Treatment Strategies for Children With Smith-Magenis Syndrome
|First Received Date ICMJE||July 21, 2007|
|Last Updated Date||November 4, 2014|
|Start Date ICMJE||July 2007|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Change in level of melatonin (pg/ml) from baseline|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00506259 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Improved sleep parameters (actigraphy). Increased daytime vigilance. Decreased maladaptive behaviors.|
|Original Secondary Outcome Measures ICMJE
||-Improved sleep parameters (actigraphy)@@@-Increased daytime vigilance@@@-Decreased maladaptive behaviors|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Treatment Strategies for Children With Smith-Magenis Syndrome|
|Official Title ICMJE||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 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:
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, 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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind
Primary Purpose: Treatment
|Study Arm (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||75|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
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=12-15 per each treatment goal; 60 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.
Healthy Adult Controls:
|Ages||5 Years to 45 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00506259|
|Other Study ID Numbers ICMJE||070076, 07-HG-0076|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )|
|Study Sponsor ICMJE||National Human Genome Research Institute (NHGRI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||April 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP