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Tracy A. Glauser, M.D., Avital Cnaan, Ph.D., Shlomo Shinnar, M.D., Ph.D., Deborah G. Hirtz, M.D., Dennis Dlugos, M.D., David Masur, Ph.D., Peggy O. Clark, M.S.N., Edmund V. Capparelli, Pharm.D., and Peter C. Adamson, M.D., for the Childhood Absence Epilepsy Study Group*
abstract background epilepsy in children the most common epilepsy syndrome in pediatrics, is usually treated with ethosuximide, valproic acid, or lamotrigine. Treatment is most efficacious and tolerable initial empirical undetermined. Method In a double-blind, randomized trial, controlled clinical trials, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed epilepsy is. Administered dose gradually until the child was free of seizures, the maximum tolerated dose is achieved or the highest allowable, or treatment failure criteria indicates met. The primary outcome was freedom from treatment failure after 16 weeks of therapy, secondary outcome was attentional dysfunction. Comparison of drug effects was determined using pairwise comparisons. Result Of 453 children who were taken randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26, 95% confidence interval [CI], 0 , 80 to 1.98, P = 0.35) and higher than the rate for lamotrigine (29%, odds ratio with ethosuximide vs. lamotrigine, 2.66, 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34, 95% CI, 2.06 to 5.42, P <0.001 for both comparisons). No significant differences between the three drug-related discontinuations due to adverse events. Attentional dysfunction is more common with valproic acid than with ethosuximide (in 49% of children vs. 33%, odds ratio, 1.95, 95% CI, 1.12 to 3.41, P = 0.03). Conclusion Ethosuximide and valproic acid were more effective than thanlamotrigine in the treatment of the symptoms of epilepsy in children. Ethosuximide was associated with fewer adverse attentional
affected children have cognitive deficits and long-term psychosocial disorders. data and safety monitoring appointed by the National Institutes of Health. the general surge disposal waves on EEG. or clinically significant medical conditions contrast with epilepsy children. Often mistaken as a benign form of epilepsy.Epilepsy in children accounted for 10 to 17% of all cases of epilepsy during childhood. epilepsy is not a child-level variables associated with improvement. more general tonic clonic seizures common. a history of seizures other than seizures nonfebrile absent (eg.5 and 13 years old are eligible to participate if they meet the following criteria: The child has a new-onset epilepsy are diagnosed clinically according to the International League Against Epilepsy classification of epileptic syndromes (including frequent seizures reported the clinical and normal development) 3. randomized trial to assess the efficacy. This syndrome is characterized by daily attacks are frequent but brief staring. usually starting at age 4 to 8 years in children. has a history consistent with seizures or epilepsy juvenile myoclonic adolescents (eg. We conducted a double-blind. has a history of severe dermatological reactions to any drugs.7 to 5 Hz) at normal background with at least one electrographically noted a seizure that lasted 3 seconds or more on the video 1 hour. afebrile tonic-clonic seizures or myoclonic common). Children between the ages of 2. making it the most common form of epilepsy in children. These drugs have different side effects and drug interactions caused. and have a normal blood count full and normal levels of serum aspartate aminotransferase alanine. weighing 10 kg or more. Children who are not eligible if they are one of the following criteria: have received antiseizure medication for more than 7 days prior to randomization. tolerability. valproic acid. For women should premenarchal. Instead look healthy The classic electroencephalogram (EEG) shows a picture of spike-wave bursts (of 3 Hz) with normal background activity. epilepsy that occurs in teenagers and in children older seizures characterized by a much less frequent (often triggered by hyperventilation). autistic spectrum disorder. generalized tonic clonic seizures or myoclonic). and neuropsychological effects of these drugs. having a body mass index below the 99th percentile. EEG monitored. and often higher frequencies (> 3 Hz). The study was approved by the institutional review boards of all participating sites. and lamotrigine but evidence of effectiveness relative pengobtan still lacking. Informed written consent was obtained from parents or guardians. . been bilateral synchronous spike wave symmetry (2. and consent obtained from subjects when applicable. serum aminotransferase and bilirubin. or have a history of major psychiatric illness. central coordination. Three drugs commonly used as initial monotherapy for this kondis ethosuximide. three drugs to determine optimal initial starting dose for children with epilepsy that occurs in childhood Method recruitment The experiment was conducted at 32 sites across the United States.
