Sleep Disturbances in Children and Adolescents With Post-traumatic Stress Disorder (PTSD): a Randomized Double-blind Placebo-controlled Trial to Investigate the Efficacy of Pediatric Prolonged-release Melatonin

Overview

Among the most sensitive and persistent symptoms of post-traumatic stress disorder (PTSD) in children are sleep disturbances in the insomnia spectrum (sleep onset disturbances, fragmented sleep with multiple nocturnal awakening, early morning awakening) as well as nightmares, affecting over 50% of children and adolescents one year after the initial trauma. There are currently no gold standard treatments or pharmacological treatment recommendations specifically for these sleep disturbances in children and adolescents with PTSD, despite the fact that they have a significant effect on daytime functioning and overall mental health of the children and their families. If not treated appropriately, these sleep disturbances in children and adolescents persist over time, and further increase anxiety in children. Sleep disturbances associated with PTSD are predictive of the persistence and long-term outcome of PTSD itself and associated depressive symptomatology, and of a decreased response rate to cognitive-behavioral psychotherapy for PTSD. We have previously shown in an international multicenter study that pediatric prolonged release melatonin (PedPRM) has high beneficial effects on sleep disturbances of the insomnia spectrum in children ages 2-17.5 years with autism spectrum disorder, and consecutive positive effects on children's daytime behavior, including anxiety and depressive symptomatology. Its benefit-risk ratio has proven to be excellent over a 2-year follow-up. Beyond its therapeutic benefit on mental health through improvement of sleep, melatonin may have a direct effect on reducing anxiety levels and overall daytime functioning in children, as well as sleep and daytime function in caregivers. Our study will be the first randomized controlled trial investigating the efficacy of prolonged release melatonin on sleep disturbances in children and adolescents with PTSD, as well as on PTSD symptoms, associated daytime function and overall mental health in these children and their caregivers.

Interventions

• Drug pediatric, prolonged released melatonin
  Initial dosage will be of 2mg, and eventually increased to 5mg at dose optimization visit if no or insufficient improvement has been observed in the first 3 weeks of treatment
• Drug Placebo
  Initial dosage will be of 2 tablets, and eventually increased to 5 tablets at dose optimization visit if no or insufficient improvement has been observed in the first 3 weeks of treatment

Primary outcome measures

• Difference in sleep-diary derived total sleep time after 13 weeks of treatment [Time frame: At Day 0 and day 92]

Eligibility criteria

Inclusion criteria

Children and adolescents (2 -17.5 years) with:

• A diagnosis of post-traumatic stress disorder (PTSD) as defined by DSM-5 (American Psychiatric Association, 2013)
• Current significant sleep disturbances defined as ≤6 hours of continuous sleep and/or ≥0.5-hour sleep latency from lights-off on 3 out of 5 nights and/or nightmare disorder as defined by the International Classification of Sleep Disorders, Third Edition (ICSD-3, Sateia, 2014), for a minimum 3 months, based on parent report and patient medical history
• No response to at least 4 weeks of sleep hygiene
• Negative pregnancy test for females with childbearing potential
• Written informed consent provided by both parents or a legal guardian, as well as the children / adolescents themselves, if possible
• Stable doses of non-excluded medications for at least 3 months

Exclusion criteria

• Known systemic or severe acute disease whose care would hinder attendance at appointments
• Pregnancy, breastfeeding
• Known diagnosis of another significant sleep disorder (e.g., moderate to severe sleep apnea)
• Treatment with any form of melatonin within 2 weeks prior to screening
• Unresponsiveness to previous prolonged release melatonin within the 2 years prior to the study
• Known allergy to melatonin or lactose
• Use of prohibited medication (benzodiazepine, z-drug, antihistaminic, among others) within 2 weeks prior to screening
• Start of a cognitive behavioural therapy (CBT) targeting sleep disturbances or mood disorders, within 6 weeks before study inclusion
• Participation in a clinical trial within the last month prior to the study
• Transmeridian travel (> 2 time zones) within the month before the start of the study
• Females not using contraceptives who are sexually active, pregnant, and/or breastfeeding
• Other reasons: inability to receive clear information, inability to participate in the entire study, lack of coverage by the social security system, refusal to sign consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

France · 1 center

• Hôpitaux Universitaires de Strasbourg — Strasbourg

Identifiers

NCT: NCT07418554 · 7679

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