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Treatment of Children With Autism Spectrum Disorders and Epileptiform EEG With Divalproex Sodium

Primary Purpose

Autism

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

divalproex sodium

Placebo

About this trial

This is an interventional treatment trial for Autism focused on measuring Abnormal EEGs

Eligibility Criteria

4 Years - 10 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female patients aged 4 to 10 years.
Diagnosis of with ASD (Autistic Disorder, Asperger's Disorder, or pervasive developmental disorder (PDD-NOS).
Frequent epileptiform discharges on EEG (defined as spikes, spike wave, and sharp waves occurring at greater than 15 events per hour).
Intelligence quotient (IQ) range 40 to 100.
Weight > or = 12.5 kg.
English speaking families

Exclusion Criteria:

History of epilepsy, known neurogenetic disorder or chromosomal abnormalities with high rates of epilepsy (15q duplication syndrome, 16p deletion/duplication syndrome, Fragile X, tuberous sclerosis complex), or structural brain lesion (prior stroke, migrational defects, brain malformations).
The presence of a severe epileptiform EEG on the sleep EEG referred to as electrical status epilepticus in sleep (ESES) in sleep
Previous treatment with divalproex sodium that is any one of the following:
- of greater than 6 months duration
- within the last 12 months
- that was associated with significant side effects leading to termination of treatment
Children who have had general anesthesia within the six months or sedation within 2 weeks of study enrollment.
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.
Presence of medical condition, such as carnitine deficiency, urea cycle disorder or other metabolic disorder that would be a contraindication to divalproex sodium usage.
Presence of a significant untreated medical problem (obstructive sleep apnea, restless legs syndrome, GERD, etc.) which may have significant impact on sleep study measures.
Renal, hepatic, pancreatic, or hematologic dysfunction as evidenced by values 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<3.0 103 /mcL.
Concomitant use of medication contraindicated with divalproex sodium including topiramate, lamotrigine, and drugs that inhibit cytochrome p450 enzymes.
Behavioral management issues (e.g. self-injury, aggressiveness) severe enough to be of safety concerns (to subject and/or staff).
Absence of primary care physician.

Sites / Locations

University of Louisville
Boston Childrens Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

divalproex sodium

Placebo

Arm Description

divalproex sodium will be administered in sprinkle capsule formulation, target dose of 30mg/kg, drug will be administered for 12 weeks

Blue and white capsules with equivalent amount of lactose spheres/beads inside Placebo will be formulated to look identical to the active medication

Outcomes

Primary Outcome Measures

effect of drug vs placebo on reduction in epileptiform EEG discharges in children with ASD

To examine the effect of divalproex sodium (valproate or VPA) on epileptiform EEG discharges in children with ASD. The investigators hypothesize that VPA will significantly reduce discharge counts (primary outcome measure) compared to placebo.

Secondary Outcome Measures

behavior changes in drug vs placebo.

To determine if administration of VPA results in improvement in behavior compared to placebo. Based on preliminary data the investigators hypothesize that VPA will be significantly associated with improvement in the areas of aggression, attention and externalizing behaviors as measured by the Child Behavior Checklist (CBCL), the primary behavioral outcome variables. A wide range of other behavioral measures (secondary outcomes) including those related to core ASD symptoms, language, adaptive functioning, sensory and motor behaviors to identify will also be examined. Behavioral measures will be examined in relation to reduction of epileptiform discharges. The investigators will also include both objective and subjective measures of sleep and examine the effect of sleep changes in relation to EEG discharge profiles and behavior.

Full Information

NCT ID

NCT02094651

First Posted

March 10, 2014

Last Updated

October 20, 2016

Sponsor

Boston Children's Hospital

Collaborators

University of Louisville

1. Study Identification

Unique Protocol Identification Number

NCT02094651

Brief Title

Treatment of Children With Autism Spectrum Disorders and Epileptiform EEG With Divalproex Sodium

Official Title

Treatment of Children With Autism Spectrum Disorders and Epileptiform EEG With Divalproex Sodium

Study Type

Interventional

2. Study Status

Record Verification Date

October 2016

Overall Recruitment Status

Withdrawn

Why Stopped

No eligible patients were enrolled

Study Start Date

April 2014 (undefined)

Primary Completion Date

October 2016 (Actual)

Study Completion Date

October 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Boston Children's Hospital

Collaborators

University of Louisville

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine if treatment of epileptiform abnormalities in children with autism spectrum disorder will improve any behaviors in these children. The investigators will study a number of different behavioral outcomes including behaviors related to attention, social communication, repetitive behaviors, maladaptive behaviors, language, motor and sensory, and sleep. The investigators will use an anticonvulsant medication called valproic acid (in the form of sodium divalproex).

