Childhood Absence Epilepsy, Petit Mal Epilepsy, Epilepsy, Seizures
Conditions
Keywords
childhood absence epilepsy, CAE, petit mal epilepsy, epilepsy, seizures, ethosuximide, lamotrigine, valproic acid
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.
Interventions
DRUGEthosuximide
Ethosuximide is a common treatment for childhood absence epilepsy.
DRUGLamotrigine
Lamotrigine is a common treatment for childhood absence epilepsy.
DRUGValproic acid
Valproic acid is a common treatment for childhood absence epilepsy.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Months to 13 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
Enrollment occurred from July 2004 through October 2007
Participants by arm
| Arm | Count |
|---|---|
| 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)
Ethosuximide: Ethosuximide is a common treatment for childhood absence epilepsy. | 155 |
| 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).
Lamotrigine: Lamotrigine is a common treatment for childhood absence epilepsy. | 149 |
| 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)
Valproic acid: Valproic acid is a common treatment for childhood absence epilepsy. | 147 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Did not receive intervention | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Ethosuximide | Lamotrigine | Valproic Acid | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 155 Participants | 149 Participants | 147 Participants | 451 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| BMI > 90th percentile for age | 43 Participants | 44 Participants | 33 Participants | 120 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 26 Participants | 29 Participants | 87 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 4 Participants | 10 Participants | 26 Participants |
| Race (NIH/OMB) White | 110 Participants | 117 Participants | 107 Participants | 334 Participants |
| Region of Enrollment United States | 155 participants | 149 participants | 147 participants | 451 participants |
| Sex: Female, Male Female | 90 Participants | 92 Participants | 76 Participants | 258 Participants |
| Sex: Female, Male Male | 65 Participants | 57 Participants | 71 Participants | 193 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 155 | 0 / 149 | 0 / 147 |
| other Total, other adverse events | 103 / 155 | 78 / 149 | 100 / 147 |
| serious Total, serious adverse events | 4 / 155 | 2 / 149 | 2 / 147 |
Outcome results
Primary
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.
Time frame: First 16-20 weeks of double blind therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ethosuximide | Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy | 81 Participants |
| Lamotrigine | Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy | 43 Participants |
| Valproic Acid | Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy | 85 Participants |
Comparison: Calculations of sample size were based on the ability to detect a 20% difference in freedom-from failure rates (three pairwise comparisons) at 16 weeks with 80% power at a two-sided P value of 0.017 and one interim analysis. Sample size of 398 was increased to 446 subjects to account for two stratification factors and a 5% dropout rate; this sample size allowed the detection of a difference of 0.5 SD in the Confidence Index on the Conners' Continuous Performance Test with a power exceeding 80%.p-value: <0.00195% CI: [1.65, 4.28]Chi-squared
Comparison: Calculations of sample size were based on the ability to detect a 20% difference in freedom-from failure rates (three pairwise comparisons) at 16 weeks with 80% power at a two-sided P value of 0.017 and one interim analysis. Sample size of 398 was increased to 446 subjects to account for two stratification factors and a 5% dropout rate; this sample size allowed the detection of a difference of 0.5 SD in the Confidence Index on the Conners' Continuous Performance Test with a power exceeding 80%.p-value: <0.00195% CI: [2.06, 5.42]Chi-squared
Secondary
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.
Time frame: First 16-20 weeks of double blind therapy
Population: Those subject who took 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ethosuximide | Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT | 35 Participants |
| Lamotrigine | Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT | 25 Participants |
| Valproic Acid | Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT | 52 Participants |
p-value: 0.0395% CI: [1.12, 3.41]Chi-squared
p-value: <0.00195% CI: [1.69, 5.49]Chi-squared
Secondary
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.
Time frame: First 12 months of double blind therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ethosuximide | Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy | 70 Participants |
| Lamotrigine | Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy | 31 Participants |
| Valproic Acid | Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy | 64 Participants |
p-value: <0.00195% CI: [1.81, 5.33]Fisher Exact
p-value: <0.00195% CI: [1.68, 5.02]Fisher Exact