valproic acid (Depakote) (25-mg capsule or 125-mg dose of sprinkles). and 12 mg per kilogram for lamotrigine (to a maximum dose of each of 2000. and GlaxoSmith-Kline. Data were collected by the Childhood Absence Epilepsy Study Group. and academic achievement on behavior and quality of life. Study visit conducted every 4 weeks for 16 weeks. which assesses attention. If bedside hyperventilation-induced seizures. Study drug was prepared at the central pharmacy and shipped in a box packaged for distribution. If parents reported having a seizure. if not. vocabulary intelligence.chewable tablets mg or 25 mg tablets) were provided by Pfizer. The authors designed the study. Ethosuximide (Zarontin) (250-mg capsule or 250 mg per 5 ml syrup). Basic neuropsychological testing conducted prior to or within 7 days after the start of study drug. up to 25minute hyperventilation test performed bedside. 3000. continued study medication dose adjustment. and to submit articles selected for publication. memory. dose adjustment increases continue. or preparation. A change of a single dose reduction allowed in the case of dose-limiting toxicity. and lamotrigine (Lamictal) (5mg and 25 . Centralized maintenance tasks performed in accordance with the schedule in the computer-generated random permuted blocks of three within strata of age (<6 years and ≥ 6 years) and the study site. analyzed the data. data accrual. Tests include age appropriate Conners Continuous Performance 'Test (CPT-II for children ≥ 6 years. verbal and nonverbal standardized tests. If . wrote the manuscript. and K-CPT for children 4 to <6 years). Blinding is maintained with the use of either double-dummy approach (for solid and liquid formulations) or overencapsulation. the image obtained 1 hour EEG. Abbott Laboratories.Protocol Eligible subjects were randomly assigned to receive one of three study drugs in the ratio 1:1:1. each of these companies has a role in study design. and 600 mg per day). visuomotor integration. increasing the dose every 1 to 2 weeks during the 16-week period until free of seizures obtained or minimal side effects to the dose given (Table 1). executive function. learning skills. 60 mg per kilogram for valproic acid. data analysis. The highest daily dose may be given is 60 mg per kilogram of body weight to ethosuximide. if no seizures were reported.
The criteria for treatment failure included persistence of seizures absent at week 16 or week 20. dazzling original condition.. total bilirubin ≥ 5 times the upper limit of the normal range. . or elevated body mass index (weight in kilograms divided by the square of height in meters) minimum of 3. platelet count <50. Subjects without seizures at their last follow-up visit continued to receive treatment in double-blind fashion for up to 2 years. an additional dose escalation allowed. At that visit. seizure status determined by clinical reports. and the subject continues to receive a dose today. dose adjustment is stopped. if no seizures were detected. the presence of clinical or electrographic seizures in subjects who received the maximum dose allowable or highest tolerated considered a treatment failure. corresponding increases continue. pancreatitis. and a picture of one hour EEG. treatment failure due to drug toxicity or general tonic-clonic seizures could happen at any time. Pretreatment serum samples obtained for pharmacokinetic analysis at 16 weeks or 20 weeks. that because persistence absence seizures may occur only on or after the visit at 16 weeks Subjects who meet any of the criteria are invited to enter the open-label phase of the study to maintain . than experiment on an ongoing basis. doctors and families were told which commissioned the study drug in the second phase of treatment coordinating center monitored the behavior. general tonic-clonic seizures at any time. dose-limiting after a single dose modification down. subjects such as randomly assigned to one of two other antiepileptic drugs study.seizures were recorded in (spikewave bursts lasted ≥ 3 seconds) EEG. the rash is severe enough (probably drugs). and withdrawal initiated by parents or doctors. ALT levels or aspartate aminotransferase ≥ 10 times the upper limit of the normal range. excessive systemic drug toxicity (eg. in which case the data in the result set as 16 weeks or 20 weeks of data.000 per cubic millimeter counts.0 from the early toxicity. and Seizure status was evaluated on the fifth visit 4 weeks later (at 20 weeks). absolute neutrophil <500 per cubic millimeter. At week 16 (fourth visit). Data for the main study outcomes (freedom-from-failure rate) is based on the findings of the visit 16 weeks except the fifth visit at 20 weeks. bedside hyperventilation test. The Conners Continuous Performance Test 'is only repeated the basic neuropsychological tests before or at 16 weeks or 20 weeks of the visit because of the potential effect of testretest or practice substantially with other neuropsychological tests. for subjects who did not receive the maximum dose allowable or highest tolerable but still have seizures.
