Trial of Diphenhydramine for Sleep in Children With Autism

Randomized Placebo-controlled Crossover Trial of Diphenhydramine for Sleep in Children With Autism

The purpose of this study is to examine the effect of diphenhydramine on sleep in children and adolescents with Autism Spectrum Disorder (ASD). Diphenhydramine is an anti-histaminergic agent with strong hypnotic properties. To accomplish this, the investigators will use a randomized double-blind placebo-controlled crossover 8-week study design to examine the effect of diphenhydramine on sleep physiology as assessed by polysomnography (PSG), actigraphy, circadian rhythm, and clinical measures.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder; Autism
• Intervention / Treatment: Drug: Diphenhydramine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Joe McGrath; Phone Number: (650)736-1235; Email: roscoe37@stanford.edu
• Study Contact Backup: Name: Richard Ellks; Phone Number: (650)736-1235; Email: ACESleepTrials@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305-5719
      • Recruiting
      • Stanford University
      • Principal Investigator: Antonio Y. Hardan, MD
      • Contact: Joe McGrath; Phone Number: 650-736-1235; Email: roscoe37@stanford.edu
      • Contact: Richard Ellks; Phone Number: (650) 736-1235; Email: ACESleepTrials@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

Participants will meet the following

• Outpatients between 8 and 17 years of age
• Diagnostic and Statistical Manual, 5th edition (DSM-5) criteria for Autism Spectrum Disorder (ASD) on the basis of clinical evaluation, confirmed with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule, 2nd Ed (ADOS-2)
• Males and females
• Availability of polysomnography (PSG) and actigraphy data
• Sleep disturbances as assessed using Children's Sleep Habits Questionnaire (CSHQ) with a score of 41 or higher
• care provider who can reliably bring participant to clinic visits, provide trustworthy ratings, and interacts with participant on a regular basis
• stable medications for at least 4 weeks
• no planned changes in psychosocial and biomedical interventions during the trial
• willingness to provide additional saliva samples and participate in key study procedures (i.e.,safety measurements every visit, PSG at weeks 4 and 8, and wear the actigraphy watch for 2 weeks before the beginning of trial as well as during the 8 weeks of the trial).

Exclusion criteria:

Participants will be excluded if one or more of the following is met

• active suicidal ideation or DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder
• active medical problems: migraine, asthma, seizure disorder, significant physical illness (e.g., anaphylaxis, serious liver, renal, or cardiac pathology)
• evidence of a genetic mutation known to cause autism or intellectual disability (e.g., Fragile X Syndrome), metabolic, or infectious etiology for the participant's autism on the basis of medical history, neurologic history, and available tests for inborn errors of metabolism and chromosomal analysis
• pregnant or sexually active females not using a reliable method of contraception (urinary tests for pregnancy will be employed in this study)
• individuals taking beta-blockers (local or systemic), benzodiazepines, antiepileptic medications, serotonin selective re-uptake inhibitors, melatonin and antihistamines
• history of hypersensitivity to diphenhydramine
• history of severe side effects from diphenhydramine
• history of adequate trial of diphenhydramine
• current use of any medications known to interact with diphenhydramine such as medications inhibiting CYP2D6
• taking anticholinergic agents (e.g., trihexyphenidyl, thioridazine).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diphenhydramine, then Placebo; Participants will first receive Diphenhydramine for a 4-week period. A 25 mg dose of Diphenhydramine will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated. Participants will then receive Placebo (fake tablet) for a 4-week period. A 25 mg dose of matching Placebo will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated.	Drug: Diphenhydramine; 25mg (and up to 50mg) Diphenhydramine given orally; Other Names: Benadryl; Drug: Placebo; Matching Placebo given orally
Experimental: Placebo, then Diphenhydramine; Participants will first receive Placebo (fake tablet) for a 4-week period. A 25 mg dose of matching Placebo will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated. Participants will then receive Diphenhydramine for a 4-week period. A 25 mg dose of Diphenhydramine will be given at bedtime for one week and then will increase to 50 mg if needed and if well tolerated.	Drug: Diphenhydramine; 25mg (and up to 50mg) Diphenhydramine given orally; Other Names: Benadryl; Drug: Placebo; Matching Placebo given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in sleep latency as measured by polysomnography (PSG)	Baseline, Week 4 and Week 8
Change from baseline in duration of non-rapid eye movement (NREM) sleep as measured by polysomnography (PSG)	Baseline, Week 4 and Week 8

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in sleep efficiency as measured by polysomnography (PSG) and actigraphy	Baseline, Week 4 and Week 8

Other Outcome Measures

Outcome Measure	Time Frame
Change from baseline on Children's Sleep Habits Questionnaire (CSHQ) subscale scores	Baseline, Week 4, Week 8
Change from baseline on Aberrant Behavior Checklist, Second Edition (ABC-2) subscale scores	Baseline, Week 4, Week 8
Change from baseline on Parent Sleep Habits Questionnaire Parent (PSHQ) scores	Baseline, Week 4, Week 8
Change from baseline on Clinical Global Impression Scale (CGI) scores	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, and Week 8
Change from baseline on Child Behavior Checklist (CBCL) scores	Baseline, Week 4, Week 8
Change from baseline on Social Responsiveness Scale, Second Edition (SRS-2) scores	Baseline, Week 4, Week 8
Change from baseline on Repetitive Behavior Scale - Revised (RBS-R) scores	Baseline, Week 4, Week 8
Change from baseline on Sensory Profile Questionnaire (SPQ) scores	Baseline, Week 4, Week 8
Change from baseline on Stanford Social Dimension Scale (SSDS) scores	Baseline, Week 4, Week 8
Change from baseline on Dimensional Assessment of Repetitive Behaviors (DARB) scores	Baseline, Week 4, Week 8
Change from baseline on NEuroPSYchological Assessment, 2nd Edition (NEPSY-2) Affect Recognition scores	Baseline, Week 4, Week 8

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Antonio Y. Hardan, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 12, 2022
• First Submitted That Met QC Criteria: August 12, 2022
• First Posted (Actual): August 15, 2022

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: autism; Sleep; clinical trial; Diphenhdramine
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autistic Disorder; Autism Spectrum Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Diphenhydramine; Promethazine
• Other Study ID Numbers: IRB-66941; 1P50HD109861 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will submit de-identified clinical data to the NIMH Data Archive (NDA) data repository.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes