Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT00088452
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 453
• Locations: 31
• Arms: 3
• Actual Duration (Months): 146
• Patients Per Site: 14.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Childhood Absence Epilepsy; Petit Mal Epilepsy; Epilepsy; Seizures	Drug: Ethosuximide; Drug: Lamotrigine; Drug: Valproic acid	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 453 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics Study
• Actual Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Aug 31, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Months to 13 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• 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

Study Documents (Full-Text)

• Informed Consent Form - Aug 18, 2005

More Information

Publications

• 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.
• 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.
• Shinnar S, Cnaan A, Hu F, Clark P, Dlugos D, Hirtz DG, Masur D, Mizrahi EM, Moshé 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.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT00088452
• Other Study ID Numbers: U01NS045911; U01NS045803
• First Posted: Jul 27, 2004
• Last Update Posted: Oct 14, 2020
• Last Verified: Feb 1, 2017

• Keywords provided by Children's Hospital Medical Center, Cincinnati: childhood absence epilepsy; CAE; petit mal epilepsy; epilepsy; seizures; ethosuximide; lamotrigine; valproic acid
• Additional relevant MeSH terms: Epilepsy; Seizures; Epilepsy, Absence; Lamotrigine; Valproic Acid; Ethosuximide

Study Results

Participant Flow

Recruitment Details	Enrollment occurred from July 2004 through October 2007

Arm/Group Title	Ethosuximide	Lamotrigine	Valproic Acid
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	156	149	148
COMPLETED	155	149	147
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Ethosuximide	Lamotrigine	Valproic Acid	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	155	149	147	451
Age (Count of Participants)
<=18 years	155 100%	149 100%	147 100%	451 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	90 58.1%	92 61.7%	76 51.7%	258 57.2%
Male	65 41.9%	57 38.3%	71 48.3%	193 42.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	0 0%	1 0.7%	2 0.4%
Asian	0 0%	2 1.3%	0 0%	2 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	32 20.6%	26 17.4%	29 19.7%	87 19.3%
White	110 71%	117 78.5%	107 72.8%	334 74.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	12 7.7%	4 2.7%	10 6.8%	26 5.8%
Region of Enrollment (participants) [Number]
United States	155 100%	149 100%	147 100%	451 100%
BMI > 90th percentile for age (Count of Participants)
Count of Participants [Participants]	43 27.7%	44 29.5%	33 22.4%	120 26.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Freedom From Treatment Failure at 16-20 Weeks of Double Blind Therapy
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ethosuximide	Lamotrigine	Valproic Acid
Arm/Group Description	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.	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.	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.
Measure Participants	154	146	146
Count of Participants [Participants]	81 52.3%	43 28.9%	85 57.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ethosuximide, Lamotrigine
	Comments	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%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.66
	Confidence Interval	(2-Sided) 95%; 1.65 to 4.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio with ethosuximide vs. lamotrigine

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lamotrigine, Valproic Acid
	Comments	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%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.34
	Confidence Interval	(2-Sided) 95%; 2.06 to 5.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio with valproic acid vs. lamotrigine

2. Secondary Outcome

Title	Number of Participants With Attention Deficit as Measured by the Confidence Index of the CPT-II and the K-CPT
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Ethosuximide	Lamotrigine	Valproic Acid
Arm/Group Description	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.	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.	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.
Measure Participants	106	104	106
Count of Participants [Participants]	35 22.6%	25 16.8%	52 35.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ethosuximide, Valproic Acid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.95
	Confidence Interval	(2-Sided) 95%; 1.12 to 3.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percentage of subjects with a Confidence Index score of 0.60 or higher in the valproic acid group than in the ethosuximide group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lamotrigine, Valproic Acid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.04
	Confidence Interval	(2-Sided) 95%; 1.69 to 5.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percentage of subjects with a Confidence Index score of 0.60 or higher in the valproic acid group than in the lamotrigine group

