Pediatric Prolonged-Release Melatonin for Sleep Disturbances in Children and Adolescents With Anorexia Nervosa (MELSom-ANOREXIA)

Official title

Efficacy of Pediatric Prolonged-Release Melatonin (PedPRM) Treatment in Children and Adolescents With Impaired Sleep and Anorexia Nervosa (AN)

Overview

Sleep disturbances are reported by more than 50% of patients with Anorexia Nervosa (AN) and are associated with increased AN severity, psychiatric comorbidities, and poorer quality of life. To date, no pharmacological treatment has been approved or recommended for sleep disorders in children and adolescents with AN. Many drugs are currently prescribed off-label for their sedative side effects, without proven safety or efficacy in this population. Pediatric prolonged-release melatonin (PedPRM, Slenyto®) is the only melatonin formulation approved by the European Medicines Agency (EMA) for chronic insomnia in children aged 2 to 18 years with neurodevelopmental disorders. Its excellent safety profile, absence of tolerance, and long-acting formulation make it a prime candidate for treating sleep disturbances in children and adolescents with AN. MELSom-ANOREXIA is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase IIIb trial. Its primary objective is to assess the efficacy of PedPRM compared to placebo in improving Total Sleep Time (TST) in children and adolescents aged 6 to 18 years with AN and impaired sleep. Participants are randomized into two groups: the experimental group receives PedPRM (2 mg or 5 mg depending on response at Day 22) and the control group receives a matching placebo, both administered 0.5 to 1 hour before habitual bedtime for 13 weeks. Sleep is assessed by Sleep Diary and actigraphy. Secondary outcomes include other sleep parameters, AN severity (BMI, EDI-2, EDE-Q), associated symptoms (anxiety, depression, physical activity, executive function, emotionality), and quality of life. Melatonin secretion profiles and specific subgroups (ASD traits, early-onset AN) are also explored. The study includes a 2-week run-in period (D-14 to D0) for baseline sleep assessment, followed by 13 weeks of treatment, with visits at D0, D22, and D93. A total of 120 participants will be enrolled across 7 French pediatric psychiatry centers over 24 months.

Interventions

• Drug Pediatric Prolonged-Released Melatonin (PedPRM)
  Pediatric prolonged-release melatonin mini-tablets (Slenyto® 1 mg and 5 mg, Neurim Pharmaceuticals). Oral administration 0.5 to 1 hour before habitual bedtime every evening for 13 weeks. Initial dose: 2 mg/day (2 × 1 mg tablets). Dose may be increased to 5 mg/day (1 × 5 mg tablet) at Day 22 in case of insufficient sleep improvement.
• Drug Placebo
  Matching placebo mini-tablets, identical in appearance and formulation to the PedPRM therapeutic units. Oral administration 0.5 to 1 hour before habitual bedtime every evening for 13 weeks. Number of units adjusted at Day 22 to match the experimental group and maintain blinding.

Primary outcome measures

• Change from baseline in mean Total Sleep Time (TST) measured by Sleep Diary [Time frame: Baseline (Day-14 to Day 0) and end of treatment (Day 78 to Day 93)]

Secondary outcome measures (11)

• Change from baseline in mean Sleep Latency (SL) measured by Sleep Diary [Time frame: Baseline and end of treatment (Day 78 to Day 93)]
• Change from baseline in mean Wake After Sleep Onset (WASO) measured by Sleep Diary [Time frame: Baseline and end of treatment (Day 78 to Day 93)]
• Change from baseline in mean number of awakenings measured by Sleep Diary [Time frame: Baseline and end of treatment (Day 78 to Day 93)]
• Change from baseline in mean Longest Sleep Episode (LSE) measured by Sleep Diary [Time frame: Baseline and end of treatment (D78 to D93)]
• Change from baseline in mean Total Sleep Time [Time frame: Baseline and end of treatment (Day 78 to Day 93)]
• Change from baseline in Body Mass Index (BMI) [Time frame: Baseline (Day 0), Day 22 and end of treatment (Day 93)]
• Change from baseline in Eating Disorder Inventory-2 (EDI-2) total score [Time frame: Baseline (Day 0) and end of treatment (Day 93)]
• Change from baseline in Eating Disorder Examination-Questionnaire (EDE-Q) score [Time frame: Baseline (Day 0) and end of treatment (Day 93)]
• Change from baseline in executive function (BRIEF-P score) [Time frame: Baseline (Day 0) and end of treatment (Day 93)]
• Change from baseline in emotionality (EPN-31 score) [Time frame: Baseline (Day 0) and end of treatment (Day 93)]
• Change from baseline in depressive symptoms (CDI score) [Time frame: Baseline (Day 0) and end of treatment (Day 93)]

Eligibility criteria

Inclusion criteria

Participants aged 6 to 18 years, inclusive, with a diagnosis of Anorexia Nervosa (AN) according to DSM-5 criteria Presence of a sleep problem for at least 1 month, defined as ≤ 6 hours of continuous sleep and/or ≥ 0.5 hours sleep latency from lights-off on 3 out of 5 nights, based on participant report (with or without parental assistance according to age), confirmed at D0 by 2-week sleep diary No response to at least 4 weeks of sleep hygiene Negative pregnancy test at baseline, prior to randomization, for female participants of childbearing potential Women of childbearing potential must agree to use a highly effective method of contraception during the study treatment period and for at least 4 weeks after the last dose of study treatment Written informed consent obtained in accordance with the participant's legal status and applicable regulations Affiliation to a social security system or equivalent

Exclusion criteria

Known diagnosis of another significant sleep disorder (e.g. moderate to severe sleep apnea) Use of prohibited medication (z-drugs, melatonin agonist, benzodiazepine, phenylpiperazine class, clomethiazole) or melatonin within 2 weeks prior to screening Declared allergy to melatonin, lactose, or any excipient included in the therapeutic units Pregnant or breastfeeding female participants Unresponsiveness to previous prolonged-release melatonin within the 2 years prior to the study Start of cognitive behavioural therapy (CBT) targeting sleep disturbances or mood disorders within 6 weeks before study inclusion Trans-meridian travel (> 2 time zones) within the month before the start of the study Patient under legal protection regimen

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

Quadruple blind

Primary purpose

Treatment

Study locations

France · 1 center

• AP-HM Hopital Salvator — Marseille

Identifiers

NCT: NCT07576764 · RCAPHM23_0329

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