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Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study

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ClinicalTrials.gov Identifier: NCT00088452
Recruitment Status : Completed
First Posted : July 27, 2004
Results First Posted : October 14, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Tracking Information
First Submitted Date  ICMJE July 26, 2004
First Posted Date  ICMJE July 27, 2004
Results First Submitted Date  ICMJE August 21, 2020
Results First Posted Date  ICMJE October 14, 2020
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE July 2004
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2020)
Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy [ Time Frame: First 16-20 weeks of double blind therapy ]
Treatment failure was defined as persistence of absence seizures at week 16 or week 20, a generalized tonic-clonic seizure at any time, excessive drug-related systemic toxicity, a moderately severe rash (possibly drug-related), pancreatitis, or increase in the body-mass index of at least 3.0 from baseline, dose-limiting toxicity after a single downward dose modification, or withdrawal initiated by the parent or physician.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2020)
  • Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT [ Time Frame: First 16-20 weeks of double blind therapy ]
    A Confidence Index of 0.60 or higher on the Conners' Continuous Performance Test at the visit at 16 or 20 weeks or at an earlier visit when treatment was discontinued (as long as the discontinuation occurred 1 month or more after the baseline visit and was not due to intolerable adverse events). A Confidence Index of 0.60 corresponds to a 60% probability that the child has clinical attention deficit disorder.
  • Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy [ Time Frame: First 12 months of double blind therapy ]
    Treatment failure was defined as persistence of absence seizures at 12 months of double blind therapy, a generalized tonic-clonic seizure at any time, excessive drug-related systemic toxicity, a moderately severe rash (possibly drug-related), pancreatitis, or increase in the body-mass index of at least 3.0 from baseline, dose-limiting toxicity after a single downward dose modification, or withdrawal initiated by the parent or physician.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study
Official Title  ICMJE Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study
Brief Summary The purpose of this study is to determine the best initial treatment for childhood absence epilepsy.
Detailed Description

Childhood absence epilepsy (CAE) is a common pediatric epilepsy syndrome that affects 10 to 15 percent of all children with epilepsy. Individuals with CAE have brief staring spell seizures that occur suddenly, unpredictably, and frequently throughout the day. These seizures impair the children's ability to learn and play, and lead to higher injury rates.

There are many medications used to treat seizures, but only 3 generally are used as the first treatment for children with CAE: ethosuximide, lamotrigine, and valproic acid. The goal of this study is to determine which of these 3 medicines is the best first choice as treatment for children with CAE.

Approximately 439 children, recruited over a 3-year period at 32 medical centers in the US, will take part in this 5-year study. Participants will be randomly given one of the 3 common CAE treatments-ethosuximide, lamotrigine, or valproic acid-and will make regular visits to a clinic every 1 to 3 months for approximately 2 years. During the visits, participants will undergo regular testing to determine if the medicine is working, to watch for side effects, and to help researchers learn more about the responses to these medicines. In addition, researchers hope to develop methods that may be used in the future to help choose the best medicine for each individual diagnosed with CAE.

Also included in the study will be pharmacokinetics and pharmacogenetics research. Pharmacokinetics is the study of how the body absorbs, distributes, metabolizes, and excretes drugs. Pharmacogenetics is the study of genetic determinants of the response to drugs. Knowledge gained from this study may lead to individualized treatment for children with CAE, and may also be beneficial for other pediatric and adult seizure disorders.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Childhood Absence Epilepsy
  • Petit Mal Epilepsy
  • Epilepsy
  • Seizures
Intervention  ICMJE
  • Drug: Ethosuximide
    Ethosuximide is a common treatment for childhood absence epilepsy.
    Other Name: Zarontin
  • Drug: Lamotrigine
    Lamotrigine is a common treatment for childhood absence epilepsy.
    Other Name: Lamictal
  • Drug: Valproic acid
    Valproic acid is a common treatment for childhood absence epilepsy.
    Other Name: Depakote
Study Arms  ICMJE
  • Active Comparator: Ethosuximide

    Ethosuximide

    Frequency and Duration: twice a day, every day for the duration of the study treatment

    Formulation: Two formulations were used (actual formulation used was dependent on the patient's weight and ability to swallow): 250mg Zarontin capsules OR 250 mg/5 mL Zarontin syrup

    Dosing: Ethosuximide was titrated in predetermined increments every 1-2 weeks during a 16-week titration period. The titration continued until the patient a) achieved seizure freedom by clinical and EEG criteria, b) reached the maximal allowed study drug dose, c) reached the maximal tolerated dose, or d) developed dose-exiting criteria (treatment failure), whichever came first. Maximum allowed dose: 60 mg/kg/day or 2000 mg/day (whichever was lower)

