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

NCT02487082 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 65708
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Autism Spectrum Disorder

Keywords

Autism Spectrum Disorder; Children; Melatonin; Donepezil; Sleep disorder

Outcome Measures

Primary Outcomes (1)

• 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 The Lethargy/Social Withdrawal subscale contains items such as: "Listless, sluggish, inactive" ; "Withdrawn, prefers solitary activities"; "Does not try to communicate by words or gestures"; "Shows few social reactions to others".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 Outcomes (4)

• Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale.

  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)

  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

  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

  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.

Study Arms (2)

Group A

OTHER

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; Other: Placebo

Group B

OTHER

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; Other: Placebo

Interventions

Melatonin and Donepezil DRUG

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.

Also known as: Aricept

Group A; Group B

Placebo OTHER

For both groups: 5 weeks of Placebo in the Run-In Phase. For Group B: an addition 5 weeks of Placebo in Phase 1.

Group A; Group B

Eligibility Criteria

• Age: 4 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Stony Brook University: lead

Study Sites (1)

Stony Brook University

Stony Brook, New York, 11794, United States

Location

Related Publications (6)

• 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.

  PMID: 21851192 BACKGROUND

• 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.

  PMID: 22430453 BACKGROUND

• 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.

  PMID: 17252887 BACKGROUND

• 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.

  PMID: 19398354 BACKGROUND

• 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.

  PMID: 22522199 BACKGROUND

• 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.

  PMID: 18078449 BACKGROUND

MeSH Terms

Conditions

Autism Spectrum Disorder; Sleep Wake Disorders

Interventions

Melatonin; Donepezil

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Polycyclic Compounds

Limitations and Caveats

No statistical comparisons were undertaken due to the small sample size in the two groups. Study enrollment/completion proved insufficient to permit any conclusions to be drawn. Enrollment/completion was likely limited because of the study requirement that all prior sleep medications, including melatonin, be discontinued as a condition for study participation.

Results Point of Contact

• Title: Ruth A. Reinsel Ph.D., Clinical Research Associate II
• Organization: Stony Brook Medicine Dept. of Neurology

ruth.reinsel@stonybrookmedicine.edu

(631) 638-2087

Study Officials

• Jill Miller-Horn, MD, MS

  Stony Brook University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology and Pediatrics

Model Details: 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.

Study Record Dates

• First Submitted: June 29, 2015
• First Posted: July 1, 2015
• Study Start: June 1, 2015
• Primary Completion: December 31, 2020
• Study Completion: January 29, 2021
• Last Updated: June 6, 2024
• Results First Posted: June 6, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)