Protocol Number: 07-HG-0076

Title:

A Phase One Treatment Trial of the Circadian Sleep Disturbance in Smith-Magenis Syndrome (SMS)

Number:

07-HG-0076

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 5 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.

Sponsoring Institute:

National Human Genome Research Institute (NHGRI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

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 Subjects (N=10-15 per each treatment goal; 75 total enrollment):

-Male and female, childhood (5-16 years old), 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.

-Ages 5-16 years (less than or equal to Tanner stage II).

-No history of seizures and/or use of anticonvulsants.

-Priority will be given to subjects who are medication free and/or willing to discontinue sleep 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.

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.

-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)

-Not willing to discontinue caffeine consumption (chocolate, coffee, tea) during study period.

-Medications that are photosensitizing: Phenothiazines (Thorazine, Stelazine), Imipramine (AD), Porphyrins (antitumor), Chloroquine (antimalarial), Hydrocholorthiazine (antihypertensive, diuretic), Lithium (mood stabilizer) and/or antibiotics (Tetracycline)

-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.

-Employed on a shift work schedule.

-Transmeridian travel within the last 2 weeks.

-Currently using melatonin.

-Pregnant women.

Special Instructions:

Currently Not Provided

Keywords:

Deletion 17P11.2

Melatonin

Phototherapy

Behavioral Phenotype

Developmental Delay/MR

Smith-Magenis Syndrome

Sleep Disturbance

Recruitment Keyword(s):

Smith-Magenis Syndrome

SMS

Sleep Disorder

Condition(s):

Developmental Delay Disorders

Chromosome Deletion

Mental Retardation

Sleep Disorders, Circadian Rhythm

Self Injurious Behavior

Investigational Drug(s):

Melatonin CR

Investigational Device(s):

None

Intervention(s):

Drug: dTR Melatonin (NIH CC PDS)

Device: Phototherapy (Bright Light)

Drug: Melatonin CR

Supporting Site:

National Human Genome Research Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Bi W, Saifi GM, Shaw CJ, Walz K, Fonseca P, Wilson M, Potocki L, Lupski JR. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. 2004 Nov;115(6):515-24. Epub 2004 Sep 30.

Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH. Mutations in RAI1 associated with Smith-Magenis syndrome.Nat Genet. 2003 Apr;33(4):466-8. Epub 2003 Mar 24.

De Leersnyder H, De Blois MC, Claustrat B, Romana S, Albrecht U, Von Kleist-Retzow JC, Delobel B, Viot G, Lyonnet S, Vekemans M, Munnich A.Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome.J Pediatr. 2001 Jul;139(1):111-6

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