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

This study has been withdrawn prior to enrollment.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01170325
First received: July 24, 2010
Last updated: December 30, 2011
Last verified: January 2011
  Purpose

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.

Condition Intervention Phase
Autism
Autism Spectrum Disorders
Drug: Divalproex Sodium
Drug: Placebo Comparator
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Study of Divalproex Sodium in Children With Autism Spectrum Disorder and Epileptiform EEG

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • epileptiform EEG discharges [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Improvement in behavior

Enrollment: 0
Study Start Date: June 2010
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A Drug: Divalproex Sodium
N/A
Placebo Comparator: Group B Drug: Placebo Comparator
N/A

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.

  Eligibility

Ages Eligible for Study:   3 Years to 10 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01170325

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
Responsible Party: Sarah J. Spence, M.D./National Institute of Mental Health, National Institutes of Health
ClinicalTrials.gov Identifier: NCT01170325     History of Changes
Other Study ID Numbers: 100157, 10-M-0157
Study First Received: July 24, 2010
Last Updated: December 30, 2011
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Valproic Acid
Divalproex
Autism
EEG
Electroencephalogram (EEG)
Depakote

Additional relevant MeSH terms:
Child Development Disorders, Pervasive
Disease
Autistic Disorder
Pathologic Processes
Mental Disorders Diagnosed in Childhood
Mental Disorders
Valproic Acid
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs

ClinicalTrials.gov processed this record on September 30, 2014