A Study of Divalproex Sodium in Children With ASD and Epileptiform EEG

June 30, 2017 updated by: National Institute of Mental Health (NIMH)

A Study of Divalproex Sodium in Children With Autism Spectrum Disorder and Epileptiform EEG

Background:

  • Electroencephalography (EEG) records electric patterns produced by the brain, and can detect conditions such as epilepsy or other l abnormalities that may affect brain function. In EEG studies, electric patterns that resemble epileptic seizures are known as epileptiform pattern. These patterns are associated with an increased risk of seizures, even in people who have not been diagnosed with epilepsy. Epileptiform patterns also appear on the EEGs of some children who have autism spectrum disorders but do not have epilepsy. It is unclear if these discharges are related in any way to the symptoms of autism (behavior, language or intellectual abilities).
  • Divalproex sodium (Depakote) is a drug that has been used for many years to treat epilepsy and other brain disorders in children and adults. Researchers are interested determining whether treatment with divalproex sodium can reduce epileptiform patterns in children with autism spectrum disorders, and in doing so study whether this treatment can improve behavior, language or cognition in children with autism spectrum disorders.

Objectives:

- To study the effectiveness of using divalproex sodium to reduce epileptiform EEG discharges in children with autism spectrum disorders.

Eligibility:

- Children between 3 and 10 years of age who have an autism spectrum disorder and show frequent epileptiform discharges on an overnight EEG.

Design:

  • This study will last for a total of 9 months, with 6 months of treatment with either divalproex sodium or a placebo followed by 3 months of treatment with divalproex sodium only.
  • Potential participants will be screened with a physical examination and medical history, blood samples, and psychological tests, and will spend the night in the NIH Clinical Center to have an overnight EEG. Children with frequent epileptiform abnormalities on the EEG will continue with the study; all others will be considered ineligible.
  • Eligible participants will receive either divalproex sodium or a placebo to be taken twice daily for 24 weeks. Neither the investigators nor the participants will know which they are taking.
  • Participants will have regular visits (every 2-4 weeks) to monitor for adverse effects and to test for possible behavioral improvement, and will also have overnight EEG testing at 12 and 24 weeks.
  • At the end of the 24-week study period, participants will have the option to have an additional 12 weeks of treatment with divalproex sodium.
  • A final evaluation (including EEG) will be conducted at the end of the final treatment period.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Objective

The objective of this study is to investigate the efficacy of divalproex sodium in reduction of epileptiform EEG discharges in children with Autism Spectrum Disorders (ASD). ASDs are neurodevelopmental disorders that result in abnormalities of social and language development and are associated with rigid and repetitive behaviors. ASD prevalence may be as common as 1 in 110 and as many as 1/3 of these individuals have seizures. Abnormal electroencephalograms (EEGs) (without seizure activity) are even more prevalent (Spence & Schneider, 2009). In an ongoing study at the NIMH, approximately 50% of children without epilepsy had epileptiform discharges present on overnight EEG. The relationship between this abnormal activity and autism symptoms has not yet been studied; however, data from other epilepsy syndromes suggest that these epileptiform discharges contribute to behavioral and cognitive deficits. It is also unknown whether or not reduction of the epileptiform discharges will result in improved behavior and more rapid intellectual and social development in children with ASD. This pilot study is designed to address that question.

Study Population

100 children with ASDs including Autistic Disorder, Asperger's or PDD-NOS ages 3-10 will be screened to find up to 40 children with frequent epileptiform discharges noted on overnight EEG. Allowing for up to 20% drop out, we expect at least 32 to complete the study.

Design

The proposed investigation is a 9 month long trial with a 6 month double-blind placebo controlled trial of divalproex sodium (Depakote) and a 3 month open label extension phase. Prior to study entry, potential subjects will be evaluated with the standard PDN diagnostic/behavioral assessment (06-M-0065). Children meeting eligibility criteria will undergo an overnight EEG and those with frequent epileptiform discharges will be randomly assigned to receive divalproex sodium or placebo. Study drugs will be administered in a blinded fashion for 24 weeks with overnight EEG at 12 and 24 weeks. Biweekly then monthly visits with laboratory studies will monitor for behavioral improvement and for potential adverse effects. A 3 month open label extension phase follows.

Outcome Measures

The primary outcome measure will be EEG changes; tolerability and changes in behavioral symptoms will be exploratory secondary outcome assessments. It is hypothesized that divalproex will be superior to placebo in reducing epileptiform discharges on the EEG. In addition, exploratory analyses will investigate whether children who demonstrate improvements and even normalization of the EEG pattern will have more associated behavioral improvements than those for whom the EEG does not improve.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 10 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:

    1. Have a diagnosis of Autistic Disorder, Asperger's syndrome, or Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS).
    2. Are aged 3 to 10 years.
    3. Weigh at least 12.5 kg.
    4. Only children with frequent epileptiform EEG activity on the overnight EEG at NIH will be randomized to start study drug. Frequent discharges are defined as spikes, spike wave, and sharp waves occurring at greater than 5 events per hour.

EXCLUSION CRITERIA:

  1. A diagnosis of epilepsy (past or present) excluding febrile seizures.
  2. The presence of a severe epileptiform EEG on the sleep EEG at NIH referred to as electrical status epilepticus in sleep (ESES).

  3. Previous treatment with divalproex sodium

    1. of greater than 6 months duration
    2. within the last 12 months
    3. that was associated with significant side effects leading to termination of treatment.
  4. Recent (less than two months prior to study entry) initiation of a behavioral therapy program or new psychotropic medication, or the plan to change or start a new therapy.
  5. Presence of medical condition, such as carnitine deficiency, urea cycle disorder or other metabolic disorder that would be a contraindication to divalproex sodium usage.
  6. Renal, hepatic, pancreatic, or hematologic dysfunction as evidenced by increase above upper limits of normal for BUN/creatinine, or values twice the upper limit of normal for serum transaminases (ALT/SGPT, AST/SGOT), values twice the upper limit of normal for serum lipase and amylase, platelets < 80,000 /mcL, WBC< 3.0 10(3)/mcL.
  7. Pregnancy
  8. Concomitant use of medication contraindicated with divalproex sodium including topiramate, lamotragine, and drugs that inhibit cytochrome p450 enzymes.
  9. Behavioral management issues (e.g. self-injury, aggressiveness) that are severe enough to be of safety concerns (to subject and/or staff).
  10. Absence of primary care physician.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A
Drug: Divalproex Sodium
Placebo Comparator: Group B
Drug: Placebo Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
epileptiform EEG discharges
Time Frame: 24 weeks
24 weeks

Secondary Outcome Measures

Outcome Measure
Improvement in behavior

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Mental Health (NIMH)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 30, 2010

Primary Completion (Actual)

January 28, 2011

Study Completion (Actual)

January 28, 2011

Study Registration Dates

First Submitted

July 24, 2010

First Submitted That Met QC Criteria

July 24, 2010

First Posted (Estimate)

July 27, 2010

Study Record Updates

Last Update Posted (Actual)

July 2, 2017

Last Update Submitted That Met QC Criteria

June 30, 2017

Last Verified

January 28, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 100157
  • 10-M-0157

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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