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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02487082

Enrollment

Registered

2015-07-01

Start date

2015-06-30

Completion date

2021-01-29

Last updated

2024-06-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Autism Spectrum Disorder

Keywords

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

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.

Interventions

DRUGMelatonin 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.

OTHERPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

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.

Eligibility

Sex/Gender

ALL

Age

4 Years to 17 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Aberrant Behavior Checklist (ABC) Lethargy/Social Withdrawal 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.	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.

Secondary

Measure	Time frame	Description
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.	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.
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.	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.
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.	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.
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.	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.

Countries

United States

Participant flow

Recruitment details

Most patients were recruited from the clinical practice of the Principal Investigator. We also posted flyers in the hospital outpatient clinics and sent Dear Physician recruitment letters to other pediatric neurologists and psychologists in our catchment area.

Participants by arm

Arm	Count
Group A Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment.	4
Group B Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment.	8
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001
Phase 1 (5 Weeks)	Withdrawal by Subject	1	0
Run-In Phase (5 Weeks)	Withdrawal by Subject	1	2

Baseline characteristics

Characteristic	Total	Group B	Group A
ABC Lethargy/Social Withdrawal	9.5 units on a scale	10 units on a scale	8 units on a scale
ABC Stereotypic Behavior	7.5 units on a scale	7.5 units on a scale	7.5 units on a scale
Age, Continuous	9.5 years	9.5 years	11 years
Race and Ethnicity Not Collected	0 Participants	—	—
Region of Enrollment United States	12 participants	8 participants	4 participants
Sex: Female, Male Female	1 Participants	1 Participants	0 Participants
Sex: Female, Male Male	11 Participants	7 Participants	4 Participants
Sleep Duration (hours)	7.1 hours	7 hours	8.2 hours

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 4	0 / 8
other Total, other adverse events	2 / 4	2 / 8
serious Total, serious adverse events	0 / 4	0 / 8

Outcome results

Primary

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.

Time frame: 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.