Trial of Melatonin to Improve Sleep in Children With Epilepsy and Neurodevelopmental Disabilities

A Randomized Controlled Trial Pilot Project to Evaluate the Efficacy of Melatonin in Children With Insomnia, Intractable Epilepsy and Neurodevelopmental Disabilities

The purpose of the study is to evaluate the safety and efficacy of oral melatonin in improving sleep continuity in children with epilepsy and neurodevelopmental delay who have chronic insomnia by comparing Fast Release Melatonin (FR MLT) to placebo and Timed Release Melatonin (TR MLT) with placebo in a randomized cross-over design trial.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Insomnia; Developmental Disability
• Intervention / Treatment: Drug: Fast Release Melatonin (FR MLT); Drug: Fast Release Placebo; Drug: Timed Release Melatonin (TR MLT); Drug: Timed Release Placebo

Detailed Description

Sleep disturbance in children is a universal concern. The prevalence of sleep disorders may be as high as 80% in children with neurodevelopmental disabilities. The majority of the parental complaints are with difficulty getting children to settle to sleep at night and stay asleep (insomnia).

Two recent studies comparing children with epilepsy to matched controls or to sibling controls both concluded that children with epilepsy have more daytime sleepiness that may be due to underlying sleep disorders, and significantly greater sleep problems than their non-epileptic peers.

Endogenous melatonin is thought to synchronize the sleep-wake pattern with the light-dark cycle of the normal day. Exogenous melatonin has been found to be effective in reducing sleep onset latency, increasing sleep duration, and increasing sleep efficiency in a meta-analysis of subjects with sleep disorders. The melatonin in fast release preparations is released quickly and has a short half-life of less than 1 hour. It is most helpful in decreasing sleep onset latency (the time to fall asleep). The melatonin in timed release tablets is released in a slower more sustained way and, in a small study in children with severe neurodevelopmental disabilities, was more useful for sleep maintenance.

Fast release melatonin has been shown to be effective in a study of children with multiple disabilities and in one trial in children with epilepsy. Further rigorous evaluation of melatonin is needed as the validity of these studies is limited by their lack of blinding, small sample sizes, and subjective methods of sleep-wake outcome evaluations.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children aged 5-17 years
• Children with epilepsy with at least 2 partial or generalized seizures per month over the last 3 months prior to starting the trial
• Children with neurodevelopmental disability, i.e. significant delay in development requiring special educational setting or educational assistant
• Anti-epileptic drugs (AED's) expected to remain unchanged for duration of trial (14 weeks)
• Not currently using melatonin or any other medication for sleep Subjects will be eligible if they have previous use of melatonin as long as there is a washout period of at least 1 week. Similarly, children taking natural health products for sleep will be included as long as there is a 30 day washout period prior to study enrollment.
• Chronic insomnia - reported by parent(s) to include one of the following: sleep onset latency of greater than one hour, duration of sleep less than 8.5 hours per night with either/or both these problems occurring at least 3 nights per week and that have occurred 3 months prior to trial, or night wakings of more than 2 per night for same time period

Exclusion Criteria:

• Planned epilepsy surgery or change in AED's during treatment trial
• Sleep disturbances that are treatable such as obstructive sleep apnea
• Allergy or severe adverse effects to melatonin
• Allergy or severe adverse effects to any of the ingredients of the study product or placebo (e.g. lactose)
• Lactose intolerance
• Pregnant
• Breastfeeding
• Known liver disease
• Ketogenic diet
• Other drugs being used for sedation
• Immunosuppressive drugs
• Known blood clotting abnormalities or who are on anticoagulant therapy (e.g. warfarin, blood thinners)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A: Fast Release Melatonin; Subjects will be randomized to one of the two treatment arms and to the order of study medication v.s. placebo. The subject will undergo the assigned treatment for 7 weeks (3 weeks of study drug, a one week wash-out and 3 weeks of placebo, or vice versa).	Drug: Fast Release Melatonin (FR MLT); 3mg capsules of melatonin will be used. The dose of FR MLT will be 3 mg for children less than or equal to 20 kg, and 6 mg for children greater than 20 kg. The study medication will be given one hour before bedtime, once daily.; Other Names: Sleep Tight TM by Nature's Harmony® Melatonin; Drug: Fast Release Placebo; A matching FR MLT placebo will be compounded by the SickKids research pharmacy. The dose of Fast Release Placebo will be 3 mg for children less than or equal to 20 kg, and 6 mg for children greater than 20 kg. The study medication will be given one hour before bedtime, once daily.
Active Comparator: Group B: Timed Release Melatonin; Subjects will be randomized to one of the two treatment arms and to the order of study medication v.s. placebo. The subject will undergo the assigned treatment for 7 weeks (3 weeks of study drug, a one week wash-out and 3 weeks of placebo, or vice versa).	Drug: Timed Release Melatonin (TR MLT); 3 mg capsules will be used. The dose of TR MLT will be will be 3 mg for children less than or equal to 20 kg, and 6 mg for children greater than 20 kg. The study medication will be given one hour before bedtime, once daily.; Other Names: Melatonin Timed Release by General Nutrition Canada; Drug: Timed Release Placebo; A matching TR MLT placebo will be compounded by the SickKids research pharmacy. The dose of Timed Release Placebo will be will be 3 mg for children less than or equal to 20 kg, and 6 mg for children greater than 20 kg. The study medication will be given one hour before bedtime, once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in duration of nocturnal sleep time	We will measure the sleep time between 7 pm and 9 am. The measures will be analyzed to determine the change from baseline and change between active treatment and placebo.	Baseline, Weeks 9 and 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep onset latency	We will measure the interval of time between lights out and the onset of sleep. The measures will be analyzed to determine the change from baseline and change between active treatment and placebo.	Baseline, Weeks 9 and 13
Sleep efficiency	We will measure the time sleeping/time in bed between lights out at night and lights on in the morning. The measures will be analyzed to determine the change from baseline and change between active treatment and placebo	Baseline, Weeks 9 and 13

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Shelly Weiss, MD, The Hospital for Sick Children, Toronto Canada

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 12, 2010
• First Posted (Estimate): July 13, 2010

Study Record Updates

• Last Update Posted (Estimate): December 2, 2014
• Last Update Submitted That Met QC Criteria: December 1, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Epilepsy; Melatonin; Insomnia; Pediatrics
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurodevelopmental Disorders; Epilepsy; Sleep Initiation and Maintenance Disorders; Developmental Disabilities; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: 1000010842