    Intervention: Drug: Ethosuximide
  • Active Comparator: Lamotrigine

    Lamotrigine

    Frequency and Duration: twice a day, every day for the duration of the study treatment

    Formulation: Three formulations were used (actual formulation used was dependent on the patient's weight): 5mg Lamictal chewable tablets OR 25 mg Lamictal chewable tablets OR 25 mg (Lamictal tablets

    Dosing: Lamotrigine was titrated in predetermined increments every 1-2 weeks during a 16-week titration period. The titration continued until the patient a) achieved seizure freedom by clinical and EEG criteria, b) reached the maximal allowed study drug dose, c) reached the maximal tolerated dose, or d) developed dose-exiting criteria (treatment failure), whichever came first. Maximum allowed dose: 12 mg/kg/day or 600 mg/day (whichever was lower).

    Intervention: Drug: Lamotrigine
  • Active Comparator: Valproic acid

    Valproic acid

    Frequency and Duration: twice a day, every day for the duration of the study treatment

    Formulation: Two formulations were used (actual formulation used was dependent on the patient's weight): 250mg Depakote capsules OR 125mg Depakote sprinkles.

    Dosing: Depakote was titrated in predetermined increments every 1-2 weeks during a 16-week titration period. The titration continued until the patient a) achieved seizure freedom by clinical and EEG criteria, b) reached the maximal allowed study drug dose, c) reached the maximal tolerated dose, or d) developed dose-exiting criteria (treatment failure), whichever came first. Maximum allowed dose: 60 mg/kg/day or 3000 mg/day (whichever was lower)

    Intervention: Drug: Valproic acid
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2007)
453
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
439
Actual Study Completion Date  ICMJE August 31, 2016
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis: Clinical diagnosis of Childhood Absence Epilepsy consistent with the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes (3).
  • EEG: Interictal EEG demonstrating bilateral synchronous symmetrical approximate 3 Hz spike waves on a normal background with at least one burst lasting >/= (greater than or equal to) 3 seconds.
  • Age > 2.5 years and < 13 years of age at study entry.
  • Body weight >/= (greater than or equal to) 10 kilograms.
  • Body Mass Index: BMI for age =/< 99th percentile (based on the CDC BMI for age growth curves for boys/girls [http://www.cdc.gov/growthcharts], Appendix 1).
  • Hepatic:
  • AST/ALT < 2.5 times the upper limit of normal
  • Total bilirubin < 1.5 times the upper limit of normal.
  • Hematologic:
  • Absolute neutrophil count >/= (greater than or equal to) 1500/mm3.
  • Platelets >/= (greater than or equal to) 120, 000 /mm3.
  • Female subjects must be premenarchal at the time of enrollment and must be willing to practice abstinence for the duration of the study.
  • Parent/legal guardian(s) willing to sign an IRB approved informed consent.
  • Subject assent (when appropriate and as dictated by local IRB).

Exclusion Criteria:

  • Treatment for CAE with anti-seizure medications (AED) for a period of greater than 7 days prior to randomization.
  • History of a major psychiatric disease (e.g., psychosis, major depression).
  • History of autism or pervasive development disorder.
  • History of non-febrile seizures other than typical absence seizures. This includes a history of an afebrile generalized tonic clonic seizure.
  • Clinical signs and symptoms consistent with a diagnosis of juvenile absence epilepsy or juvenile myoclonic epilepsy as delineated by the International League against Epilepsy Proposal for Revised Classification of Epilepsies and Epileptic Syndromes (3).
  • History of recent or present significant or medical disease, i.e., cardiovascular, hepatic, renal, gynecologic, musculoskeletal, metabolic, or endocrine.
  • History of a severe dermatologic reaction (e.g., Stevens Johnson, toxic epidermolysis necrosis) to medication.
  • Subject or parent/legal guardian might not be reasonably expected to be compliant with or to complete the study.
  • Participation in a trial of an investigational drug or device within 30 days prior to screening.
  • Use of systemic contraceptive for any indication, including acne.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Months to 13 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00088452
Other Study ID Numbers  ICMJE U01NS045911( U.S. NIH Grant/Contract )
U01NS045803 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Hospital Medical Center, Cincinnati
Study Sponsor  ICMJE Children's Hospital Medical Center, Cincinnati
Collaborators  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: Tracy A. Glauser, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Peter Adamson, MD Children's Hospital of Philadelphia
Principal Investigator: Avital Cnaan, PhD Children's National Research Institute
PRS Account Children's Hospital Medical Center, Cincinnati
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP