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Clínica de Epilepsia | Trabalhos na Íntegra

A RANDOMIZED, RATER-BLIND STUDY OF HIGH- VERSUS LOW-DOSE OXCARBAZEPINE MONOTHERAPY IN INFANTS AND CHILDREN WITH PARTIAL SEIZURES

Arthur Cukiert (1), Rajesh C. Sachdeo (2), Ricardo Ayala (3), Douglas R. Nordli (4), Debra A. Bennett (5), Aida Navarrete (5), Chunlin Qian (6), Yvonne Sturm (7), MaryAnn Karolchyk (5)

1- Hospital Brigadeiro, Sao Paulo, Brazil;
2- NJ Comprehensive Epilepsy Center, New Brunswick, NJ, USA;
3- AMO Corporation, Tallahassee, Florida, USA;
4- Children’s Memorial Hospital, Chicago, Illinois, USA;
5- Clinical Research & Development, Novartis Pharmaceuticals, East Hanover, New Jersey, USA;
6- Biostatistics, Novartis Pharmaceuticals, East Hanover, New Jersey, USA;
7- Clinical Research & Development, Novartis Pharma AG, Basel, Switzerland

Summary

Purpose: To evaluate the efficacy, safety and pharmacokinetics of high- versus low-dose oxcarbazepine monotherapy in children and infants 1 month to <17 years of age with partial seizures.
Methods: Pediatric patients with new-onset or inadequately controlled partial seizures were enrolled in the study. Prior to a 5-day treatment phase, patients were randomized to receive either low-dose (10 mg/kg/day) or high-dose (40-60 mg/kg/day) oxcarbazepine. Patients completed the study by completing the treatment phase or by meeting exit criteria based upon seizure frequency/severity. Seizures were measured by continuous video-EEG monitoring from Day 3 onwards. Post-dose and trough plasma concentrations of the oxcarbazepine active metabolite MHD (monohydroxy derivative) were measured at the end of the treatment phase.

Results: Overall, 46 patients received high-dose and 46 received low-dose oxcarbazepine. There was no significant difference in exit rates between the two treatment groups. The majority of patients in both groups completed the treatment phase and remained seizure-free during the 72-hour video-EEG monitoring period. Post-dose and trough plasma MHD concentrations in the high-dose group clearly differentiated from those in the low-dose group. Oxcarbazepine was well tolerated in both groups.
Conclusions: This study shows that, over a 5-day treatment phase, there was no significant difference between high- and low-dose oxcarbazepine monotherapy in controlling partial seizures in children. However, most patients remained seizure free during the study and exit rates were low. The short duration of the study, necessary to minimize patient exposure to low-dose oxcarbazepine, may help explain the lack of separation between high- and low-dose oxcarbazepine.

Introduction

The majority of patients with epilepsy experience their first seizure during childhood, and approximately 0.5-1.0% of children are affected by this condition (1,2). The selection of an appropriate antiepileptic drug (AED) for the treatment of epilepsy is influenced by several factors, including seizure type and severity, co-morbid conditions, co-medication, and AED efficacy and tolerability profiles (3). Older AEDs such as phenobarbital are commonly used to treat children with epilepsy. However, approximately 25% of children receiving older AEDs continue to experience seizures and many suffer intolerable adverse effects (4,5).

The introduction of several newer AEDs in the 1990s has increased the number of pharmacologic options for the treatment of adults with epilepsy. However, treatment options for children are limited as several newer AEDs are not approved for pediatric use. The treatment of infants and young children (<4 years of age) is especially challenging; AED treatment, particularly as monotherapy, has not been systematically investigated in this pediatric population through well-designed clinical studies. Furthermore, extrapolation of data from studies conducted in older children and adults may be complicated by developmental, physiological and metabolic influences on drug pharmacokinetics (6).

