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

This study has been terminated.
(Poor recruitment)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01891890
First Posted: July 3, 2013
Last Update Posted: September 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
David Loring, PhD, Emory University
  Purpose

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.


Condition Intervention Phase
Epilepsy, Partial Epilepsy, Localization Related Drug: Oxcarbazepine Drug: Levetiracetam Drug: Lamotrigine Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Cognitive AED Outcomes in Pediatric Localization Related Epilepsy (COPE)

Resource links provided by NLM:


Further study details as provided by David Loring, PhD, Emory University:

Primary Outcome Measures:
  • Conners' Continuous Performance Test II (CPT-II) Confidence Index [ Time Frame: Baseline, Month 6 ]
    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 [ Time Frame: Baseline, Month 6 ]
    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.


Other Outcome Measures:
  • Wechsler Intelligence Scale for Children-IV Processing Speed [ Time Frame: Baseline, Month 3, Month 6 ]
    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.

  • Story Memory [ Time Frame: Baseline, Month 6 ]
    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".

  • Symbol Digit Modalities Test [ Time Frame: Month 3, Month 6 ]
    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.

  • Grooved Pegboard [ Time Frame: Baseline, Month 6 ]
    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.

  • The Number of Participants With a Positive Response on the Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline, Month 3, Month 6 ]
    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.

  • Youth Self Report [ Time Frame: 6 months ]
  • Affective Reactivity Scale [ Time Frame: Baseline, Month 3, Month 6 ]
    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.

  • Pediatric Neuro-QOL Score [ Time Frame: Baseline, Month 6 ]
    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.

  • Parenting Stress Inventory Short Form (PSI-4-SF) [ Time Frame: Baseline, Month 6 ]
    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.

  • Pediatric Inventory for Parents [ Time Frame: Baseline, Month 6 ]
    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.


Enrollment: 72
Study Start Date: August 2013
Study Completion Date: October 23, 2015
Primary Completion Date: October 23, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Lamotrigine
Lamotrigine 7.0 mg/kg tablets or chewable tablets administered daily in 2 equally divided doses
Drug: Lamotrigine
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.
Other Name: Lamictal
Active Comparator: Oxcarbazepine
Oxcarbazepine 25 mg/kg tablets or liquid administered daily in 2 equally divided doses
Drug: Oxcarbazepine
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.
Other Name: Trileptal
Active Comparator: Levetiracetam
Levetiracetam 30 mg/kg tablet or liquid administered daily in 2 equally divided doses
Drug: Levetiracetam
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.
Other Name: Keppra

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.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   5 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01891890


Locations
United States, Arkansas
Arkansas Children's Hospital
Little Rock, Arkansas, United States, 72205
United States, California
University of California at San Diego
San Diego, California, United States, 92092
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center
Washington, D.C., District of Columbia, United States, 20010
United States, Georgia
Children's Healtcare of Atlanta
Atlanta, Georgia, United States, 30342
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New York
University of Rochester
Monroe, New York, United States, 14642
United States, Ohio
Cincinnati Children's Hospital
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Le Bonheur Children's Hospital
Memphis, Tennessee, United States, 38105
United States, Virginia
Eastern Virginia Medical School
Norfolk, Virginia, United States, 23510
Virginia Commonwealth University
Richmond, Virginia, United States, 23284
Sponsors and Collaborators
Emory University
Patient-Centered Outcomes Research Institute
Investigators
Principal Investigator: David W. Loring, PhD Emory University
  More Information

Responsible Party: David Loring, PhD, Professor, Emory University
ClinicalTrials.gov Identifier: NCT01891890     History of Changes
Other Study ID Numbers: IRB00066541
PCORI 527 ( Other Grant/Funding Number: PCORI )
First Submitted: June 28, 2013
First Posted: July 3, 2013
Results First Submitted: July 14, 2017
Results First Posted: September 19, 2017
Last Update Posted: September 19, 2017
Last Verified: July 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by David Loring, PhD, Emory University:
Pediatrics

Additional relevant MeSH terms:
Epilepsy
Epilepsies, Partial
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Etiracetam
Lamotrigine
Oxcarbazepine
Anticonvulsants
Carbamazepine
Piracetam
Nootropic Agents
Neuroprotective Agents
Protective Agents
Physiological Effects of Drugs
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Analgesics, Non-Narcotic