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Cognitive AED Outcomes in Pediatric Localization Related Epilepsy (COPE) (COPE)

Primary Purpose

Epilepsy, Partial, Epilepsy, Localization Related

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Oxcarbazepine
Levetiracetam
Lamotrigine
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epilepsy, Partial focused on measuring Pediatrics

Eligibility Criteria

5 Years - 16 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age of participant between 5 years, 6 months and 16 years, 0 months at the time of enrollment
  • Weight is between ≥ 15 kg the lower limit BMI 99th percentile at study entry at study entry

  • Child has diagnosed epilepsy as defined by one of the following definitions :

    • At least two unprovoked seizures occurring more than 24-hours apart, or
    • One unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 75% or more), or
    • At least two seizures in a setting of reflex epilepsy
  • Child has a diagnosis of Localization Related Epilepsy (LRE) with or without secondary generalization according to International League Against Epilepsy (ILAE) criteria and which may include Benign Rolandic Epilepsy and Benign Occipital Epilepsy or other LREs.
  • Localization related seizures will be based upon at least one of the following: 1) focal EEG abnormalities (sharp waves, spikes, or slowing) and the absence of generalized spike waves discharges, 2) focal MRI abnormalities other than active cysticercosis, which may include temporal lobe sclerosis, dysembryoplastic neuroepithelial tumor , ganglioglioma, or focal malformations of cortical development, 3) focal neurologic abnormalities, or 4) clinical semiology, which may include Todd's phenomenon, unilateral dystonia, or fencing posture, or distinct aura consistent with localization related seizure onset (e.g., classic déjà vu or bad smell).
  • Participants must either be antiepileptic drug (AED) therapy naïve or on an AED (excluding benzodiazepines) for 1-week or less. Children may be on a stable dose of psychostimulants at the time of enrollment, but no change in medication, dose, or schedule in 3 months prior to study enrollment, with no anticipated dosing changes during the 6 months of the study. If participants are taking psychostimulants at the time of study entry, they should plan on continuing them for the 6 month duration of the study protocol including the 3-month and 6-month cognitive and behavioral testing time points.
  • Females of child bearing potential must agree to acceptable forms of birth control, which may include abstinence.
  • The child's parent/guardian must be able to keep an accurate seizure diary and be able and willing to comply with instructions and study procedures.
  • Informed consent from the child's legal guardian or legal representative.
  • Assent will be obtained from children according to each site's institutional guidelines.

Exclusion Criteria:

  • Children with history of primary generalized seizures (absence, myoclonic, drop)
  • Children with mixed seizure disorder (e.g., Lennox-Gastaut Syndrome)
  • Children with sensory seizures only (i.e., auras)
  • Children with 6+ seizures in the previous week
  • Children with a history of status epilepticus
  • Children with a history of neonatal seizures
  • Children with diagnoses of pervasive developmental disorders (e.g., autism/autism spectrum disorders)
  • Children with progressive neurological disease (e.g., degenerative, progressive neoplasm)
  • Children with major medical disease (e.g., Insulin-Dependent Diabetes Mellitus (IDDM), cancer, renal failure)
  • Children with diseases with cognitive impact (e.g., inborn errors of metabolism, sickle cell disease with history of stroke)
  • Children with active cysticercosis documented on MRI
  • Children with cognitive impairment of sufficient severity that, in the opinion of the investigator, would diminish the likelihood of valid test performance (roughly corresponding to Full Scale Intelligence Quotient (FSIQ) less than 70)
  • Children with suicide attempt(s) at any point during their lifetime
  • Children with active suicide ideation
  • Children with chronic use of first generation antihistamines
  • Children using recreational drugs (including alcohol)
  • Children not fluent in either English or Spanish
  • Female children who are pregnant
  • Female children who are using oral contraceptives for birth control or for any other indication (e.g. acne treatment)

Sites / Locations

  • Arkansas Children's Hospital
  • University of California at San Diego
  • Children's Hospital Colorado
  • Children's National Medical Center
  • Children's Healtcare of Atlanta
  • Johns Hopkins University
  • Boston Children's Hospital
  • Washington University
  • University of Rochester
  • Cincinnati Children's Hospital
  • Children's Hospital of Philadelphia
  • Le Bonheur Children's Hospital
  • Eastern Virginia Medical School
  • Virginia Commonwealth University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Lamotrigine