this sample size allows detection of differences in the SD 0. (A Confidence Index of 0.017 and an interim analysis. The sample size of 398 subjects increased to 446 to account for the two stratification factors and dropout rate of 5%.) Sample size calculation was based on the ability to detect a difference of 20% in freefromfailure level (three pairwise comparisons) at 16 weeks with 80% power at two-sided P value of 0. with the use of O'Brien-Fleming boundary for stopping the study and adjustments with Lan-DeMets spending functions. planned to do when 50% of subjects achieved the primary outcome. Confidence Index of 0.Statistical analysis The primary outcome of the study was freedom from treatment failure at week 16 or week 20.5 Confidence Index on the Conners Continuous Performance Test 'with powers exceeding 80%. Basic characteristics and security variables for the three treatments compared either with the exact test or chi-square two-way analysis of variance (with treatment as a factor and . secondary outcome is evidence that attentional dysfunction.60 or higher on the Conners Continuous' Test12 performance on a visit at 16 or 20 weeks or earlier visit when treatment is stopped (for the termination occurred 1 month or more after the initial visit. An interim analysis is for both successes and failures.60 equated to 60% probability that the child has attention deficit disorder clinical trials. in children 4 years or older. and not because of intolerable side effects).
however. Five subjects found to be ineligible central study: three did not meet the criteria of the EEG. two subjects never received study drug. Confidence Index on the Conners Continuous Performance Test 'was elevated (≥ 0. After randomization. An independent data and safety monitoring board appointed by the National Institutes of Health monitored the trial. A post hoc Tukey-Kramer analysis attentional function at the final visit included basic attentional differences. depending on whether the characteristics analyzed are discrete or continuous.017 is considered to indicate statistical significance (accounting for Bonferroni correction). Overall P value of 0. They were treated with either valproic acid or ethosuximide have freedom fromfailure high levels (53% and 58%. Post hoc comparisons of drug concentrations between treatment failure and success in the treatment group performed using t-test. Primary and secondary outcome were analyzed using Fisher's exact test for pairwise comparisons between treatments. 209 of 446 children (47%) were free from treatment failure at 16 weeks or 20 weeks of visits (Table 3).05 was considered to indicate statistical significance. which has abnormal neutrophil count. 184 (41%) is 8 to less than 12 years. No significant differences between treatment groups in each stratum age or in connection with the overall demographic characteristics (Table 2). Kaplan Meier curve was built to show the time to treatment failure during the 20-week study period. All subjects who received at least one dose of study drug included in the safety analysis. and all analyzes were prespecified. Available with the full text of this article at NEJM. A precise overall chi-square test was also performed. Basic testing cohort suggests that cognition is still within normal limits. 242 (53%) is 4 to less than 8 years.1 (SAS Institute) and StatXact software. as well as the calculation of odds ratio with 95% confidence intervals. there was no significant difference in performance continuous basis Confidence Index Test between subjects tested before starting the study drug and those tested during the weeks after randomization Freedom from Treatment Failure Overall. and 10 (2%) aged 12 to 13 years.org).. respectively) than given . version 9.age strata as other factors). without correction for multiple comparisons. All analyzes were performed using SAS software. Thus. The results of the analysis based on the modified intent-to-treat approach. Both in the cohort as a whole and within each treatment group. 451 subjects included in the safety analysis and 446 in the efficacy analysis. version 8. At enrollment.0 (Cytel Software). 17 children (4%) were under 4 years. A logrank test of three pairs of drug studies were done at 16 weeks or 20 weeks. whereas the efficacy analysis excluded five children were deemed ineligible on central review.60) on 141 of 399 subjects (35%) could be evaluated. Result Characteristics of Subjects From July 2004 until October 2007. the average age of the cohort was 7 years 5 months. the P value of 0. a total of 453 children were enrolled and randomly assigned to one of three treatment groups (see Figure 1 in the Supplementary Appendix. and one had a BMI greater than the 99th percentile.
