Abstracts

We have reviewed aggregated data to determine the comparative risk of seizure during the initial 8 weeks of treatment using LTG and comparator anti-epileptic drugs (AEDs) for initial monotherapy. A meta-analysis was conducted using data from 5 double-blind, randomized, active comparator studies comparing LTG with standard AEDs for initial epilepsy monotherapy. The goal of this analysis is to assess the efficacy of LTG relative to standard AEDs during the titration period. The studies were of similar design, duration (26-50 weeks), and patient population. The primary comparison in this analysis is the seizure-free rate during the first 8 weeks for pooled LTG data versus pooled comparator AED data using survival estimates of the proportion seizure-free at each week to assess therapeutic equivalence. Therapeutic equivalence is characterized as [gt]/= 50% of the [lsquo]treatment effect[rsquo] of standard therapy. For this analysis, treatment effect is defined as the difference in seizure-free rate between an active comparator and an estimated placebo response rate of 35%. LTG was considered therapeutically equivalent to the pooled comparator AEDs if the lower limit (LL) of the 95% confidence interval (CI) was more positive than the 50% of the treatment effect. Over the 5 studies, 383 patients were treated with LTG. Three studies used carbamazepine (CBZ, n=176) as a comparator, and one study each used valproic acid (VPA, n=68) and phenytoin (PHT, n=95). Study completion rates were similar and ranged from 47% for PHT to 64% LTG.
Analysis of the primary comparison showed that LTG retained [gt]50% of the comparator treatment effect in each of the first 8 weeks. The difference between the LTG and the pooled comparator AED response rate was never more than 8% (LTG seizure-free, 56-77%) and the difference decreased during the 8 weeks. For all therapies, seizure occurrence was greatest during the first week. Subsequently, first seizures occurred at a much lower frequency in all groups throughout the remaining 7 weeks of treatment. The results are similar when the analysis is limited to partial seizures.
In some of the studies, the dose escalation period was extended for CBZ (1 week) or PHT (2 weeks). Data were reanalyzed to exclude all first seizures during these times in patients randomized to these drugs. In this analysis, LTG maintained at least 50% of the comparator treatment effect for the first 3 weeks and was only marginally less for weeks 4-8. During the first 8 weeks of therapy, LTG was therapeutically equivalent to the pooled active comparator AEDs using an estimated placebo seizure-free rate of 35%. The difference in response between LTG and the pooled AEDs was never greater than 8%. This analysis supports the position that the risk of seizure during dose escalation of LTG does not exceed the risk with other AEDs commonly used as initial monotherapy. (Supported by GlaxoSmithKline.)