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Sponsored by: |
National Human Genome Research Institute (NHGRI) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00506259 |
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:
NIH admission phase:
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.
Condition | Intervention | Phase |
---|---|---|
Developmental Delay Disorders Chromosome Deletion Mental Retardation Sleep Disorders, Circadian Rhythm Self Injurious Behavior |
Drug: dTR Melatonin (NIH CC PDS) Device: Phototherapy (Bright Light) Drug: Melatonin CR |
Phase I |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Single Blind, Placebo Control, Crossover Assignment, Safety/Efficacy Study |
Official Title: | A Phase One Treatment Trial of the Circadian Sleep Disturbance in Smith-Magenis Syndrome (SMS) |
Estimated Enrollment: | 75 |
Study Start Date: | July 2007 |
Estimated Study Completion Date: | October 2009 |
Estimated Primary Completion Date: | October 2009 (Final data collection date for primary outcome measure) |
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, urine and/or saliva (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.
Ages Eligible for Study: | 5 Years to 45 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
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):
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.
EXCLUSION CRITERIA:
SMS Subjects:
Healthy Adult Controls:
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 |
Study ID Numbers: | 070076, 07-HG-0076 |
Study First Received: | July 21, 2007 |
Last Updated: | August 24, 2009 |
ClinicalTrials.gov Identifier: | NCT00506259 History of Changes |
Health Authority: | United States: Federal Government |
Deletion 17P11.2 Melatonin Phototherapy Behavioral Phenotype Developmental Delay/MR |
Smith-Magenis Syndrome Sleep Disturbance Smith-Magenis Syndrome SMS Sleep Disorder |
Developmental Disabilities Mouth Diseases Antioxidants Sleep Disorders, Circadian Rhythm Craniofacial Abnormalities Disorders of Environmental Origin Sleep Disorders Chronobiology Disorders Maxillofacial Abnormalities Musculoskeletal Abnormalities Signs and Symptoms Musculoskeletal Diseases Mental Disorders Mental Disorders Diagnosed in Childhood Melatonin |
Occupational Diseases Congenital Abnormalities Neurobehavioral Manifestations Chromosome Deletion Heart Diseases Smith-Magenis Syndrome Cardiovascular Abnormalities Central Nervous System Depressants Dyssomnias Behavioral Symptoms Cleft Palate Mental Retardation Chromosome Aberrations Neurologic Manifestations Stomatognathic Diseases |
Mouth Diseases Developmental Disabilities Antioxidants Sleep Disorders, Circadian Rhythm Molecular Mechanisms of Pharmacological Action Craniofacial Abnormalities Physiological Effects of Drugs Jaw Diseases Disorders of Environmental Origin Stomatognathic System Abnormalities Sleep Disorders Chronobiology Disorders Maxillofacial Abnormalities Musculoskeletal Abnormalities Signs and Symptoms |
Pathologic Processes Musculoskeletal Diseases Mouth Abnormalities Mental Disorders Therapeutic Uses Syndrome Mental Disorders Diagnosed in Childhood Melatonin Occupational Diseases Cardiovascular Diseases Jaw Abnormalities Congenital Abnormalities Neurobehavioral Manifestations Chromosome Deletion Heart Diseases |