The newer AED oxcarbazepine is approved for the treatment of partial seizures (with or without secondarily generalized seizures) in more than 70 countries worldwide. Oxcarbazepine is indicated for the treatment of partial seizures in adults and children (US 4 years of age, Europe 6 years of age) as monotherapy and adjunctive therapy. Following oral administration, oxcarbazepine is rapidly absorbed and extensively metabolized to its 10-monohydroxy derivative (MHD). MHD is primarily responsible for the pharmacological effects of oxcarbazepine, largely via modulation of voltage-sensitive sodium and calcium ion channels (7,8).
Extensive clinical experience has shown oxcarbazepine to be safe and well tolerated in children 16 years of age (9–15). Oxcarbazepine also showed good safety and tolerability profiles in open-label pilot studies in young children and infants 1 month to <4 years of age (16). Randomized controlled trials have proven the efficacy of oxcarbazepine in children 5-18 years of age as monotherapy (13) and in children 3-17 years of age as adjunctive therapy (12).

The aim of this study was to investigate the efficacy, safety and pharmacokinetics of oxcarbazepine monotherapy in patients 1 month to <17 years of age with inadequately controlled or new-onset partial seizures. This is one of two clinical studies that have evaluated oxcarbazepine monotherapy or adjunctive therapy in infants and very young children, and is the first controlled study of oxcarbazepine monotherapy in pediatric patients as young as 1 month of age.

Methods

Patients
Patients who were 1 month to <17 years of age, weighed a minimum of 3 kg, and had a diagnosis of new-onset or inadequately controlled partial seizures (including the subtypes of simple, complex and/or partial seizures evolving to secondarily generalized seizures) were eligible for inclusion in the study. Seizure types were based on the International League Against Epilepsy Classification (17). Eligible patients had an EEG showing focal epileptiform discharges and/or a focal abnormality, and experienced 2-30 partial seizures (reported by patients or caregivers) during the 7-day pre-randomization phase of the study. All patients had a computed tomography or magnetic resonance imaging scan confirming the absence of progressive space-occupying lesions or neurological disease. Patients with inadequately controlled partial seizures must have been maintained on a stable dose of no more than one concomitant AED during the pre-randomization phase, with all additional AEDs discontinued at least 7 days prior to this phase. Females of childbearing age were only enrolled if they were using a suitable method of contraception and were not pregnant, trying to become pregnant or nursing an infant. Written, informed consent was obtained from patients or from a parent/legal guardian, depending on patient age.

Patients were excluded if the following medications were taken prior to the start of the treatment phase: felbamate (within 6 months of the treatment phase); zonisamide (within 1 month); barbiturates (within 1 month [patients <3 months of age] or 2 weeks [patients >3 months of age]); or benzodiazepines (within 1 week). Other main exclusion criteria included: a diagnosed treatable etiology of seizures; a primary diagnosis of generalized seizures, excluding secondarily generalized seizures; occurrence of status epilepticus within 30 days prior to the start of the study; psychogenic or non-epileptic seizures; seizures only occurring in clusters, defined as multiple seizures occurring in a <30-minute period; serum sodium <135 mmol/L; cardiac, respiratory, hepatic, gastrointestinal, renal, hematologic or oncologic disorder(s); and hypersensitivity to carbamazepine.

Study design
This rater-blind, randomized, age-stratified, parallel-group study was conducted between July 2002 and February 2004 in 42 centers in the USA, Germany, Brazil, Mexico and Lithuania. The study consisted of three phases: a 7-day pre-randomization phase, a 5-day treatment phase and a 6-month open-label extension phase (Fig. 1). Only data from the first two phases of the study are presented here. The pre-randomization phase was conducted on an outpatient basis. Prior to the start of the treatment phase, patients were hospitalized for either conversion to or initiation of oxcarbazepine monotherapy treatment. The treatment phase was restricted to 5-days’ duration because of ethical concerns related to the exposure of young pediatric patients to low-dose oxcarbazepine. The study was performed in accordance with the Declaration of Helsinki, European Directive 2001/83/EC and the US Code of Federal Regulations Part 21.

Patients were stratified by age as follows: 1-<6, 6-<12, 12-<24, 24-<48 months, or 4-<8 and 8-<17 years. Within each age category, patients were randomized in a 1:1 ratio to receive oxcarbazepine 10 mg/kg/day (low-dose group) or 40-60 mg/kg/day (high-dose group).

