Abstracts

Rationale: The FDA requires superiority trials for new AEDs, which for monotherapy is problematic due to the ethics of using a known inferior treatment as a comparator. This study evaluated the efficacy and safety of 250 and 300 mg/day of lamotrigine extended-release (LTG XR) as monotherapy for partial seizures using the conversion to monotherapy design and historic data as control. Methods: Eligible subjects experienced at least 4 partial seizures during an 8-week baseline phase while receiving monotherapy with a non-enzyme-inducing antiepileptic drug (non-EIAED). Conversion to LTG XR monotherapy occurred over 10-11 weeks, followed by 12 weeks of monotherapy with LTG XR. A daily seizure diary was maintained. Efficacy endpoints were meeting pre-defined Escape Criteria and all-cause discontinuation. Efficacy analysis compared the upper 95% confidence limit of the proportion of subjects in the LTG XR 300 mg/day group who met an Escape Criterion with the lower 95% prediction limit of the historic pseudoplacebo control database (65.3%). Non-overlap of limits establishes efficacy. The historic database is comprised of aggregated pseudoplacebo data from 8 similarly-conducted conversion monotherapy studies. Results: A total of 226 subjects (LTG-XR 300 mg/day=113, LTG-XR 250 mg/day=113) from 7 countries were randomized: 223 subjects were in the Safety and ITT populations, and 174 (LTG XR 300 mg/day=93; LTG XR 250 mg/day=81) were in the Per-Protocol population (all subjects who began withdrawal of background AED excluding major protocol violations). Baseline partial seizure frequency was approx. 6/month. Premature discontinuation was higher in the 250 mg/day group (30% vs 17% for 300 mg/day). Main reasons for discontinuation were withdrawn consent (8%), adverse event (AE) and inadequate response (6% each) with balance between treatment groups except for AE withdrawals (4% for 300 mg/day; 9% for 250 mg/day). The proportion of subjects meeting Escape Criteria was 22% in the 300 mg/day group and 26% in the 250 mg/day group. Upper 95% confidence limits were 29.9 and 35.5 for the 300 and 250 mg/day groups, respectively. When the proportion of subjects meeting Escape Criteria was determined for the ITT population (all subjects who received at least 1 dose of study drug), the upper 95% confidence limits were 33.0 and 30.3 for 300 and 250 mg/day, respectively. Since the upper 95% confidence limits did not overlap the lower 95% prediction limit (65.3%) for the historic control, efficacy of both dose groups was established. The most common AEs were headache (300 mg/day=26%, 250 mg/day=28%) and dizziness (300 mg/day=11%, 250 mg/day=9%). Rash was 4% in the 300 mg/day group and 11% in the 250 mg/day group. 4% and 10% of subjects discontinued due to AE in the 300 and 250 mg/day groups, respectively. Conclusions: LTG XR at 300 and 250 mg/day used in monotherapy is safe and effective as demonstrated by non-overlap of escape statistical parameters when compared to historic control data.