Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study

The purpose of this study is to determine the best initial treatment for childhood absence epilepsy.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Seizures; Childhood Absence Epilepsy; Petit Mal Epilepsy
• Intervention / Treatment: Drug: Ethosuximide; Drug: Lamotrigine; Drug: Valproic acid

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: Interventional
• Enrollment (Actual): 453
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • The Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • La Jolla, California, United States, 92093
      • University of California at San Diego
    • Los Angeles, California, United States, 90095
      • Mattel Children's Hospital at UCLA
  • Colorado
    • Denver, Colorado, United States, 80218
      • Children's Hospital of Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • New York, New York, United States, 10016
      • NYU Comprehensive Epilepsy Center, Manhattan
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Children's Hospital, Inc., PCTI
  • Oregon
    • Portland, Oregon, United States, 97239
      • Doernbecher Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • LeBonheur Children's Medical Center
  • Texas
    • Dallas, Texas, United States, 75230
      • Dallas Pediatric Neurology Associates
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah/Primary Children's Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • Children's Hospital of The King's Daughter (Monarch Medical Research)
  • Washington
    • Seattle, Washington, United States, 98105-0371
      • Children's Hospital & Regional Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201-1997
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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)	Drug: Ethosuximide; Ethosuximide is a common treatment for childhood absence epilepsy.; Other Names: Zarontin
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).	Drug: Lamotrigine; Lamotrigine is a common treatment for childhood absence epilepsy.; Other Names: Lamictal
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)	Drug: Valproic acid; Valproic acid is a common treatment for childhood absence epilepsy.; Other Names: Depakote

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Freedom From Treatment Failure at 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.	First 16-20 weeks of double blind therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT	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.	First 16-20 weeks of double blind therapy
Number of Participants With Freedom From Treatment Failure at 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.	First 12 months of double blind therapy

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: 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

Publications and helpful links

General Publications

• Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC; Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. 2013 Jan;54(1):141-55. doi: 10.1111/epi.12028. Epub 2012 Nov 21.
• Cnaan A, Shinnar S, Arya R, Adamson PC, Clark PO, Dlugos D, Hirtz DG, Masur D, Glauser TA; Childhood Absence Epilepsy Study Group. Second monotherapy in childhood absence epilepsy. Neurology. 2017 Jan 10;88(2):182-190. doi: 10.1212/WNL.0000000000003480. Epub 2016 Dec 16.
• Shinnar S, Cnaan A, Hu F, Clark P, Dlugos D, Hirtz DG, Masur D, Mizrahi EM, Moshe SL, Glauser TA; Childhood Absence Epilepsy Study Group. Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial. Neurology. 2015 Sep 29;85(13):1108-14. doi: 10.1212/WNL.0000000000001971. Epub 2015 Aug 26.
• Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC; Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010 Mar 4;362(9):790-9. doi: 10.1056/NEJMoa0902014.
• Shinnar RC, Shinnar S, Cnaan A, Clark P, Dlugos D, Hirtz DG, Hu F, Liu C, Masur D, Weiss EF, Glauser TA; Childhood Absence Epilepsy Study Group. Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. Neurology. 2017 Oct 17;89(16):1698-1706. doi: 10.1212/WNL.0000000000004514. Epub 2017 Sep 15.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2004
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): August 31, 2016

Study Registration Dates

• First Submitted: July 26, 2004
• First Submitted That Met QC Criteria: July 26, 2004
• First Posted (Estimate): July 27, 2004

Study Record Updates

• Last Update Posted (Actual): October 14, 2020
• Last Update Submitted That Met QC Criteria: September 18, 2020
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: epilepsy; seizures; valproic acid; lamotrigine; childhood absence epilepsy; CAE; petit mal epilepsy; ethosuximide
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Neurologic Manifestations; Epilepsy; Seizures; Epilepsy, Absence; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; GABA Agents; Anticonvulsants; Sodium Channel Blockers; Antimanic Agents; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Lamotrigine; Valproic Acid; Ethosuximide
• Other Study ID Numbers: U01NS045911 (U.S. NIH Grant/Contract); U01NS045803 (U.S. NIH Grant/Contract)