Patients randomized to the low-dose group received 10 mg/kg/day oxcarbazepine on Days 1-5 of the treatment phase. Those patients randomized to the high-dose group received 20 mg/kg/day oxcarbazepine on Days 1-2, 40 mg/kg/day on Day 3 and 40-60 mg/kg/day on Days 4-5 (depending on individual patient response). Patients received oxcarbazepine every 12 hours in equally divided doses. In the event of poor tolerability, the dose received by patients in the high-dose group could be reduced by 5 mg/kg/day to no less than 40 mg/kg/day. For patients converting to oxcarbazepine monotherapy, the dose of the existing AED was reduced to 50% of the pre-randomization dose on Day 2 and discontinued on Day 3.

Since oxcarbazepine is only available as a 6% oral suspension with no placebo or lower strength formulations, it was not possible to securely blind the administration of the study drug. Therefore, this study used a “rater-blind” design in which video-EEG recorded seizures were assessed by an independent pediatric neurologist who was not involved in the conduct of the study and was blind to study treatment.

Patients were considered to have completed the core study by either finishing the 5-day treatment phase or by meeting one of two exit criteria based on seizure frequency and severity. Data from the 6-month extension phase will be reported separately.

Efficacy assessment
Beginning with the first dose of oxcarbazepine on Day 3 of the treatment phase, patients were continuously monitored by video-EEG. Partial seizures evaluated by video-EEG during this study were characterized by a recognizable focal ictal pattern on EEG involving at least two contiguous electrodes, which must have demonstrated a spatial and temporal evolution consistent with an ictal discharge and been distinct from the patient’s background cerebral electrical activity, and an electrographic duration of at least 20 seconds. Two types of seizures were evaluated: electrographic partial seizures with a behavioral correlate, as observed on video or by trained site personnel or a parent (type 1) and electrographic partial seizures without a behavioral correlate (type 2).

The primary efficacy variable was the time to meeting one of the exit criteria, starting from the time of the first dose of oxcarbazepine on Day 3. The video-EEG confirmed exit criteria were: (1) three type 1 seizures (with or without secondarily generalized seizures) or (2) a prolonged type 1 seizure lasting 5 minutes.

Secondary efficacy variables were: (1) the percentage of patients meeting one of the exit criteria and (2) type 1 and type 2 seizure frequency per 24 hours during the treatment phase.

Safety assessments
Safety assessments included the monitoring and recording of all adverse events and serious adverse events. The relationship of adverse events and serious adverse events to the study drug was also reported. Baseline laboratory values (hematology, blood chemistry and urinalysis) were collected at least 3 days prior to randomization. Baseline ECG and physical and neurological exam were performed during the pre-randomization phase. Vital signs were measured on each day of the treatment phase. Laboratory value collection, ECG, physical and neurological exam, and vital sign measurements were repeated when patients either completed the treatment phase, met one of the exit criteria, or prematurely discontinued.

Pharmacokinetic assessments
Patients in each treatment group were assigned to provide blood samples for the determination of plasma MHD concentrations at either 0.5, 2, or 5 hours post-morning dose on Day 5 of the treatment phase. For patients who completed the treatment phase, a final termination visit (trough) sample was also obtained 12 hours after the Day 5 evening dose. For patients who exited the study, samples were obtained at the time of meeting one of the exit criteria. Plasma MHD concentrations were determined by liquid chromatography-tandem mass spectrometry and are expressed in molar units (mol/L).

Statistical analyses
The intent-to-treat (ITT) population included all randomized patients for whom video-EEG data were available and was used for all efficacy analyses. The safety population included all patients who received at least one oxcarbazepine dose.

Power calculation
The sample size calculation for this study was based on the time to meeting one of the exit criteria and was chosen to detect a 35% difference between the two treatment groups, with the assumption that 35% of patients in the high-dose group and 70% of patients in the low-dose group would meet one of the exit criteria. Given a log-rank test with a significance level of 0.05 and a statistical power of 80%, approximately 40 patients per treatment group were necessary. The assumptions used in the sample size calculation were based on data collected in a presurgical study of similar design in adults (18).