Detailed Description

Epilepsy and epileptiform EEG abnormalities are common co-morbidities in Autism Spectrum Disorders (ASD) that can be considered important biomarkers of cortical dysfunction in these disorders. They may represent a measure of the excitatory-inhibitory imbalance posited to be involved in the pathogenesis of the disorder. Treatment of epilepsy is always indicated, but treatment of isolated epileptiform EEG (i.e. in the absence of clinical seizures) is frankly controversial. Since data suggest that these epileptiform discharges are associated with deficits in attention, language and behavior, the investigators believe that they may represent an important and novel treatment target in this population. The proposed study brings together a group of investigators long interested in this problem in order to investigate the efficacy of using an anticonvulsant medication with spike suppression capabilities (VPA in the form of divalproex sodium) to treat children with ASD and isolated epileptiform EEGs. Recruiting from 3 large autism centers (Boston Children's Hospital (BCH) and Vanderbilt University (VU) and University of Louisville (U of L)) with very large pediatric epilepsy units, the investigators propose a 26 week randomized placebo controlled cross over study of VPA in 4-8 year old children with ASD with frequent epileptiform EEG discharges.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Autism

Keywords

Abnormal EEGs

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

divalproex sodium

Arm Type

Experimental

Arm Description

divalproex sodium will be administered in sprinkle capsule formulation, target dose of 30mg/kg, drug will be administered for 12 weeks

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Blue and white capsules with equivalent amount of lactose spheres/beads inside Placebo will be formulated to look identical to the active medication

Intervention Type

Drug

Intervention Name(s)

divalproex sodium

Other Intervention Name(s)

Depakote, valproic acid, VPA, sodium valproate

Intervention Description

The drug is an FDA approved medication for seizures but has not been approved for the treatment of epileptiform EEG abnormalities in the absence of clinical seizures.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

The placebo is an inactive substance that looks like the active drug.

Primary Outcome Measure Information:

Title

effect of drug vs placebo on reduction in epileptiform EEG discharges in children with ASD

Description

Time Frame

In this crossover study participants will be on drug and placebo for 12 weeks each

Secondary Outcome Measure Information:

Title

behavior changes in drug vs placebo.

Description

Time Frame

In this crossover study participants will be on drug and placebo for 12 weeks each

10. Eligibility

Sex

All

Minimum Age & Unit of Time

4 Years

Maximum Age & Unit of Time

10 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female patients aged 4 to 10 years. Diagnosis of with ASD (Autistic Disorder, Asperger's Disorder, or pervasive developmental disorder (PDD-NOS). Frequent epileptiform discharges on EEG (defined as spikes, spike wave, and sharp waves occurring at greater than 15 events per hour). Intelligence quotient (IQ) range 40 to 100. Weight > or = 12.5 kg. English speaking families Exclusion Criteria: History of epilepsy, known neurogenetic disorder or chromosomal abnormalities with high rates of epilepsy (15q duplication syndrome, 16p deletion/duplication syndrome, Fragile X, tuberous sclerosis complex), or structural brain lesion (prior stroke, migrational defects, brain malformations). The presence of a severe epileptiform EEG on the sleep EEG referred to as electrical status epilepticus in sleep (ESES) in sleep Previous treatment with divalproex sodium that is any one of the following: of greater than 6 months duration within the last 12 months that was associated with significant side effects leading to termination of treatment Children who have had general anesthesia within the six months or sedation within 2 weeks of study enrollment. 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. Presence of medical condition, such as carnitine deficiency, urea cycle disorder or other metabolic disorder that would be a contraindication to divalproex sodium usage. Presence of a significant untreated medical problem (obstructive sleep apnea, restless legs syndrome, GERD, etc.) which may have significant impact on sleep study measures. Renal, hepatic, pancreatic, or hematologic dysfunction as evidenced by values 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<3.0 103 /mcL. Concomitant use of medication contraindicated with divalproex sodium including topiramate, lamotrigine, and drugs that inhibit cytochrome p450 enzymes. Behavioral management issues (e.g. self-injury, aggressiveness) severe enough to be of safety concerns (to subject and/or staff). Absence of primary care physician.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sarah Spence, MD PhD

Organizational Affiliation

Boston Children's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Louisville

City

Louisville

State/Province

Kentucky

ZIP/Postal Code

40202

Country

United States

Facility Name

Boston Childrens Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Treatment of Children With Autism Spectrum Disorders and Epileptiform EEG With Divalproex Sodium

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