference between the Children Depression Inventory/CDI total score administered at week 8 and week 32. The CDI is comprised of 27 items assessing self-reported symptoms of depression in children and adolescents 7-17 years of age. | week 32 | 
| Children Depression Inventory/CDI total score - Week 60 | The difference between the Children Depression Inventory/CDI total score administered at week 8 and week 60. The CDI is comprised of 27 items assessing self-reported symptoms of depression in children and adolescents 7-17 years of age. | week 60 | 
| Children's Sleep Habits Questionnaire/CSHQ Parent version total score | The difference between the Children's Sleep Habits Questionnaire/CSHQ Parent version total score administered at week 8 and week 0.The CSHQ was designed by clinical researchers at Brown University for children aged 4 through 12 years, to screen for the most common sleep problems in that age group.The first column 'of responses are scored: Usually=3, Sometimes=2, Rarely=1 for the entire questionnaire (except for the R=reversed items, which are considered to be desirable sleep behaviors, and thus scored in the opposite direction) | week 8 | 
| Children's Sleep Habits Questionnaire/CSHQ Parent version total score - Week 32 | The difference between the Children's Sleep Habits Questionnaire/CSHQ Parent version total score administered at week 8 and week 32.The CSHQ was designed by clinical researchers at Brown University for children aged 4 through 12 years, to screen for the most common sleep problems in that age group.The first column 'of responses are scored: Usually=3, Sometimes=2, Rarely=1 for the entire questionnaire (except for the R=reversed items, which are considered to be desirable sleep behaviors, and thus scored in the opposite direction) | week 32 | 
| Children's Sleep Habits Questionnaire/CSHQ Parent version total score - Week 60 | The difference between the Children's Sleep Habits Questionnaire/CSHQ Parent version total score administered at week 8 and week 60.The CSHQ was designed by clinical researchers at Brown University for children aged 4 through 12 years, to screen for the most common sleep problems in that age group.The first column 'of responses are scored: Usually=3, Sometimes=2, Rarely=1 for the entire questionnaire (except for the R=reversed items, which are considered to be desirable sleep behaviors, and thus scored in the opposite direction) | week 60 | 
| Comorbidity of other mental disorders | Using the K-SADS-PL DSM-5 | week 8 | 
| Corsi Blocks task | The difference between the Corsi blocks task administered at week 0 and at week 8. The Corsi Blocks task assesses the visuospatial component of working memory but uses various cognitive processes. The subject needs to reproduce, in the same or reverse order, a sequence of pointing movements to different cubes shown by the rater | week 8 | 
| CGAS Children's Global Assessment Scale total score | The difference between the CGAS Children's Global Assessment Scale total score administered at week 8 and the score administered at week 32. The Childrens Global Assessment Scale (CGAS) is a measure developed by Schaffer and colleagues at the Department of Psychiatry, Columbia University to provide a global measure of level of functioning in children and adolescents. The measure provides a single global rating only, on scale of 0-100. | week 32 | 
| CGAS Children's Global Assessment Scale total score - Week 60 | The difference between the CGAS Children's Global Assessment Scale total score administered at week 8 and the score administered at week 60. The Childrens Global Assessment Scale (CGAS) is a measure developed by Schaffer and colleagues at the Department of Psychiatry, Columbia University to provide a global measure of level of functioning in children and adolescents. The measure provides a single global rating only, on scale of 0-100. | week 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, traumatic memory reactivation, pediatric, Propranolol, Post-traumatic stress disorder