Abstract #8: Trial Methodology of a Randomized, Double-blind, Parallel-Group Study Evaluating the Clinical Effectiveness of Carisbamate, Topiramate, and Levetiracetam As Adjunctive Treatment of Partial Onset Seizures in Adults

Abstract

Introduction International guidelines recommend assessing the overall long-term benefit of antiepileptic drugs (AEDs) using multidimensional measures. Effectiveness encompasses the effects of a product's efficacy, safety, and tolerability. Retention reflects effectiveness over time. This double-blind study (NCT00563459) was designed to compare the 6- and 12-month retention (as the primary parameter) of patients taking carisbamate (the investigational drug), topiramate, and levetiracetam when used as adjunctive treatment for partial onset seizures (POS). The retention hypotheses were that carisbamate would be at least as good as each comparator. Additionally, because cognitive and neuropsychiatric adverse events (AEs) have an impact on acceptance of therapy, the incidences of these AEs were assessed with the hypotheses that carisbamate would be superior to topiramate on cognitive AEs and superior to levetiracetam on neuropsychiatric AEs. The aforementioned hypotheses were analyzed using a fixed-sequence testing procedure. Methods Following a screening phase, ∼600 adult patients with POS and a history of inadequate response to treatment with e1AED had to be randomized in a 1:1:1 ratio to enter a 7-week titration period. Target daily doses of study medications were carisbamate 800 mg/day, topiramate 300 mg/day or levetiracetam 2000 mg/day, (dose adjustment could be done within the limits of 400–1200 mg/day; 200–400 mg/day; or 1000–3000 mg/day, respectively). After titration, patients entered the 17-week maintenance period. The 7-week titration and 17-week maintenance phases comprise the 6-month (24-week) core double-blind phase, with an option for an additional 6-month double-blind extension phase. The primary endpoint was the time from the first intake of study medication to any cause of discontinuation over the 6-month core double-blind phase. Cognitive AEs, neuropsychiatric AEs, reasons for discontinuation, seizure rates, cognitive changes relative to baseline assessed with a computerized cognitive test battery, and patient-reported mood states, behavioral, and cognitive changes relative to baseline using the Profiles of Mood Status questionnaire, Center for Epidemiologic Studies Depression Scale, and patient- and observer-reported Overall Mental Effects Questionnaire among the 3 treatment arms were assessed at 6- and 12-months post-randomization. This study design can provide unique information and meaningful data that might be valuable for clinical decision-making. Support Support was provided by Johnson & Johnson Pharmaceutical Research & Development , LLC.