Pilot Study of Sleep Therapy and Biomarkers in Children With Autism Spectrum Disorders

The purpose of this study is to test the combined effect of melatonin and donepezil on improving sleep and behavior in children with Autism Spectrum Disorders. Melatonin is a natural neurohormone that helps regulate sleep and wake cycles. Donepezil is used to improve mental function for people with Alzheimer's disease. Children with Autism Spectrum Disorders are more likely to have problems sleeping than other children. This difficulty has been linked to daytime behavioral problems and family stress.

Study Overview

• Status: Terminated
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Drug: Melatonin and Donepezil; Other: Placebo

Detailed Description

The goal of the present exploratory investigation is to see if there is a suggestion of a large additive or synergistic effect of melatonin and donepezil given together. Individually both medications improve sleep, but appear do so in different ways, with melatonin altering circadian rhythm and donepezil altering the characteristics of REM sleep. In this pilot investigation we will examine whether their combined effects on sleep lead to a large improvement in the behavior of children with ASD. Combined pharmacotherapy is very common in clinical practice, but is rarely studied in research (Comer et al. 2010). These two medications are both well tolerated and there is no negative drug interaction between the two. This investigation will use an RCT as well as a set of exploratory analyses to assess the combined effects of these two medications compared to placebo in terms of behavioral and sleep measures. In addition we will collect exploratory biomarkers (e.g., digit ratio, the ratio of the lengths different fingers as a measure of the balance of sex hormones during embryonic development) to relate to the various sleep and behavioral measures. A positive signal from this study may be used to guide a follow-up study with greater numbers of study subjects and statistical power.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Both male and female children
• Ages 4 to 17 1/2 years
• Diagnosis with Autism Spectrum Disorder on the basis of the clinical judgment of an autism specialist, preferably using the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview-Revised.

Exclusion Criteria:

• Abnormal electroencephalogram in the past month
• Cardiovascular problems
• Asthma
• Respiratory disease
• Peptic ulcer disease
• Renal or hepatic dysfunction (abnormal blood urea nitrogen/creatinine or 2 times elevated liver transaminases)
• Urinary tract obstruction
• Underweight (body mass index < 5th percentile compared to age and sex matched population)
• Other serious illness
• Use of any of the following drugs that might interact with study medications (anticholinergics, systemic corticosteroids, phenobarbital, peginterferon, beta-blockers or any drug that may cause arrhythmias). Drugs that induce or inhibit cytochrome P450 2D6 and cytochrome P450 3A4 (enzymes important for drug metabolism) will be allowed because any effects of such medications are likely to be lost in individual variability due to genetic polymorphisms.
• Use of medications affecting sleep with a half-life of 7 days or more. [Children on medications affecting sleep with a half-life of less than 7 days (including melatonin and donepezil) are eligible if they agree to discontinue use for the duration of the trial.]
• Pregnancy and lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group A; Run-In Phase: Placebo. Phase 1 & Phase 2: Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) for 10 weeks Wash-Out Phase: no active or placebo medication. Note: Dosage of study drug varies with age/weight. Younger children (<12 years or < 80 lbs. weight start at a lower dose of donepezil (1.25 mg/night) and increase to 2.5 mg/night after one week. Older children (>= 12 years or >= 80 lbs weight) start at 3 mg donepezil and increase to 5 mg after one week. The dose of melatonin remains stable at 3 mg throughout for both groups.	Drug: Melatonin and Donepezil; 10 weeks of active study medication in Group A during Phase 1 & Phase 2. 5 weeks of active study medication in Group B during Phase 2.; Other Names: Aricept; Other: Placebo; For both groups: 5 weeks of Placebo in the Run-In Phase. For Group B: an addition 5 weeks of Placebo in Phase 1.
Other: Group B; Run-In Phase: Placebo. Phase 1: Placebo. Phase 2: Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 5 weeks Wash-out Phase: no active or placebo medication. Note: Dosage of study drug varies with age/weight. Younger children (<12 years or < 80 lbs. weight start at a lower dose of donepezil (1.25 mg/night) and increase to 2.5 mg/night after one week. Older children (>= 12 years or >= 80 lbs weight) start at 3 mg donepezil and increase to 5 mg after one week. The dose of melatonin remains stable at 3 mg throughout for both groups.	Drug: Melatonin and Donepezil; 10 weeks of active study medication in Group A during Phase 1 & Phase 2. 5 weeks of active study medication in Group B during Phase 2.; Other Names: Aricept; Other: Placebo; For both groups: 5 weeks of Placebo in the Run-In Phase. For Group B: an addition 5 weeks of Placebo in Phase 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aberrant Behavior Checklist (ABC) Lethargy/Social Withdrawal Subscale	Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC checklist is considered sensitive to drug effects. The Lethargy/Social Withdrawal subscale contains items such as: "Listless, sluggish, inactive" ; "Withdrawn, prefers solitary activities"; "Does not try to communicate by words or gestures"; "Shows few social reactions to others". The subscale consists of 16 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 48. Higher scores mean more lethargy and/or more social withdrawal.	Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale.	Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC Checklist is considered sensitive to drug effects. The Stereotypic Behavior subscale contains items such as: "Meaningless, recurring body movements" ; "Odd, bizarre in behavior"; "Waves, shakes the extremities repeatedly"; "Rocks body back and forth". The subscale consists of 7 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 21. Higher scores mean more stereotyped behavior.	Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks.
Sleep Duration (Hours)	A brief seven item questionnaire adapted from the Children's Sleep Habits Questionnaire (CSHQ). This parental questionnaire assesses sleep behaviors in children. It has been validated in children with ASD, correlates with polysomnographic recordings, and has been used successfully in previous studies of melatonin with such children. The CSHQ items chosen for this study come from the subscales found to be most often disturbed in children with autism.	Rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks.
Clinical Global Impressions Scale, Clinician Impression of Global Improvement	Measured by the Clinical Global Impressions Scale. The Clinician Impression of Global Improvement is a single item rated as follows: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline.	Rating was made by clinician every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks.
Clinical Global Impressions Scale, Parent Reported Global Improvement	Parent Impression of Global Improvement is a single item rated as follows: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline.	Rating was made by parent every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks.