Oxcarbazepine

Levetiracetam

Arm Description

Lamotrigine 7.0 mg/kg tablets or chewable tablets administered daily in 2 equally divided doses

Oxcarbazepine 25 mg/kg tablets or liquid administered daily in 2 equally divided doses

Levetiracetam 30 mg/kg tablet or liquid administered daily in 2 equally divided doses

Outcomes

Primary Outcome Measures

Conners' Continuous Performance Test II (CPT-II) Confidence Index
The Conners' Continuous Performance Test II (CPT-II) is a measure of sustained attention. Letters are individually presented on a computer screen, and participants are instructed to press the space bar when they are presented with any letter except the letter "X". For children younger than 6 years of age at enrollment, the Kiddie CPT will be used in which the child is instructed to press the space bar every time the ball appears on the screen. The outcome measure is a confidence index representing the probability that the respondent has a clinically relevant problem in sustained attention. Possible scores range from 0 to 100. Scores between 40 and 60 are considered inconclusive while scores above 60 indicate that the child exhibits inattentiveness.

Secondary Outcome Measures

Child Behavior Checklist
The Child Behavior Checklist is a measure of specific behavioral and emotional problems are rated by the child's parent or guardian. The Child Behavior Checklist examines three domains (Social Functioning, Mood and Anxiety Symptoms, and Externalizing Symptoms) by assessing 118 problem items that describe specific behavioral and emotional problems. Respondents indicate how accurately the statements describe the child by selecting from options on a 3-point Likert-type scale (0=Not True, 1= Somewhat or Sometimes True, or 2=Very True or Often True). Total raw scores are converted to t-scores with a mean of 50 and standard deviation of 10. A t-score of 67 or greater is considered to be in the clinical range for problematic behavior.

