Abstracts

Rationale: Retigabine (RTG, ezogabine in North America) is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (Kv7) potassium channels. Treatment-emergent adverse events (TEAEs) were assessed from 3 pivotal controlled trials of RTG 600-1200mg/day vs placebo (PBO) in adults with drug-resistant epilepsy and summarized by study phase. Methods: Study 205 (Phase IIb), and RESTORE 1 and 2 (Studies 301[NCT00232596] and 302[NCT00235755], Phase III) were multicenter, randomized, double-blind, placebo-controlled, parallel-group trials in adults with drug-resistant epilepsy, ?4 partial-onset seizures per 28 days, receiving 1-2 (Study 205) or 1-3 (RESTORE 1/2) AEDs, with/without vagus nerve stimulator. Patients were randomized to RTG or PBO (administered tid) and underwent forced-titration to RTG 600 or 900mg/day (Study 205, RESTORE 2) or 1200mg/day (Study 205, RESTORE 1) followed by an 8- (Study 205) or 12-week (RESTORE 1/2) maintenance phase. TEAEs were summarized by study phase (titration/maintenance), in which only new events were counted for each phase. If an event started during titration and continued into maintenance, it was only counted for titration. If an event started during titration, resolved, and was reported again during maintenance, it was counted for both phases. Results: The titration and maintenance populations totaled 1240 and 1041, respectively (titration: PBO, n=427; RTG 600mg/day, n=281; 900mg/day, n=273; 1200mg/day, n=259; maintenance: PBO, n=383; RTG 600mg/day, n=243; 900mg/day, n=226; 1200mg/day, n=189). TEAEs reported in ?5% of patients in any treatment group including PBO tended to be higher during titration vs maintenance. The most frequent TEAEs in both study phases for all RTG doses combined were CNS-related and included dizziness, somnolence, headache and fatigue, but incidences were higher during titration than maintenance for all treatment groups including PBO. During titration, TEAE incidence was dose-related: 58%, 62%, 70% and 82% of the PBO, 600-, 900- and 1200-mg/day groups, respectively. During maintenance, overall incidence of TEAEs was comparable for PBO and RTG 600 and 900mg/day and higher only with 1200mg/day: 58%, 55%, 56% and 72%, respectively. However, an apparent dose relationship was observed for dizziness, confusional state, tremor, abnormal coordination, memory impairment, aphasia, dysarthria and constipation during maintenance. TEAEs that were dose-related in the overall analysis (titration maintenance) but not during maintenance alone were somnolence, blurred vision, speech disorder, gait disturbance and balance disorder. Urinary tract infection was the only TEAE observed at a greater incidence during maintenance than titration in all RTG doses combined (3% and 2%, respectively). Conclusions: In this integrated analysis of 3 pivotal controlled trials, RTG 600-1200mg/day was generally tolerated. Fewer new TEAEs associated with RTG occurred during maintenance than forced-titration. Funded by Valeant Pharmaceuticals International and GlaxoSmithKline.