Abstracts

Rationale: Retigabine (RTG) is the first AED to reduce neuronal hyperexcitability by directly activating (opening) neuronal KCNQ channels to enhance M-current. This study (RESTORE 2/Study 302) determined the efficacy and safety of RTG 600 or 900 mg/day as adjunctive therapy in adults with refractory partial-onset seizures. Methods: Multicenter, randomized, double-blind, placebo-controlled Phase 3 trial in adults (18-75 yrs old) with ≥4 partial-onset seizures/mo despite 1-3 AEDs, with/without VNS, during prospective baseline. RTG administered t.i.d. as immediate-release tablets was force-titrated to 600 mg/day (achieved in 2 wks) or 900 mg/day (4 wks), without downward dosage adjustments, and continued during 12-wk maintenance phase. Results: Intent-to-treat population comprised 538 patients (placebo, n=179; RTG 600, n=181; RTG 900, n=178); 471 (88%) patients (placebo, n=164; RTG 600, n=158; RTG 900, n=149) entered maintenance phase. Baseline demographics: age (mean), 38yrs; female, 52%; epilepsy duration, 23 yrs; >2 background AEDs, 77%. Discontinuations due to adverse events: placebo, 8%; RTG 600, 14%; RTG 900, 26%, occurring mostly during forced titration Most common (>10%) adverse events in RTG-treated patients: dizziness (placebo, 6%; RTG 600, 17%; RTG 900, 26%); somnolence (10%, 14%, 26%); headache (14%, 11%, 17%); and fatigue (3%, 17%, 15%). Conclusions: RTG 600 and RTG 900 mg/day were effective and generally well-tolerated as adjunctive therapy in adults with partial-onset seizures. Seizures were significantly reduced during titration, suggesting early onset of therapeutic effect. Study results further validated the therapeutic usefulness of neuron-specific potassium (KCNQ/M-current) channel openers and complemented findings from a Phase 2 dose-ranging trial and Phase 3 trial with RTG 1200 mg/day. Funded by Valeant Pharmaceuticals International