AutismPhase 1/2NCT00695136
The Effect of Donepezil (Aricept(Registered Trademark)) on REM Sleep in Children With Autism
A Phase 1/2 study testing Donepezil hydrochloride and Increase REM sleep percentage in people with Autism and Cognition Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 2 to 10 years
- Conditions the study is for
- Autism, Cognition Disorder
- What is being tested?
- Donepezil hydrochloride and Increase REM sleep percentage
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2008to Jan 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 10 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Diagnosis of autism spectrum disorder
- Male or female subjects, ages 2 through 10 years.
- Each legal guardian must have a level of understanding sufficient to agree to all required tests and examinations. Each legal guardian must understand the nature of the study.
- Each subject must be stable for at least 6 weeks on any medication or therapy regimen prior to entry into study and must have no newly (within 6 weeks) recognized or intolerable adverse effects from that medicine or therapy. No subjects will be asked to discontinue any medication in order to qualify for enrollment.
Who cannot join
- Serious, unstable illnesses including, gastroenterologic, respiratory, cardiovascular endocrinologic, immunologic,or hematologic disease.
- Renal or hepatic dysfunction that would interfere with excretion or metabolism of donepezil as evidenced by increase above upper limits of normal for BUN/creatinine, or two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT) or gamma glutamate (GGT)
- Documented history of hypersensitivity or intolerance to donepezil or other piperidine derivative.
- Subjects must not be taking any medication known to affect REM sleep or that is contraindicated for co-administration with donepezil.
- Presence or history of neurological disorders, including seizure disorders.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: An Investigation of the Relationship Between Donepezil Enhanced REM Sleep, Sleep Architecture and Behavior in the Prepubertal Child With Autism
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.
Read more
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...
Read the detailed description
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.
- Conditions
- Autism, Cognition Disorder
- Being tested
- Donepezil hydrochloride, Increase REM sleep percentage
- Keywords
- Autism, Cognitive Disorder, Sleep, Autism Spectrum Disorder, ASD
- Medical subject headings
- Autistic Disorder, Cognition Disorders, Cognitive Dysfunction, Autism Spectrum Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Donepezil hydrochlorideDrug
Increase REM sleep percentageBehavioural
| Study group | Role | What they receive |
|---|---|---|
| Open label single arm | Experimental | Single group study of Donepezil Receives: Drug: Donepezil hydrochloride; Behavioral: Increase REM sleep percentage |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Percentage of Time That Subjects With Autism Spend in REM Sleep.
Measured: 1 month (from baseline to 1.25 mg dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2008 (estimated)
- Study startJun 2008
- Primary completionJan 2011
- Study completionJan 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for AutismStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Susan Swedo, M.D., National Institutes of Health Clinical Center (CC)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00695136
- Sponsor's protocol ID
- 080154
- Other IDs
- 08-M-0154
- Status last verified
- Apr 2013
- First submitted
- 10 Jun 2008
- Last updated
- 24 Apr 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
McGrath MJ, Cohen DB. REM sleep facilitation of adaptive waking behavior: a review of the literature. Psychol Bull. 1978 Jan;85(1):24-57. No abstract available.
PubMed 203966Mirmiran M, van den Dungen H, Uylings HB. Sleep patterns during rearing under different environmental conditions in juvenile rats. Brain Res. 1982 Feb 11;233(2):287-98. doi: 10.1016/0006-8993(82)91203-3.
PubMed 7059812Guzman-Marin R, Ying Z, Suntsova N, Methippara M, Bashir T, Szymusiak R, Gomez-Pinilla F, McGinty D. Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats. J Physiol. 2006 Sep 15;575(Pt 3):807-19. doi: 10.1113/jphysiol.2006.115287. Epub 2006 Jul 6.
PubMed 16825295
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigation of the Relationship Between Donepezil Enhanced REM Sleep, Sleep Architecture and Behavior in the Prepubertal Child With Autism
- ClinicalTrials.gov ID
- NCT00695136
- Acronym / sponsor ID
- 080154
- Conditions
- Autism, Cognition Disorder
- Keywords
- Autism, Cognitive Disorder, Sleep, Autism Spectrum Disorder, ASD
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- Jun 2008
- Primary completion
- Jan 2011 (actual)
- Study completion
- Jan 2011 (actual)
- First posted
- 11 Jun 2008 (estimated)
- Results
- Posted 24 Apr 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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...
Detailed description
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.
Study design
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open label single arm | Experimental | Drug: Donepezil hydrochloride, Behavioral: Increase REM sleep percentageSingle group study of Donepezil |
Who may qualify
- Ages
- 2 to 10 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Diagnosis of autism spectrum disorder
- Male or female subjects, ages 2 through 10 years.
- Each legal guardian must have a level of understanding sufficient to agree to all required tests and examinations. Each legal guardian must understand the nature of the study.
- Each subject must be stable for at least 6 weeks on any medication or therapy regimen prior to entry into study and must have no newly (within 6 weeks) recognized or intolerable adverse effects from that medicine or therapy. No subjects will be asked to discontinue any medication in order to qualify for enrollment.
Key exclusion criteria (5 listed)
- Serious, unstable illnesses including, gastroenterologic, respiratory, cardiovascular endocrinologic, immunologic,or hematologic disease.
- Renal or hepatic dysfunction that would interfere with excretion or metabolism of donepezil as evidenced by increase above upper limits of normal for BUN/creatinine, or two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT) or gamma glutamate (GGT)
- Documented history of hypersensitivity or intolerance to donepezil or other piperidine derivative.
- Subjects must not be taking any medication known to affect REM sleep or that is contraindicated for co-administration with donepezil.
- Presence or history of neurological disorders, including seizure disorders.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Donepezil hydrochloride | Drug | Open label single arm |
| Increase REM sleep percentage | Behavioural | Open label single arm |
Primary outcome
Change in Percentage of Time That Subjects With Autism Spend in REM Sleep.
Time frame: 1 month (from baseline to 1.25 mg dose)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 203966McGrath MJ, Cohen DB. REM sleep facilitation of adaptive waking behavior: a review of the literature. Psychol Bull. 1978 Jan;85(1):24-57. No abstract available.
- Background: PubMed 7059812Mirmiran M, van den Dungen H, Uylings HB. Sleep patterns during rearing under different environmental conditions in juvenile rats. Brain Res. 1982 Feb 11;233(2):287-98. doi: 10.1016/0006-8993(82)91203-3.
- Background: PubMed 16825295Guzman-Marin R, Ying Z, Suntsova N, Methippara M, Bashir T, Szymusiak R, Gomez-Pinilla F, McGinty D. Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats. J Physiol. 2006 Sep 15;575(Pt 3):807-19. doi: 10.1113/jphysiol.2006.115287. Epub 2006 Jul 6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Donepezil hydrochloride and Increase REM sleep percentage in people with Autism and Cognition Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Apr 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Percentage of Time That Subjects With Autism Spend in REM Sleep. (time frame: 1 month (from baseline to 1.25 mg dose)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00695136, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2013.