Treatment Strategies for Children With Smith-Magenis Syndrome
| Status: | Completed |
|---|---|
| Conditions: | Cognitive Studies, Insomnia Sleep Studies, Other Indications, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | 3 - 45 |
| Updated: | 3/27/2019 |
| Start Date: | July 17, 2007 |
| End Date: | May 22, 2018 |
A Phase One Treatment Trial of the Circadian Sleep Disturbance in Smith-Magenis Syndrome (SMS)
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.
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.
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.
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.
- INCLUSION CRITERIA:
SMS subjects enrolled in protocol 01-HG-0109 will be invited to participate in this study.
Protocol 01-HG-0109 has approximately 90 SMS subjects.
SMS inpatient admissions for the dTR-MT trial will be deferred until the BL study completes
10 SMS subjects who demonstrate expected SMS inverted diurnal MT profiles at baseline (T0).
SMS Subjects (N=12-15 per each treatment goal; 60 total enrollment):
- Male and female, childhood (average 5-16 years old; under age 5 years on case-by-case
basis), all ethnicities with confirmed diagnosis of SMS (del 17p11.2). In some cases,
molecular cytogenetic FISH screening (RAI1 FISH probe) may be required to confirm the
SMS diagnosis prior to enrollment.
- Prepubertal (less than or equal to Tanner stage II).
- No history of seizures
- Priority will be given to subjects who are medication free and/or willing to
discontinue sleep/behavioral medications during the study trial. We anticipate
significant interest from families whose children are currently enrolled in the
01-HG-0109 protocol. We will also consider drug-free new referrals (self-referrals
and/or via health care providers) eligible for enrollment.
- Documented sleep disturbance (by sleep log diary and/or actigraphy).
Unaffected Healthy Control Subjects (N=15). The pharmacokinetics of melatonin release by
the dTR tablet will be evaluated in unaffected healthy control subjects prior to use in the
inpatient SMS trial.
- Males and females of any ethnicity and between the ages 18-45 years.
- Regular (11PM - 7AM) sleep schedule for at least 1 week prior to study.
- Non-smokers, who have no history of seizures.
- Willing to discontinue coffee consumption for a period of 1-2 weeks prior to trial.
- BMI within normal limits (10-90 percentile).
- Unaffected with SMS.
EXCLUSION CRITERIA:
SMS Subjects:
- Inability to obtain informed consent.
- Failure to confirm clinical diagnosis of SMS by standard molecular cytogenetic (FISH)
methods and/or DNA-based mutation analysis of RAI1 gene.
- Retinal diseases: macular degeneration, retinitis pigmentosa, diabetes, cataracts.
- Skin disease: Lupus (lupus erythematosis), history of skin cancer, history of adverse
reaction(s) to sun (rash, reddening).
- Medications that are photosensitizing: Phenothiazines (Thorazine, Stelazine),
Imipramine (AD), Porphyrins (antitumor), Chloroquine (antimalarial),
Hydrocholorthiazine (antihypertensive, diuretic), Lithium (mood stabilizer) and/or
antibiotics (Tetracycline).
- SMS subjects with extensive medication use may be excluded, depending on medications
used and whether or not discontinuing medications for the trial presents a significant
health risk. These include medications that might affect daytime vigilance (e.g., some
seratonin antagonists such as Trazadone, SSRIs) and/or MAOIs, and/or antipsychotics
(Risperidone), and/or some SSRIs (e.g., fluvoxamine) that affect the metabolism of
melatonin and/or are strong CYP1A2 inhibitors.
Healthy Adult Controls:
- Individuals who have been diagnosed with a sleep disorder (e.g, restless legs, sleep
apnea) known to impact sleep may be excluded at the discretion of the PI.
- Not willing to discontinue caffeine consumption (chocolate, coffee, tea) during study
period.
- Persons with extensive medication use may be excluded, depending on medications used
and whether or not discontinuing medications for the trial presents a significant
health risk. These include medications that might affect daytime vigilance (e.g., some
seratonin antagonists such as Trazadone, SSRIs) and/or MAOIs, and/or antipsychotics
(Risperidone), and/or some SSRIs (e.g., fluvoxamine) that affect the metabolism of
melatonin and/or are strong CYP1A2 inhibitors.
- Employed on a shift work schedule.
- Transmeridian travel within the last 2 weeks.
- Currently using melatonin.
- Women currently taking oral contraceptives (BCPs)
- Pregnant women and/or nursing mothers
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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