Analyses
For the primary efficacy variable, treatment group differences in the time to meeting one of the exit criteria were assessed using a log-rank test. An additional analysis was performed on the primary efficacy variable using Cox’s proportional hazard regression model with treatment and age group (<4 years; 4 years) as explanatory variables.

For the first of the secondary efficacy variables, treatment group differences in the percentage of patients meeting one of the exit criteria in the treatment groups were assessed using the Cochran-Mantel-Haenszel test, modified for the additional consideration of age groups. The percentage of patients meeting one of the exit criteria was also analyzed using a logistic regression model with treatment and age group (<4 years; ≥4 years) as explanatory variables.

The secondary efficacy variable type 1 and type 2 seizure frequency per 24 hours was calculated as the number of type 1 and type 2 seizures experienced during the period of continuous video-EEG monitoring, divided by the length of this period (hours) and multiplied by 24. Treatment group differences were assessed using the rank analysis of covariance, with age as the covariate.

For the pharmacokinetic analyses, summary statistics of plasma MHD concentrations by dose group and sampling time were calculated. Summary statistics of trough plasma MHD concentrations were also stratified according to age (<4 years; 4 years) within each treatment group.

Results

Patient demographics
Overall, 110 patients were screened for entry in the study (Fig. 2); 18 patients did not meet the entry criteria and were excluded. A total of 92 patients were randomized to oxcarbazepine monotherapy: 46 to the low-dose group and 46 to the high-dose group. The two groups were comparable in terms of age, race and seizure classification (Table 1). There were more new-onset patients in the high-dose group (n = 10, 22%) compared with the low-dose group (n = 5, 11%) and slightly fewer male patients in the high-dose group (n = 21, 46%) compared with the low-dose group (n = 28, 61%). More than half the patients (55%) were <4 years of age.

Patient disposition and exposure
Overall, 86 (93%) patients completed the study and 6 (7%) patients prematurely discontinued from the study. Of the six patients who discontinued prematurely, three (3%) patients discontinued due to administrative problems (all in the low-dose group) and three patients discontinued due to adverse events (two in the high-dose group, one in the low-dose group). Efficacy data were available for 87 patients (42 in the high-dose group, 45 in the low-dose group) in the ITT population. The safety population consisted of 92 patients (46 in each dose group).

The mean (median) daily dose on the last day of treatment was 10.4 (9.9) mg/kg in the low-dose group and 44.5 (42.7) mg/kg in the high-dose group.

Efficacy
As shown in Fig. 3, there was no significant difference between the high- and low-dose groups for the time to meeting one of the video-EEG confirmed exit criteria (p = 0.904). Within treatment groups, there was no significant difference in the time to meeting one of the exit criteria between patients <4 years of age and patients 4 years of age (p = 0.650).

The exit criteria was similar between treatment groups (Table 2). By the end of the treatment phase, 21% and 22% of patients in the high- and low-dose groups, respectively, met one of the exit criteria. There was no significant difference in the percentage of patients meeting one of the exit criteria between patients <4 years of age and patients 4 years of age (p = 0.704, Table 3).

There was no significant difference in the type 1 and type 2 seizure frequency per 24 hours between the two treatment groups (p = 0.371). The majority of patients in both the low- and high-dose groups were seizure-free during the 72-hour video-EEG monitoring period, as demonstrated by the median [range] type 1 and type 2 seizure frequency per 24 hours (0.0 [0.0-10.1] low-dose group, n = 45; 0.0 [0.0-25.6] high-dose group, n = 42). The mean (SD) type 1 and type 2 seizure frequency per 24 hours was 1.0 (2.2) in the low-dose group and 1.3 (4.3) in the high-dose group. Overall, 29/42 (69%) and 29/45 (64%) of patients in the high- and low-dose groups, respectively, did not experience any type 1 seizures.

