Clinical trial NCT02487082: Pilot Study of Sleep Therapy and Biomarkers in Children With Autism Spectrum Disorders
Official title: Pilot Study of Sleep Therapy and Biomarkers in Children With Autism Spectrum Disorders
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Autism Spectrum Disorder
Keywords: Autism Spectrum Disorder
Children
Melatonin
Donepezil
Sleep disorder
Lead sponsor: Stony Brook University
Sponsor class: OTHER
First posted: 2015-07-01
Enrollment: 12
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is conducted in 2 main phases, supplemented by an initial Run-In Phase and a Final Wash-Out Phase.

The Run-In phase (5 weeks) - All subjects receive Placebo and instructions about how to improve sleep hygiene. This allows us to evaluate a) response to placebo and b) the effect of improved sleep hygiene in the absence of study drug in both groups.

Phase 1 (5 weeks) - Group A receives study drug (donepezil \& melatonin). Group B receives Placebo. Here we assess the benefit of study drug vs. Placebo in a parallel group design.

Phase 2 (5 weeks) - Both groups receive study drug (donepezil \& melatonin). Here we assess the effect of switching from Placebo to study drug in Group B, and the effect of an extra 5 weeks of study drug in Group A.

Wash-Out Phase (variable length, 2-12 weeks) - study drug is discontinued.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Aberrant Behavior Checklist (ABC) Lethargy/Social Withdrawal Subscale
timeFrame: 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 outcomes:
measure: Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale.
timeFrame: 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.
measure: Sleep Duration (Hours)
timeFrame: 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.
measure: Clinical Global Impressions Scale, Clinician Impression of Global Improvement
timeFrame: 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.
measure: Clinical Global Impressions Scale, Parent Reported Global Improvement
timeFrame: 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.
Other outcomes:
Locations:
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
Study officials:
affiliation: Stony Brook University
name: Jill Miller-Horn, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.