Full Information

First Posted
June 28, 2013
Last Updated
August 20, 2017
Sponsor
Emory University
Collaborators
Patient-Centered Outcomes Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01891890
Brief Title
Cognitive AED Outcomes in Pediatric Localization Related Epilepsy (COPE)
Acronym
COPE
Official Title
Cognitive AED Outcomes in Pediatric Localization Related Epilepsy (COPE)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Terminated
Why Stopped
Poor recruitment
Study Start Date
August 2013 (undefined)
Primary Completion Date
October 23, 2015 (Actual)
Study Completion Date
October 23, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
Patient-Centered Outcomes Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Seizures that arise in specific areas in the brain are called Localization Related Epilepsy (LRE) and are the most common seizure disorder in children. Children that receive drug treatment for this disorder may suffer from treatment related side effects which impact their ability to think or concentrate and their ability to interact socially. These negative treatment effects can impact the child's performance in school and long term may impact employment and job options. This study will determine whether changes in attention and social interactions are seen in children treated for LRE using three of the most common medications used to treat pediatric LRE. Children who are newly diagnosed with LRE by their doctors and are between the ages of 5 years 6 months and 16 years 0 months will be randomized to receive levetiracetam, lamotrigine, or oxcarbazepine. There will be 14 study sites throughout the US. Children will undergo evaluation of their thinking and ability to pay attention before and after starting drug treatment for LRE. Regardless of the specific findings, results of this study will provide the information needed to help parents and their clinicians choose treatment options that maximize cognitive abilities in children with LRE, and provide the data needed for practice guidelines to be established on the basis of cognitive side effect risks.
Detailed Description
This is a prospective multicenter, randomized, open-label, central assessor, parallel-group study of children ages 5 years, 6 months to 16 years, 0 months with newly diagnosed Localization Related Epilepsy (LRE) to establish whether three common antiepileptic drugs (AEDs) used as first line LRE treatment (lamotrigine (LTG), levetiracetam (LEV), or oxcarbazepine (OXC)) are associated with differential cognitive side effects on attention. It is predicted that one AED will be identified with greater negative cognitive effects on attention. The study will also examine whether there are differential risks for drug-related behavior change. The study will address whether 6 month attentional outcomes can be reliably predicted based upon shorter term cognitive change assessed soon after beginning AED therapy, and establish practice effects associated with repeated test exposure when on constant doses of AED. Children will undergo cognitive testing after study enrollment and no more than a week after AED initiation. Selected measures will be repeated at the first follow up clinic visit after beginning AED treatment, and the primary endpoint will be the attention performance obtained at the subjects' 6 month follow-up clinic visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epilepsy, Partial, Epilepsy, Localization Related
Keywords
Pediatrics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
72 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lamotrigine
Arm Type
Active Comparator
Arm Description
Lamotrigine 7.0 mg/kg tablets or chewable tablets administered daily in 2 equally divided doses
Arm Title
Oxcarbazepine
Arm Type
Active Comparator
Arm Description
Oxcarbazepine 25 mg/kg tablets or liquid administered daily in 2 equally divided doses
Arm Title
Levetiracetam
Arm Type
Active Comparator
Arm Description
Levetiracetam 30 mg/kg tablet or liquid administered daily in 2 equally divided doses
Intervention Type
Drug
Intervention Name(s)
Oxcarbazepine
Other Intervention Name(s)
Trileptal
Intervention Description
Titration to target dose starting at week 3. Dose increments above target may be made to a maximum of 3 increments with a minimum interval between dose escalations of 2 weeks.
Intervention Type
Drug
Intervention Name(s)
Levetiracetam
Other Intervention Name(s)
Keppra
Intervention Description
Titration to target dose starting at week 3. Dose increments above target may be made to a maximum of 3 increments with a minimum interval between dose escalations of 2 weeks.
Intervention Type
Drug
Intervention Name(s)
Lamotrigine
Other Intervention Name(s)
Lamictal
Intervention Description
Titration to target dose starting at week 11. Dose increments above target may be made to a maximum of 3 increments with a minimum interval between dose escalations of 2 weeks.
Primary Outcome Measure Information:
Title
Conners' Continuous Performance Test II (CPT-II) Confidence Index
Description
The Conners' Continuous Performance Test II (CPT-II) is a measure of sustained attention. Letters are individually presented on a computer screen, and participants are instructed to press the space bar when they are presented with any letter except the letter "X". For children younger than 6 years of age at enrollment, the Kiddie CPT will be used in which the child is instructed to press the space bar every time the ball appears on the screen. The outcome measure is a confidence index representing the probability that the respondent has a clinically relevant problem in sustained attention. Possible scores range from 0 to 100. Scores between 40 and 60 are considered inconclusive while scores above 60 indicate that the child exhibits inattentiveness.
Time Frame
Baseline, Month 6
Secondary Outcome Measure Information:
Title
Child Behavior Checklist
Description