Safety and tolerability
The most common adverse events (≥10% of patients in either treatment group) during the treatment phase were somnolence, dizziness, nausea and vomiting (Table 4). Somnolence, dizziness and nausea were seen only in the high-dose group. Adverse event data was also stratified according to age (<4 years; 4 years of age) (Table 4). No relevant age-related differences within treatment groups were observed, with the exception of dizziness in the high-dose group, which was less frequent in patients <4 years of age (8%) than in patients ≥4 years of age (19%). Three patients discontinued due to adverse events; only one of which was considered related to oxcarbazepine (mild maculo-papular rash, high-dose group).

No deaths occurred during this study. Three patients experienced serious adverse events: one in the low-dose group (apnea, cardiac arrest and an abnormal EEG) and two in the high-dose group (both status epilepticus). None of the serious adverse events were considered related to oxcarbazepine treatment and none led to patient discontinuation.

There were no unexpected findings for laboratory and vital sign parameters. There were no incidences of clinically notable hyponatremia (serum sodium <125 mmol/L). One patient in the low-dose group, who had a baseline ECG showing incomplete right bundle branch block with a QT/QTc value of 394/446, had an ECG on day 6 of oxcarbazepine treatment showing a prolonged QT interval (QT/QTc, 432/529), right axis deviation, incomplete right bundle branch block, possible right ventricular hypertrophy and nonspecific T wave abnormality. The patient completed the treatment phase and entered the extension phase. An ECG on day 12 of oxcarbazepine treatment showed a QT/QTc value of 394/479. The prolonged QT interval was reported as an adverse event, but was not considered related to oxcarbazepine treatment. An ECG on day 28 of treatment showed that the QT prolongation had resolved (QT/QTc, 416/455); right axis deviation and nonspecific T wave abnormality were the only ECG findings. At this point, the patient, who was now receiving approximately 40 mg/kg/day oxcarbazepine, discontinued from the study due to lack of efficacy.

Another patient in the low-dose group experienced QT prolongation. This patient had sinus bradycardia with sinus arrhythmia and a QT/QTc value of 418/428 at baseline. An ECG on day 6 of oxcarbazepine treatment showed a possible prolonged QT interval (QT/QTc, 550/502) with sinus bradycardia and ST abnormality. This was reported as an adverse event, and the investigator suspected a relationship to study drug. The patient completed the treatment phase and entered the extension phase. An ECG on day 20 of oxcarbazepine treatment showed that QT prolongation had resolved (QT/QTc, 424/398), and the only ECG finding was continued sinus bradycardia. At this point, the patient was receiving approximately 27 mg/kg/day oxcarbazepine. Approximately 4.5 months later, when the oxcarbazepine dose was 62 mg/kg/day, a termination ECG confirmed the absence of QT prolongation (QT/QTc, 468/431).

Pharmacokinetics
Blood samples were available from 87 patients, with a total of 152 measurements of plasma MHD concentrations obtained. Data from seven patients were excluded: three patients had samples taken after entering the extension phase of the study; two patients had not received oxcarbazepine for 48 hours at the time of sampling; one patient received an oxcarbazepine dose not consistent with the patient’s dose group; and one patient in the high-dose group was considered an outlier (trough plasma MHD concentration 20.8 mol/L).

A total of 140 plasma MHD concentrations, including 66 trough MHD concentrations, were used for the summary statistical analysis. Median trough MHD concentrations in the high-dose group differentiated from those in the low-dose group, with no overlap in the ranges of trough MHD concentration (Table 5). Similar differentiation between treatment groups was observed for the other sampling times (0.5, 2 and 5 hours post-dose, Table 5).

For both treatment groups, median trough MHD concentrations were 35-40% lower in patients <4 years of age compared with patients 4 years of age. In the low-dose group, median (range) trough MHD concentrations were 15.4 (4.64-40.2) mol/L in patients <4 years of age (n = 19) and 22.2 (11.0-38.9) mol/L in patients 4 years of age (n = 15). In the high-dose group, median (range) trough MHD concentrations were 72.4 (44.7-137) mol/L in patients <4 years of age (n = 11) and 97.8 (68.8-160) mol/L in patients 4 years of age (n = 20). Reduced patient numbers prevented a comparable analysis for the other sampling times, however, similar trends were observed.