3. Secondary Outcome

Title	Number of Participants With Freedom From Treatment Failure at 12 Months of Double Blind Therapy
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ethosuximide	Lamotrigine	Valproic Acid
Arm/Group Description	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.	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.	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.
Measure Participants	154	146	146
Count of Participants [Participants]	70 45.2%	31 20.8%	64 43.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ethosuximide, Lamotrigine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.08
	Confidence Interval	(2-Sided) 95%; 1.81 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio for FFF for ethosuximide versus lamotrigine

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lamotrigine, Valproic Acid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.88
	Confidence Interval	(2-Sided) 95%; 1.68 to 5.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio for FFF for valproic acid versus lamotrigine

Adverse Events

Time Frame	Adverse event data was collected over 3.5 years
Adverse Event Reporting Description	The definition of adverse event and/or serious adverse event, used to collect adverse event information, is the same as clinicaltrials.gov defintions
Arm/Group Title	Ethosuximide		Lamotrigine		Valproic Acid
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Ethosuximide		Lamotrigine		Valproic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/155 (0%)		0/149 (0%)		0/147 (0%)
Serious Adverse Events
	Ethosuximide		Lamotrigine		Valproic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/155 (2.6%)		2/149 (1.3%)		2/147 (1.4%)
Infections and infestations
Enteritis	0/155 (0%)	0	1/149 (0.7%)	1	0/147 (0%)	0
Nervous system disorders
Generalized tonic clonic seizure	2/155 (1.3%)	2	0/149 (0%)	0	1/147 (0.7%)	1
Prolonged Absence Seizure	0/155 (0%)	0	1/149 (0.7%)	1	0/147 (0%)	0
Pneumonia, diarrhea, vomiting	1/155 (0.6%)	1	0/149 (0%)	0	0/147 (0%)	0
Psychiatric disorders
Non-epileptic movements	1/155 (0.6%)	1	0/149 (0%)	0	0/147 (0%)	0
Acting Out	0/155 (0%)	0	0/149 (0%)	0	1/147 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Ethosuximide		Lamotrigine		Valproic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/155 (66.5%)		78/149 (52.3%)		100/147 (68%)
Gastrointestinal disorders
Nausea, vomiting, or both	23/155 (14.8%)	23	2/149 (1.3%)	2	10/147 (6.8%)	10
Stomach upset	16/155 (10.3%)	16	4/149 (2.7%)	4	8/147 (5.4%)	8
Increased appetite	5/155 (3.2%)	5	7/149 (4.7%)	7	13/147 (8.8%)	13
Decreased appetite	8/155 (5.2%)	8	5/149 (3.4%)	5	3/147 (2%)	3
Weight increase	1/155 (0.6%)	1	3/149 (2%)	3	10/147 (6.8%)	10
General disorders
Fatigue	15/155 (9.7%)	15	13/149 (8.7%)	13	18/147 (12.2%)	18
Headache	19/155 (12.3%)	19	12/149 (8.1%)	12	12/147 (8.2%)	12
Sleep problem	10/155 (6.5%)	10	5/149 (3.4%)	5	14/147 (9.5%)	14
Nervous system disorders
Decrease in concentration	6/155 (3.9%)	6	5/149 (3.4%)	5	11/147 (7.5%)	11
Somnolence	14/155 (9%)	14	3/149 (2%)	3	4/147 (2.7%)	4
Attentional difficulties	3/155 (1.9%)	3	5/149 (3.4%)	5	10/147 (6.8%)	10
Dizziness	9/155 (5.8%)	9	4/149 (2.7%)	4	2/147 (1.4%)	2
Memory problems	0/155 (0%)	0	4/149 (2.7%)	4	8/147 (5.4%)	8
Psychiatric disorders
Hyperactivity	14/155 (9%)	14	10/149 (6.7%)	10	15/147 (10.2%)	15
Hostility	4/155 (2.6%)	4	10/149 (6.7%)	10	18/147 (12.2%)	18
Personality change	4/155 (2.6%)	4	9/149 (6%)	9	16/147 (10.9%)	16
Depression	4/155 (2.6%)	4	8/149 (5.4%)	8	8/147 (5.4%)	8

Limitations/Caveats

This short-term study was not designed to detect long-term systemic or other cognitive effects of these three medications.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.