The Child Behavior Checklist is a measure of specific behavioral and emotional problems are rated by the child's parent or guardian. The Child Behavior Checklist examines three domains (Social Functioning, Mood and Anxiety Symptoms, and Externalizing Symptoms) by assessing 118 problem items that describe specific behavioral and emotional problems. Respondents indicate how accurately the statements describe the child by selecting from options on a 3-point Likert-type scale (0=Not True, 1= Somewhat or Sometimes True, or 2=Very True or Often True). Total raw scores are converted to t-scores with a mean of 50 and standard deviation of 10. A t-score of 67 or greater is considered to be in the clinical range for problematic behavior.
Time Frame
Baseline, Month 6
Other Pre-specified Outcome Measures:
Title
Wechsler Intelligence Scale for Children-IV Processing Speed
Description
Coding and Symbol Search subtests from the Wechsler Intelligence Scale for Children (WISC)-IV are measures of processing speed and combine to form the Processing Speed Index. Processing speed refers to how quickly the child understands and responds to information. Coding presents children with a row of boxes containing a numeral in the top line and a symbol in the bottom line with the task of copying the symbol corresponding to each numeral as quickly as possible in 120 seconds. In Symbol Search, children are given rows of symbols and target symbols and are asked to mark whether or not the target symbols appear in each row as quickly as possible during 120 seconds. Composite scores compare the test-taker to peers with a mean score of 100 and a standard deviation of 15. Possible scores range from 40 to 160 with higher scores indicating increased processing speeds. Scores between 85 and 115 are considered average, with 2/3 of test takers falling between these values.
Time Frame
Baseline, Month 3, Month 6
Title
Story Memory
Description
Story Memory will be measured at baseline with the Children's Memory Scale (CMS) and then with the Wide Range Assessment of Memory and Learning-2 (WRAML-2) at the 6 month follow up visit. Two different tests are used to avoid practice effects in memory assessment associated with repeated assessments using the same stimulus material. The Story Memory sub-test of the CMS and the WRAML-2 Story Memory are measures of prose passage recall. Stories are read to the subject for recall, with different stories presented based upon participant age. Scores are converted to percentile ranks for both measurements of story memory. Possible scores can fall between the 1st and 99th percentile and higher values indicate better performance with story recall. Values between the 9th and 25 percentiles are considered "low average", values between the 25th and 75th percentiles are "average", while values between the 75th and 91st percentile are "high average".
Time Frame
Baseline, Month 6
Title
Symbol Digit Modalities Test
Description
Symbol Digit Modalities Test (SDMT) is a test of graphomotor speed using numbers as the response rather than copying symbols, and is timed at 90 seconds. The SDMT is designed for people who are 8 years of age and older and detects brain dysfunction as well as measures function over time. Possible total scores range from 0 to 110; where 110 indicates that all values were entered within the 90 second limit. An increase between initial and retest scores indicates that the respondent is correctly matching numbers to symbols at a faster speed. The SDMT was administered at the Month 3 and Month 6 visits for this study.
Time Frame
Month 3, Month 6
Title
Grooved Pegboard
Description
The Grooved Pegboard assesses fine motor speed and dexterity. The participant fits keyhole-shaped pegs into similarly shaped holes on a square board. The pegs, which have an edge along one side, must be rotated to match the holes before they can be inserted. The scores represent the number of seconds it took for the participant to correctly insert the pegs into the require number of grooves, using their dominant hand.
Time Frame
Baseline, Month 6
Title
The Number of Participants With a Positive Response on the Columbia-Suicide Severity Rating Scale (C-SSRS)
Description
Suicidal behaviors and suicidal ideation were assessed through an interview using the Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS guides interviewers to ask a series of simple questions in order to identify people at risk for suicide, as well as the severity and urgency of suicidal thoughts and behaviors. The Children's Baseline/Screening C-SSRS was used at the initial study visit while the Children's Since Last Visit C-SSRS was used for subsequent study visits. Any responses of "yes" to the C-SSRS questions are considered a positive response, indicating that the participant is experiencing thoughts of suicide or has exhibited suicidal behaviors.
Time Frame
Baseline, Month 3, Month 6
Title
Youth Self Report
Time Frame
6 months
Title
Affective Reactivity Scale
Description
The Affective Reactivity Scale is a 7-item survey completed by the child participants which asks questions concerning their level of agreement with statements about anger and irritability. Respondents select between "not true" (scored as 0), "somewhat true" (scored as 1), and "certainly true (scored as 2). Total scores range from 0 to 14 with higher values indicating increased feelings of annoyance and anger.
Time Frame
Baseline, Month 3, Month 6
Title
Pediatric Neuro-QOL Score
Description
The Pediatric Neuro-QOL is a Quality of Life instrument developed in conjunction with NIH with a pediatric specific form utilized in this protocol. Pediatric Neuro-QOL assesses the domains of Anger, Anxiety, Cognition, Depression, Fatigue, Pain, Social Relations, and Stigma. Each domain has 8 to 10 items and respondents indicate how often they experienced feelings and circumstances related to each domain on a scale of 1 to 5 (such as 1=never, 2=almost never, 3=sometimes, 4=often, 5=almost always). Higher values indicate increased difficulty for most of the scales but this pattern is reversed for two of the domains. Raw scores are rescaled to standardized scores with a mean of 50 and a standard deviation of 10. Higher values for the standardized scores indicate more problematic characteristics while scores below 50 indicate that the child is experiencing less trouble in the domains measured by the Pediatric Neuro-QOL.
Time Frame
Baseline, Month 6
Title
Parenting Stress Inventory Short Form (PSI-4-SF)
Description
