Treatment Strategies for Children With Smith-Magenis Syndrome
Condition: Developmental Delay Disorders; Chromosome Deletion; Mental Retardation; Sleep Disorders, Circadian Rhythm; Self Injurious Behavior
MeSH terms: Sleep Wake Disorders; Parasomnias; Intellectual Disability; Sleep Disorders, Circadian Rhythm; Smith-Magenis Syndrome; Chromosome Deletion; Self-Injurious Behavior; Developmental Disabilities
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will examine the effect of bright light or melatonin treatment on sleep in
      children with Smith-Magenis syndrome (SMS), a genetic disorder characterized by certain
      physical, behavioral and developmental features. Patients have a disrupted sleep cycle
      involving early waking, frequent daytime napping and frequent nighttime awakenings. Melatonin
      is a hormone normally produced at night in healthy people. People with SMS produce high
      levels of melatonin during the daytime and very low levels at night. This may affect their
      behavior, mood, attention span and sleep patterns.

      Healthy volunteers between 18 and 45 years of age and children with SMS who are between 3 and
      16 years of age may be eligible for this study.

      Healthy subjects are admitted to the NIH Clinical Center overnight. In the morning they take
      one dose of time-release melatonin and have blood and saliva samples collected hourly from
      7:00 AM to 6:00 PM.

      Children with SMS participate in a 2-part study, as follows:

      Part 1 Inpatient Trial

      Pre-trial at-home phase: During the month before NIH inpatient admission, participants do the
      following:

        -  Wear an actiwatch device or keep a daily sleep diary to monitor daytime alertness, mood
           shifts and sleep patterns.

        -  Complete a behavior assessment survey related to the child s behaviors and sleep
           patterns.

        -  Obtain frequent body temperature measurements.

        -  Collect several saliva samples over a 24-hour period.

      NIH admission phase:

        -  Children are admitted to the NIH Clinical Center for 2-3 nights for bright light
           treatment. They remain in their rooms for alternating periods of exposure to standard
           dim room light and bright light, using a light box placed within 3 to 5 feet of the
           child. An electroencephalogram (EEG) with additional electrodes to track eye movements
           is used to monitor the child s attention. Between 8AM and 6PM serial blood samples are
           collected to measure melatonin levels. A parent rates the child s mood and behavior
           during the 2-day test period.

        -  Children are admitted to the NIH Clinical Center for 2-3 nights for melatonin treatment.
           They take a single dose of melatonin or placebo tablet at bedtime. During the daytime,
           EEG electrodes are placed to track eye movements. Between 7 PM and 7 AM serial blood
           samples are collected to measure melatonin levels. A parent rates the child s behavior
           and mood as described for the bright light study.

        -  Children may receive either or both of the bright light and melatonin treatments.

      Part 2 Outpatient Trial

      Children participate in a combined bright light with melatonin trial at home. They undergo
      the same procedures outlined in the pre-trial at-home phase of Part 1 (actiwatch, behavior
      assessments, body temperature measurements, saliva samples) over an 11-week period. If saliva
      samples cannot be collected for melatonin testing, 24-hour urine samples may be collected
      instead.
    

Detailed description: 
      Smith-Magenis syndrome (SMS) is a rare (1/25,000) clinically recognizable syndrome,
      characterized by the following features: a distinct pattern of minor craniofacial and
      skeletal anomalies, expressive speech/language delays, psychomotor and growth retardation,
      and a striking neurobehavioral phenotype. This phenotype includes stereotypies,
      self-injurious and aggressive behaviors, and a chronic sleep disorder associated with an
      inverted circadian melatonin rhythm. Sleep disturbances include daytime sleepiness, early
      sleep onset, and early morning awakening. Disturbed sleep is the strongest predictor of
      maladaptive behavior in children with SMS. Diminished nocturnal sleep is virtually universal
      in SMS, representing a major challenge to the patient and family. The majority (greater than
      95%) of cases are due to interstitial deletion of 17p11.2; however, rare cases due to RAI1
      gene mutations are also reported.

      One of the likely contributing factors to these sleep disturbances is an inverse circadian
      pattern of the sleep-promoting hormone, melatonin. In SMS, plasma melatonin is high during
      the day and low at night, which is opposite the normal pattern. The underlying reason for
      this regular daytime melatonin secretory pattern is unknown. To our knowledge this pattern is
      distinctive to persons with SMS and not found elsewhere. SMS therefore offers a unique human
      syndrome for the study of melatonin function. At the present time, there is no effective
      treatment for sleep disturbances in SMS. Moreover, there are currently no controlled
      treatment trials underway in the U.S. with the specific goal of correcting the disturbed
      sleep pattern observed in this disease.

      The aim of this Phase 1 treatment trial is to improve the quality of nocturnal sleep and
      decrease the need for daytime sleep by restoring a normal circadian pattern of melatonin
      levels in children with Smith-Magenis syndrome (SMS). We predict that the inverse pattern of
      release can be corrected by the combination of non-pharmacological suppression of daytime
      melatonin release and pharmacological replacement of nocturnal melatonin. Negative behaviors
      associated with accumulated sleep debt are expected to diminish as sleep quality improves.

      Two treatment modalities will be evaluated alone and in combination: 1) light-induced
      suppression of daytime melatonin release and delay of nighttime sleep; and 2) pharmacological
      replacement of nocturnal melatonin. Melatonin levels measured in blood (Pre- vs.
      Post-treatment) will serve as the primary outcome parameter. A dTR-melatonin tablet developed
      by the Clinical Center Pharmaceutical Development Services (CC-PDS) will be used in this
      trial.
    

Intervention name(s): dTR Melatonin (NIH CC PDS); Phototherapy (Bright Light); Melatonin CR
Intervention type(s): Drug; Device; Drug
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Crossover Assignment
Primary purpose: Treatment
Keywords: Deletion 17p11.2; Melatonin; Phototherapy; Behavioral Phenotype; Developmental Delay/MR; Smith-Magenis Syndrome; Sleep Disturbance; SMS; Sleep Disorder