A Phase 1/2 interventional study of Donepezil hydrochloride and Increase REM sleep percentage in Autism and Cognition Disorder, sponsored by National Institute of Mental Health (NIMH). Completed at 1 site in United States. Open to participants aged 2 Years to 10 Years. Per ClinicalTrials.gov, last updated 2013-04-24.
Sponsored by National Institute of Mental Health (NIMH) · Phase 1/2 and Interventional
This study will test whether donepezil (Aricept(Registered Trademark)), a drug that is approved by the Food and Drug Administration to treat Alzheimer's disease, can increase rapid eye movement (REM) sleep in children with autism and autism spectrum disorder (ASD). Some children with autism and ASD spend very little time in REM sleep. In some studies, decreased REM sleep has been associated with learning and behavior problems. Donepezil can increase REM sleep in some adults with different disorders. If it can increase REM sleep in children in this study, it might be able to be used in future studies to see if it can help learning and behavior problems in children with autism and ASD.
Children between 2 and 10 years of age with autism or an ASD whose percentage of REM sleep time is well below the average for children of the same age may be eligible for this study. Candidates are screened with a medical history, physical and neurological examinations, blood tests, electroencephalogram (EEG) and a sleep study. The sleep study requires an overnight stay at the NIH Clinical Center in which the child is monitored with electrodes for EEG and heartbeat recording, a tube taped below the nose to measure airflow, a probe on a finger to record oxygen levels and a small watch-like machine on the wrist to record movements.
Participating children may be required to have up to six overnight stays for sleep studies at the Clinical Center. The children start by taking 1.25 mg of donepezil for 2 to 4 weeks. Then they are admitted to the NIH Clinical Center for a sleep study, blood tests and EKG. Those whose REM sleep increases to normal levels stay on 1.25 mg of donepezil for 8 more weeks, after which they are admitted to the Clinical Center for a final physical examination, blood draw and sleep study. That ends their participation in the study.
Children whose REM sleep does not increase to normal on 1.25 mg of donepezil are given a higher dose (2.5 mg) for 2 to 4 weeks, and the above procedure is repeated. Those whose REM sleep does not increase to normal on 2.5 mg of donepezil take 5 mg of the drug for 2 to 4 weeks, and the above procedure is repeated once more. Children whose REM sleep does not increase to normal on 5 mg of donepezil stop the medication and end their participation in the study.
At each study visit, study researchers talk to the parents and examine the children to determine if donepezil is affecting the child's behavior and if the child is hav...
Autism spectrum disorders are defined by aberrant development of communication and socialization in the presence of restrictive and/or repetitive behaviors. Recent epidemiologic studies have documented an increase in the number of children identified with autism spectrum disorder over the past decade and according to some, the current numbers indicate a prevalence of 1 per 150 (CDC, MMWR 2007, Feb 9th release). Despite the pressing need to identify causal factors, etiology remains elusive. Furthermore, the heterogeneity of presentation complicates attempts to locate autism's home in the brain.
Polysomnography is a reliable non-invasive tool that can be used to study the basic pathophysiological mechanisms of autism and other developmental and neuropsychiatric disabilities. Our preliminary data in young children with autism supports a growing body of literature demonstrating that sleep architecture is abnormal in this disorder. Previous studies in children with autism have identified various abnormalities in REM sleep including the following: immature organization, decreased quantity, abnormal twitches, undifferentiated sleep and REM sleep behavior disorder characterized by the absence of the muscle atonia that is normal in REM sleep and resulting in an acting out of dreams phenomenon (Tanguay et al ,.1976, Elia et al., 2000, Diomedi et al. 1999, and Thirumalai et al., 2002).