34. 3. lamotrigine.28. four groups of valproic acid. The two most common reasons for treatment failure at week 16 and 20 is the lack of seizure control (in 109 subjects [24%]) and intolerable side effects (in 97 subjects [22%]). 1. and one in the group. much longer than the duration of the previous seizures.66. and one subject each had nonepileptic events. No significant differences between treatment groups in the frequency of treatment failure due to intolerable side effects or withdrawal from the study either (Table 3). 2. The majority of children who experience seizures are ongoing in the lamotrigine group. Similar results were found in the analysis of the freedom-from-failure rate within each stratum of age along with the log-rank test of time to treatment failure through traffic at 16 or 20 weeks (Figure 1).lamotrigine (29%. odds ratio with valproic acid vs. 2. in three subjects. Seventeen types of adverse events reported in 5% or more of subjects in at least one treatment group (Table 4). treatment was discontinued because of generalized tonic-clonic seizures: three subjects in the ethosuximide group. Reasons for hospitalization included generalized tonic clonic seizures. With visits to 16 or 20 weeks. P <0. eight subjects (2%) had serious side effects that required hospitalization: four groups of ethosuximide and two each in trigine Lamothe and valproic acid group.06 to 5. odds ratio with ethosuximide vs. 95% CI.65 to 4.001 for both comparisons). In eight subjects. There were 13 cases of severe rash (probably drugs) cause of treatment failure but no cases of Stevens Johnson syndrome. episodes of acting. . 95% confidence interval [CI] . lamotrigine.42. salmonella enteritis and pneumonia to diarrhea and vomiting. lamotrigine.
95% CI. there was no significant difference in outcomes between subjects with Confidence Index seizures and they are free of seizures. odds ratio. 1. P <0. whereas there was no significant difference between ethosuximide and lamotrigine group (P = 0. P = 0. 0 to 7.Confidence Index Scores on the Continuous Performance Test The results of the confidence index of the Conners Sustainable Performance Test 'available for 316 subjects at week 16 and week 20 visits (Table 3 and Figure 1 in the Supplementary Appendix. On this visit.03) and lamotrigine group (49% vs 24%. even after adjustment for differences in basic values Confidence Index.15) for the 96 subjects in the lamotrigine group.5 ± 15. there was no significant difference in the steady state pretreatment serum concentrations between seizure-free subjects and those who continue to have seizures (Fig. 95% CI. 8 mg per kilogram per day and 94 mg per milliliter (95% CI.43).69 to 5. 3.9 ± 15. 0 to 185) for 94 subjects in the ethosuximide group.8 mg per milliliter (95% CI.60 or higher was greater in the group of valproic acid than ethosuximide group (49% vs 33%.7 ± 6.12 to 3. 1.3 mg per kilogram per day and 93 mg per milliliter (95% CI. the proportion of subjects . 1. the percentage of subjects with Confidence Index score of 0.95.).04. odds ratio.49. Clinical Pharmacology Mean (± SD) daily dose and steady-state pretreatment serum concentrations at weeks 16 and 20 were as follows: 33. In the post hoc analysis (data not shown). 9. At weeks 16 weeks or 20 visits. 8 to 180) for the 104 subjects in the valproic acid group. 41.3 mg per kilogram per day and 7. In the treatment group. 2 in the Supplementary Appendix).001 for both comparisons) . and 34. In the treatment group. valproic acid group had significantly worse scores at week 16 and week 20 visits than did ethosuximide and lamotrigine group (P <0.001) (Table 3).