Discussion

The results of this randomized, rater-blind study show that, over a 5-day treatment phase, there was no significant difference between high- and low-dose oxcarbazepine monotherapy in controlling partial seizures in infants and children. The time to meeting one of the exit criteria was not significantly different between treatment groups. Similarly, rates of exit from the study and mean partial seizure frequencies in patients receiving high- or low-dose oxcarbazepine were comparable. The majority of patients in both treatment groups completed the study without exiting and did not experience any seizures during the period of continuous video-EEG monitoring.

This study did not have a placebo arm primarily because, apart from the technical aspect of the lack of matching placebo, there were ethical concerns related to the inclusion of very young children in the study population. Therefore, a parallel-group design was used in which patients either received low-dose oxcarbazepine, corresponding to the labeled starting dose for children (10 mg/kg/day), or high-dose oxcarbazepine (40-60 mg/kg/day).

To minimize the exposure of patients to low-dose oxcarbazepine, the period of efficacy data collection during the treatment phase was limited to 3 days. The short duration of the study may help explain why the efficacy variables did not separate the two treatment groups. The majority of patients in the high-dose (69%) and low-dose (64%) groups did not experience any type 1 seizures during the treatment phase. In addition, exit rates measured during the treatment phase were considerably lower than the assumed exit rates, particularly in the low-dose group. A study of longer duration would have probably been needed to separate the two treatment groups according to the meeting of exit criteria based on the frequency of type 1 seizures.

Trough MHD plasma concentrations in the low-dose group (median [range]: 19.7 mol/L [4.6-40.2]) were comparable to those obtained in a dose-ranging study in adults treated with 600 mg/day oxcarbazepine as adjunctive therapy (17.0 mol/L [1.5-41.9]) (19). In the adult study (19), 600 mg/day oxcarbazepine, the labeled starting dose for adults, was significantly more effective than placebo. It is possible that patients in the low-dose group in the present study benefited from oxcarbazepine treatment during the 5-day treatment phase.

Because of the short duration of this study, the doses received by patients in the high-dose group may not have been high enough to demonstrate superiority over the low-dose group. In a study of oxcarbazepine adjunctive therapy with a similar design, high-dose oxcarbazepine was statistically significantly more effective in controlling partial seizures than low-dose oxcarbazepine [data on file]. The duration of the adjunctive study was 35 days and the median daily dose on the last day of treatment in the high-dose group was 56.7 mg/kg, markedly higher than in the present study (42.7 mg/kg). In addition, the majority of patients in the high-dose group in this study probably did not reach steady-state during the short period of efficacy data collection from days 3-5. In a presurgical study of similar design in adults (18), there was no discernible relationship between trough MHD plasma concentrations and the time to exit during the first 4 days, before steady state MHD levels were reached [data on file]. However, on days 5-10 of the adult study, there was a trend toward a longer time-to-exit being with higher trough MHD concentrations.

Another study design factor to consider is the method of seizure assessment used during the pre-randomization phase. There is an inherent difficulty in identifying seizure frequency and type in young pediatric populations and, therefore, only video-EEG confirmed seizures were counted toward meeting the exit criteria during the treatment phase. However, study eligibility was assessed during the pre-randomization phase on an outpatient basis according to the number of clinical seizures recorded by the patient or caregiver in a diary, not on video-EEG confirmation of seizures. It is possible, therefore, that some patients may not have had a baseline seizure type and frequency consistent with that used to determine whether patients met the exit criteria.
Although the primary and secondary efficacy variables did not separate the two treatment groups, seizures were well controlled in the majority of patients. Furthermore, these results confirm the findings of previous studies in children >4 years of age (13,15). In a randomized, double-blind, phenytoin-controlled study of oxcarbazepine monotherapy in children 5-17 years of age with newly diagnosed epilepsy, 61% of patients receiving oxcarbazepine and 60% receiving phenytoin were seizure free during the 48-week maintenance period (13).