Collaborators and Investigators

• Sponsor: Stony Brook University
• Investigators: Principal Investigator: Jill Miller-Horn, MD, MS, Stony Brook University

Publications and helpful links

General Publications

• Buckley AW, Sassower K, Rodriguez AJ, Jennison K, Wingert K, Buckley J, Thurm A, Sato S, Swedo S. An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders. J Child Adolesc Psychopharmacol. 2011 Aug;21(4):353-7. doi: 10.1089/cap.2010.0121.
• Cidav Z, Marcus SC, Mandell DS. Implications of childhood autism for parental employment and earnings. Pediatrics. 2012 Apr;129(4):617-23. doi: 10.1542/peds.2011-2700. Epub 2012 Mar 19.
• Malow BA, Marzec ML, McGrew SG, Wang L, Henderson LM, Stone WL. Characterizing sleep in children with autism spectrum disorders: a multidimensional approach. Sleep. 2006 Dec;29(12):1563-71. doi: 10.1093/sleep/29.12.1563.
• Richdale AL, Schreck KA. Sleep problems in autism spectrum disorders: prevalence, nature, & possible biopsychosocial aetiologies. Sleep Med Rev. 2009 Dec;13(6):403-11. doi: 10.1016/j.smrv.2009.02.003. Epub 2009 Apr 24.
• Taylor MA, Schreck KA, Mulick JA. Sleep disruption as a correlate to cognitive and adaptive behavior problems in autism spectrum disorders. Res Dev Disabil. 2012 Sep-Oct;33(5):1408-17. doi: 10.1016/j.ridd.2012.03.013. Epub 2012 Apr 21.
• Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, Hamilton D, Weiss MD. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57-64. doi: 10.1111/j.1600-079X.2007.00528.x.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): January 29, 2021

Study Registration Dates

• First Submitted: June 29, 2015
• First Submitted That Met QC Criteria: June 30, 2015
• First Posted (Estimated): July 1, 2015

Study Record Updates

• Last Update Posted (Actual): June 6, 2024
• Last Update Submitted That Met QC Criteria: May 10, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; Children; Autism Spectrum Disorder; Donepezil; Sleep disorder
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Cholinergic Agents; Enzyme Inhibitors; Protective Agents; Antioxidants; Nootropic Agents; Cholinesterase Inhibitors; Melatonin; Donepezil
• Other Study ID Numbers: 65708

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No