Our cohort spent an abnormally short time in the REM sleep stage of sleep compared to total sleep time (hereafter referred to as SPT REM% for REM sleep as a percent of sleep period time), and had a prolonged latency to REM sleep. The function of REM sleep and its relationship to cognition and overall neurological health is unknown and a subject of ongoing research. We know from animal studies that REM sleep increases after intensive learning sessions. These laboratory findings formed the basis for the hypothesis that this sleep stage is important for cognitive processes and that REM sleep may be useful as an indicator of brain plasticity. Current studies continue to add support for this idea. REM sleep has most recently been implicated in the process of human memory consolidation and several studies suggest that it is crucial to normal cognitive function and in the processing of emotion in memory systems. Acetylcholine (Ach) is one of the major neurotransmitters necessary for normal sleep transitions and abnormalities in Ach have been implicated in REM deficient sleep in other populations, most notably Alzheimer's disease.
This proposal is for a 6 to 20 week, single arm, open-label study to evaluate the ability of donepezil hydrochloride to enhance REM sleep in children with autism spectrum disorder found to have a low SPT REM% (defined as below 2 standard deviations of observed normative data for age). All patients will come through the screening protocol 06-M-0065. Those who meet a research diagnosis of autism spectrum disorder and are ages 2 to 11 (through the tenth year) will be evaluated for inclusion/exclusion criteria for the study.
The primary outcome measure of this protocol is to increase the SPT REM% in children with autism such that their REM/non-REM ratios begin to approach normative values. Donepezil enhanced REM sleep has been achieved in young healthy adults, in elderly, healthy adults and in elderly, demented adults with Alzeheimer's disease. Furthermore, the studies in Alzheimer disease by Mizuno et al showed a positive correlation between improved cognition and increased SPT REM %. If REM sleep is necessary for normal cognition, and its deficiency or absence can be remedied by pharmacologic intervention, then it may follow that improvement of REM sleep correlates with improved short and long term cognition in children with autism. Donepezil enhanced REM sleep has not been documented in children. Polysomnography provides a non-invasive tool to assess the effects of enhancing cholinergic tone on the abnormal sleep architecture we have documented in our pediatric, autistic population.
1,344 studies on the registry are indexed under Autistic Disorder; 334 are open to participants now.
This study's enrollment of 17 is below the median of 45 across 1,044 interventional studies indexed under Autistic Disorder.
Browse Autistic Disorder studies →National Institute of Mental Health (NIMH) is the lead sponsor of 359 studies on the registry; 46 are open to participants now.
Of its 25 completed or terminated interventional studies of FDA-regulated products, 24 (96%) have results posted.
Counted across the registry records on this site, refreshed daily.
EXCLUSION CRITERIA:
Single group study of Donepezil
Drug: Donepezil hydrochloride · Behavioral: Increase REM sleep percentage
Change in Percentage of Time That Subjects With Autism Spend in REM Sleep.
Time frame: 1 month (from baseline to 1.25 mg dose)
| Milestone | Open Label Single Arm |
|---|---|
| Started | 7 |
| Completed | 5 |
| Not completed | 2 |
| Withdrew: Withdrawal by subject | 1 |
| Withdrew: Unrelated adverse event | 1 |
| percentage of REM sleep | Open Label Single Arm |
|---|---|
| Change in Percentage of Time That Subjects With Autism Spend in REM Sleep. | 9.2 ± 2.6 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Open Label Single Arm | — | 0/7 (0%) | 1/7 (14.3%) |
| Event | Open Label Single Arm |
|---|---|
| otherNervous system disorders | 1/7 |
16 subjects completed screening and had baseline data. However, only 8 of them were eligible for further study participation and only 5 completed the drug and provided data for analysis.
| Age, Categorical(Participants) | Open Label Single Arm |
|---|---|
| <=18 years | 5 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Age Continuous(years) | Open Label Single Arm |
|---|---|
| Mean | 5.08 ± 1.62 |
| Sex: Female, Male(Participants) | Open Label Single Arm |
|---|---|
| Female | 0 |
| Male | 5 |
| Region of Enrollment(participants) | Open Label Single Arm |
|---|---|
| United States | 5 |
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National Institute of Mental Health (NIMH)