Although some of the newer AEDs, including oxcarbazepine, have demonstrated efficacy in children >4 years of age with new-onset or refractory partial seizures (20,21), data from prospective clinical studies in younger children and infants are lacking. More than half of the patients in this study were <4 years of age. Stratification of efficacy data according to age revealed no significant differences between patients <4 years of age and patients ≥4 years of age. The majority of patients <4 years of age remained seizure free during the study.
Oxcarbazepine was well tolerated in both treatment groups and the overall adverse event profile was in accordance with previous findings (9–15). Adverse event profiles were similar in patients <4 years of age and patients ≥4 years of age. The lower incidence of dizziness noted for patients in the high-dose group <4 years of age compared with patients ≥4 years of age was most likely due to the limited reporting capability of younger children and infants. The good safety and tolerability profiles of oxcarbazepine noted in patients <4 years of age in this study confirms those reported in previous open-label studies in a similar pediatric population (16).

The population pharmacokinetics of oxcarbazepine have been studied in children 3-17 years of age (22). MHD concentration-time profiles were described using a one-compartment model with first-order absorption and elimination. In another study, it was shown that MHD concentration-time profiles in infants and young children <4 years of age can be described by a similar population pharmacokinetic model (23). In the present study, trough plasma MHD concentrations were 35-40% lower in patients <4 years of age compared with older patients. This is consistent with the increased MHD clearance reported in young children and infants compared with children ≥4 years of age (23).

In conclusion, this study–the first of its kind in this pediatric population–demonstrated no significant difference between efficacy variables in patients receiving high- or low-dose oxcarbazepine as monotherapy. However, most patients remained seizure free during the study and exit rates in both treatment groups were much lower than the assumed rates of exit. The short duration of the study, necessary to minimize the exposure of pediatric patients to low-dose oxcarbazepine, may help explain the lack of separation between high- and low-dose oxcarbazepine. Oxcarbazepine showed good safety and tolerability profiles consistent with previous findings in pediatric patients.

Acknowledgements

This study was sponsored by Novartis Pharmaceuticals Inc. The authors would like to thank the following Oxcarbazepine Pediatric Monotherapy Study principal investigators:
Brazil: A. Cukiert, MD, PhD, Sao Paulo. Germany: U. Brandl, MD, Jena; J.-P. Ernst, MD, Kehl-Kork; D. Rating, MD, Heidelberg. Mexico: S. Garza, MD, Mexico; I. Rodriguez, MD, San Luis Potosi; J.C. Perez Garcia, MD, Puebla. USA: R. Ayala, MD, Tallahassee, FL; M. Duchowny, MD, Miami, FL; J.A. Ferreira, MD, Tampa, FL; M.D. Frost, MD, St. Paul, MN; H.T. Hutchinson, MD, PhD, Madera, CA; P. Kankirawatana, MD, Birmingham, AL; S.B. Legarda, MD, Spartanburg, SC; P.M. Levisohn, MD, Denver, CO; P. Maertens, MD, Mobile, AL; W. Marks, MD, Forth Worth, TX; J.T. Parke, MD, Oklahoma City, OK; J.E. Pina-Garza, MD, Nashville, TN; C.M. Roberts, MD, Portland, OR; W.E. Rosenfeld, MD, Chesterfield, MO; R.C. Sachdeo, MD, New Brunswick, NJ; M.S. Scher, MD, Cleveland, OH; A. Weinstock, MD, Buffalo, NY; A.A. Wilfong, MD, Houston, TX; J.D. Wooten, MD, Raleigh, NC.

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19. Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia 2000;41:1597-607.
20. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1252-60.
21. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261-73.
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23. Mangat S, Nedelman JR. Pharmacokinetics of oxcarbazepine during adjunctive therapy in pediatric patients with inadequately controlled partial seizures. Epilepsia 2003;44 Suppl 9:102. Abstract.