The Parenting Stress Inventory-4-Short Form is a 36 item questionnaire, completed by the parent/guardian, designed to evaluate parenting and family characteristics based upon child characteristics (behavioral and emotional problems), parent characteristics, and situational/demographic life stress. Respondents indicate the degree to which they agree with a variety of statements by selecting 1=strongly agree, 2=agree, 3=not sure, 4=disagree, or 5=strongly disagree. Raw scores range from 36 to 180 and higher scores are associated with higher parental stress.
Time Frame
Baseline, Month 6
Title
Pediatric Inventory for Parents
Description
The Pediatric Inventory for Parents consists of 42 items involving communication, medical care, emotional disturbance, and change in role function. Parents respond to a list of difficult events (such as "difficulty sleeping") that are often experienced by parents of children who are seriously ill. Parents indicated how frequently an event occurred by selecting 1=Never, 2=Rarely, 3=Sometimes, 4=Often, or 5=Very often. Raw score values range from 4 to 210 with higher scores indicating increased frequency of difficult events.
Time Frame
Baseline, Month 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age of participant between 5 years, 6 months and 16 years, 0 months at the time of enrollment Weight is between ≥ 15 kg the lower limit BMI 99th percentile at study entry at study entry Child has diagnosed epilepsy as defined by one of the following definitions : At least two unprovoked seizures occurring more than 24-hours apart, or One unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 75% or more), or At least two seizures in a setting of reflex epilepsy Child has a diagnosis of Localization Related Epilepsy (LRE) with or without secondary generalization according to International League Against Epilepsy (ILAE) criteria and which may include Benign Rolandic Epilepsy and Benign Occipital Epilepsy or other LREs. Localization related seizures will be based upon at least one of the following: 1) focal EEG abnormalities (sharp waves, spikes, or slowing) and the absence of generalized spike waves discharges, 2) focal MRI abnormalities other than active cysticercosis, which may include temporal lobe sclerosis, dysembryoplastic neuroepithelial tumor , ganglioglioma, or focal malformations of cortical development, 3) focal neurologic abnormalities, or 4) clinical semiology, which may include Todd's phenomenon, unilateral dystonia, or fencing posture, or distinct aura consistent with localization related seizure onset (e.g., classic déjà vu or bad smell). Participants must either be antiepileptic drug (AED) therapy naïve or on an AED (excluding benzodiazepines) for 1-week or less. Children may be on a stable dose of psychostimulants at the time of enrollment, but no change in medication, dose, or schedule in 3 months prior to study enrollment, with no anticipated dosing changes during the 6 months of the study. If participants are taking psychostimulants at the time of study entry, they should plan on continuing them for the 6 month duration of the study protocol including the 3-month and 6-month cognitive and behavioral testing time points. Females of child bearing potential must agree to acceptable forms of birth control, which may include abstinence. The child's parent/guardian must be able to keep an accurate seizure diary and be able and willing to comply with instructions and study procedures. Informed consent from the child's legal guardian or legal representative. Assent will be obtained from children according to each site's institutional guidelines. Exclusion Criteria: Children with history of primary generalized seizures (absence, myoclonic, drop) Children with mixed seizure disorder (e.g., Lennox-Gastaut Syndrome) Children with sensory seizures only (i.e., auras) Children with 6+ seizures in the previous week Children with a history of status epilepticus Children with a history of neonatal seizures Children with diagnoses of pervasive developmental disorders (e.g., autism/autism spectrum disorders) Children with progressive neurological disease (e.g., degenerative, progressive neoplasm) Children with major medical disease (e.g., Insulin-Dependent Diabetes Mellitus (IDDM), cancer, renal failure) Children with diseases with cognitive impact (e.g., inborn errors of metabolism, sickle cell disease with history of stroke) Children with active cysticercosis documented on MRI Children with cognitive impairment of sufficient severity that, in the opinion of the investigator, would diminish the likelihood of valid test performance (roughly corresponding to Full Scale Intelligence Quotient (FSIQ) less than 70) Children with suicide attempt(s) at any point during their lifetime Children with active suicide ideation Children with chronic use of first generation antihistamines Children using recreational drugs (including alcohol) Children not fluent in either English or Spanish Female children who are pregnant Female children who are using oral contraceptives for birth control or for any other indication (e.g. acne treatment)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David W. Loring, PhD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Arkansas Children's Hospital
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
University of California at San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92092
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington, D.C.
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's Healtcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Rochester
City
Monroe
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Cincinnati Children's Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Le Bonheur Children's Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Eastern Virginia Medical School
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23510
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23284
Country
United States

12. IPD Sharing Statement

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Cognitive AED Outcomes in Pediatric Localization Related Epilepsy (COPE)

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