who received maximal doses of lamotrigine was higher in the group (58. In children. Although certain side effects occur more frequently in children treated with ethosuximide or valproic acid. Discussion For children with childhood absence epilepsy. Drug effectiveness (efficacy and tolerability of the combination) selected a priori as the primary outcome for the study is very important in the initial selection of antiepileptic drugs doctors. these side effects usually are temporary and do not require discontinuation of treatment. was chosen to help clinicians differentiate .9%) than in the ethosuximide group (17.5%) or valproic acid group (20. and ethosuximide had a negative effect on the significantly smaller attentional measures than sour valproic (secondary outcome). Prespecified secondary outcome.5%). cognitive side effects may be an important factor when choosing one drug from the drug equally effective. There is no significant difference between the three groups with respect to treatment discontinuation due to intolerable side effects. the short-term effects of drugs on attention. ethosuximide and valproic acid were significantly more effective than lamotrigine in controlling seizures without intolerable side effects (primary outcome).
drug exposure and efficacy endpoints. and P30 HD26979). Both ethosuximide and valproic acid were more effective than lamotrigine. Johnson & Johnson. 5 U10 HD037249. Relative lack of efficacy against seizures Lamotrigine presence was first detected at 16 and 20 weeks. in the short term. as evidenced by the disproportionately higher number of subjects who discontinued treatment at times (Fig. UCB Pharma. and serving as an expert witness on seizure cases for both the plaintiff and defense. receiving consulting fees from Eisai. 37 long-term follow-up of the cohort studies are needed. Shinnar. The combination of primary and secondary outcomes showed that ethosuximide is the optimal initial empirical monotherapy for epilepsy in children do not exist. These results suggest that ethosuximide. age. Short-term effectiveness of ethosuximide and valproic acid were observed in the experiment double-blind. despite the similarities in the range of doses. There was no difference in outcome between the Confidence Index seizure-free subjects and those who continue to have seizures. Adamson. and Arpida Pharmaceuticals. Dr. and given the lack of ethosuximide report on the effectiveness in preventing seizures. but in the analysis of both prespecified and post hoc.60 or higher as an indicator of clinically significant difficulties with attention. receiving consulting fees from Cadence Pharmaceuticals. and it seems to be a core feature of the syndrome. Glauser reports receiving consulting and lecture fees from Eisai. Capparelli. ethosuximide resulted in fewer attentional effects compared to valproic acid. one of the oldest anti-seizure medications available. Bristol-Myers Squibb. Even the best empirical therapy. We use a Confidence Index of 0.between the study drug has the same effectiveness. which confirms that attentional problems persist despite successful treatment. and King Pharmaceuticals and lecture fees from Eisai and UCB Pharma. it is a reasonable choice for initial empirical monotherapy in childhood epilepsy no. 1). failed in nearly 50% of newly diagnosed cases. attentional deficits have been identified as the most important marker of cognitive dysfunction and associated with reduced academic performance. not only because of frequent seizures. This short-term study was not designed to detect long-term cognitive effects of systemic or other of the three drugs. Although this measure is not indisputable for the diagnosis of attention deficit disorder in clinical practice offers strong evidence for the classification Both prespecified and post-hoc analysis showed that. randomized. Dr. In no childhood epilepsy. 1 UL1 RR026314. Supported by grants from the National Institutes of Health (NS045911. smaller open-label studies have shown a higher success rate for lamotrigine compared to levels observed in our study. the maximum daily dose. however. Dr. and GlaxoSmithKline. NS045803. 5 U10 HD031318. Given the increased risk of generalized tonic clonic seizures as children with absence epilepsy. . Conners Continuous Performance 'Test Confidence Index is a measure that provides an overall indication whether the subject profile best fits the pattern of clinical or nonclinical attentional problems. valproic acid negatively impacted noticed a greater degree than either lamotrigine or ethosuximide. and Johnson & Johnson. Abbott Laboratories. similar to those previously observed in open-label trials. However. Study medications were provided free of charge by Pfizer. No other potential conflict of interest relevant to this article was reported. receiving grant support from Abbott Laboratories. and Dr.
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