TABLE 1.  Patient demographics

Demographic

No. patients (%)

 

Low dose
(n = 46)

High dose
(n = 46)

All
(N = 92)

Age
            1-<6 months
            6-<12 months
            12-<24 months
            24-<48 months
            4-<8 years
            8-<17 years

 

4 (9)
7 (15)
6 (13)
9 (20)
10 (22)
10 (22)

 

4 (9)
6 (13)
6 (13)
9 (20)
11 (24)
10 (22)

 

8 (9)
13 (14)
12 (13)
18 (20)
21 (23)
20 (22)

Sex
            Male
            Female

 

28 (61)
18 (39)

 

21 (46)
25 (54)

 

49 (53)
43 (47)

Race
            Black
            Caucasian
            Other

 

8 (17)
30 (65)
8 (17)

 

4 (9)
26 (57)
16 (35)

 

12 (13)
56 (61)
24 (26)

Partial seizure type
            New-onset seizures
            Previously treated

 

5 (11)
41 (89)

 

10 (22)
36 (78)

 

15 (16)
77 (84)

ILAE classification*
            Simple partial seizures
            Complex partial seizures
            Partial seizures with secondary GTC
            Other seizures

 

13 (28)
35 (76)
22 (48)
13 (28)

 

13 (28)
35 (76)
23 (50)
12 (26)

 

26 (28)
70 (76)
45 (49)
25 (27)


ILAE, International League Against Epilepsy; GTC, generalized tonic-clonic
*A patient may have experienced more than one type of seizure and may be listed in multiple categories.

TABLE 2.  Patients meeting one of the exit criteria in low- and high-dose groups, ITT population (N = 87)

 

No. patients (%) meeting exit criteria

Treatment group

Day 3
[day 1 of EEG]

Day 4
[days 1-2 of EEG]

Day 5
[days 1-3 of EEG]

Low-dose (n = 45)
High-dose (n = 42)
p value*

5 (11)
6 (14)

9 (20)
9 (21)

10 (22)
9 (21)
0.939

*p value based on comparison between high- and low-dose groups using Cochran-Mantel-Haenszel test.

TABLE 3.  Patients meeting one of the exit criteria in low- and high-dose groups stratified according to age, ITT population (N = 87)

 

No. patients (%) meeting exit criteria by day 5 [day 3 of EEG]

Low-dose

            <4years (n = 25)
            ³4 years (n = 20)

 

5 (20)
5 (25)

High-dose
            <4years (n = 22)
            ³4 years (n = 20)
p value*

 

6 (27)
3 (15)
0.704

*p value based on logistic regression model with treatment and age group (<4 years; ≥4 years) as explanatory variables

TABLE 4.  Most common adverse events (³10% in either treatment group) regardless of relationship to study drug, safety population (N = 92)

 

No. patients (%)

 

Low dose

High dose

Adverse event

All
(n = 46)

<4years
(n = 26)

³4 years
(n = 20)

All
(n = 46)

<4years
(n = 25)

³4 years
(n = 21)

Somnolence

0 (0)

0 (0)

0 (0)

8 (17)

4 (16)

4 (19)

Dizziness

0 (0)

0 (0)

0 (0)

6 (13)

2 (8)

4 (19)

Nausea

0 (0)

0 (0)

0 (0)

5 (11)

3 (12)

2 (10)

Vomiting

6 (13)

4 (15)

2 (10)

5 (11)

3 (12)

2 (10)

TABLE 5.  Summary statistics of plasma MHD concentrations by treatment group and sampling time.

 

Median (range) MHD concentration, mmol/L

Sampling time, h

Low-dose

High-dose

0.5

26.1 (12.9-58.4), n = 13

90.3 (69.4-125), n = 9

2

26.8 (6.21-45.4), n = 17

99 (67.2-150), n = 12

5

37.8 (20.2-48.9), n = 13

95.4 (57.0-123), n = 11

12 [trough]

19.0 (4.64-40.2), n = 34

93.2 (44.7-160), n = 31

Figure legends

Fig. 1.  Study design
Fig. 2.  Patient disposition
Fig. 3.  Time to meeting one of the exit criteria in low- and high-dose groups, ITT population (N = 87)