Clinical trial NCT01887132: A Trial of the Drug Donepezil for Sleep Enhancement and Behavioral Change in Children With Autism
Official title: A Randomized Controlled Trial of Donepezil for REM Enhancement and Behavioral Change in Autism
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Autism Spectrum Disorders
Keywords: Sleep Architecture
Autism
Language Development
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2013-06-26
Enrollment: 5
Sex: ALL
Minimum age (years): 24
Maximum age (years): 50
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

- Some children with autism spectrum disorders (ASD) do not have normal sleep cycles. Some of these children spend very little time in the rapid eye movement (REM) stage of sleep. Some studies suggest that less time in REM sleep can be associated with learning and behavior problems. Donepezil is a medication used to treat Alzheimer s disease. Donepezil can increase REM sleep in some adults with different disorders. A small study showed that Donepezil can also increase REM sleep in children with ASD. Researchers now want to see if Donepezil can improve communication skills and social interaction in children with ASD. They also want to see if any change in symptoms seems to come from changes in REM sleep.

Objectives:

- To see if a medication, Donepezil, can improve the way communication skills and social interaction develop in young children with autism spectrum disorders.

Eligibility:

- Children 22 to 44 months of age with ASD.

Design:

* Participants will be screened with a blood test, heart tests, and a sleep study. During the sleep study, children will sleep in a darkened room for 2 nights with electrodes on their body and a tube under their nose. Parents can sleep in the room with their child. A technician will monitor the room all night.
* Participants will take the study medication once a day.
* Treatment will be monitored at visits every 3 months. At each visit the participant will take blood tests, heart tests, or behavior tests. Participants will have 2 more sleep studies.
* Participation will end after 18 months.

Detailed description: i. Objective

The objective of this study is to investigate the efficacy of donepezil to improve the developmental trajectory for core behavioral domains specific to autism, namely reciprocal social interaction and communication.

ii. Study population

90 children with an autism spectrum disorder between the ages of 24 to 50 months will be screened via polysomnogram to find 45 with a relative REM deficiency. This group will then be divided into two arms of drug versus placebo. Allowing for a 22 % drop out rate we expect 17 in each group to complete the study. Additionally, we will enroll 16 children with an ASD who do not meet criteria for relative REM deficiency in an open label arm to ascertain whether or not donepezil is beneficial to behavior in this group.

iii. Design

The proposal is for a 6 month treatment trial of 2.5 mg donepezil/placebo/day followed by 12 months of longitudinal follow-up. The primary study endpoint will be an examination of autism core symptoms and sleep architecture after 12 months.

iv. Outcome measures

The primary outcome measure will be:

1. An improvement in the Expressive Language and the Receptive Language subscales of the Mullen Scales of Early Learning (MSEL) at 12 months.

   Secondary outcome measures will be:
2. We will also measure the change in REM sleep parameters after 6, 12 and 18 months in relation to improvements in behavioral indices.

   Exploratory Outcome Measures will be:
3. An improvement in the Expressive Language and the Receptive Language subscales of the Mullen Scales at 18 months.
4. An improvement on the severity scale of the Autism Diagnostic Observation Schedule (ADOS) at 6, 12 and 18 months.
5. An improvement on the Vineland at 3, 6, 12 and 18 months
6. An exploratory analysis will investigate whether normalization of REM parameters also improves other measurements of sleep quality in children with autism.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Diagnosis of an Autism Spectrum Disorder (DSM-IV diagnoses of autistic disorder or Pervasive Developmental Disorder, Not Otherwise Specified).
  2. Male or Female subjects between the ages of 24 and 50 months.
  3. Language scores (from the Mullen Scales of Early Learning) that are at least 1.5 SD lower than the mean.

  5. 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.

  6. 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 but subjects taking contraindicated drugs will not qualify for enrollment.

  7. Demonstrated REM% two standard deviations or more below the normative values for age for the randomized controlled trial part.

  8. English language is primarily spoken at home.

EXCLUSION CRITERIA:

1. Serious, unstable illnesses including gastroenterologic, respiratory, cardiovascular endocrinologic, immunologic, or hematologic disease.
2. 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).
3. Documented history of hypersensitivity or intolerance to donepezil or other piperidine derivative.
4. Subjects must not be taking any medication known to affect REM sleep (or sleep

   architecture in general) or that is contraindicated for co-administration with donepezil.
5. Presence or history of other unstable neurological disorders such as seizure disorders,

metabolic disorders, narcolepsy or movement disorders.

Primary outcomes:
measure: Nonverbal Developmental Quotient (NVDQ)
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: REM Percentage at Baseline, 6, 12 and 18 Months
timeFrame: Baseline, 6, 12 and 18 months
Other outcomes:
measure: An Exploratory Analysis Will Investigate Whether Normalization of REM Parameters Also Improves Other Measurements of Sleep Quality in Children With Autism.
timeFrame: 12 months
measure: Mullen Scales at 18 Months
timeFrame: 18 months
measure: Autism Diagnostic Observation Schedule (ADOS) at 6, 12 and 18 Months
timeFrame: 6, 12 and 18 months
measure: Vineland Parent Questionnaire at 3, 6, 12 and 18 Months
timeFrame: 3, 6, 12 and 18 months
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Mental Health (NIMH)
name: Ashura W Buckley, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson DK, Lord C, Risi S, DiLavore PS, Shulman C, Thurm A, Welch K, Pickles A. Patterns of growth in verbal abilities among children with autism spectrum disorder. J Consult Clin Psychol. 2007 Aug;75(4):594-604. doi: 10.1037/0022-006X.75.4.594.
citation: Anderson DK, Oti RS, Lord C, Welch K. Patterns of growth in adaptive social abilities among children with autism spectrum disorders. J Abnorm Child Psychol. 2009 Oct;37(7):1019-34. doi: 10.1007/s10802-009-9326-0.
citation: Bliwise DL, Carroll JS, Lee KA, Nekich JC, Dement WC. Sleep and "sundowning" in nursing home patients with dementia. Psychiatry Res. 1993 Sep;48(3):277-92. doi: 10.1016/0165-1781(93)90078-u.