The effectiveness of Trileptal® (oxcarbazepine) as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials.
The effectiveness of Trileptal as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.
Trileptal Monotherapy Trials
Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of Trileptal as monotherapy. Two trials compared Trileptal to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Trileptal, after substituting Trileptal 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose Trileptal treatment groups.
One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or Trileptal given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of Trileptal (see Figure 1), p=0.0001.
Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group
The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or Trileptal, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of Trileptal (see Figure 2), p=0.046.
Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group
A third trial substituted Trileptal monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Trileptal dose for 56 days (baseline phase). Patients who were able to tolerate titration of Trileptal to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Trileptal or 2400 mg/day Trileptal. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the Trileptal 2400 mg/day group (see Figure 3), p=0.0001.
Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group
Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either Trileptal 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the Trileptal 2400 mg/day group (14/34; 41.2%) compared to the Trileptal 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Trileptal 2400 mg/day group (see Figure 4), p=0.0001.
Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group
A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Trileptal 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of Trileptal therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting.
Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.
Trileptal Adjunctive Therapy Trials
The effectiveness of Trileptal as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age).
Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of Trileptal in addition to their other AEDs.
In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.
In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of Trileptal at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 1. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study (see ADVERSE REACTIONS section), an outcome not seen in the monotherapy studies.
Table 1: Summary of Percentage Change in Partial Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials
| Trial || Treatment Group |
| N || Baseline |
| Median % |
|2 (adults)||Trileptal 2400 mg/day||174||10.0||49.91|
|Trileptal 1200 mg/day||177||9.8||40.21|
|Trileptal 600 mg/day||168||9.6||26.41|
1 p=0.0001; * = # per 28 days
Subset analyses of the antiepileptic efficacy of Trileptal with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.
The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either Trileptal 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of Trileptal 60 mg/kg/day. In this study, there was no evidence that Trileptal was effective in patients below the age of 2 years (N=75).