Abstracts

Rationale: Retigabine (RTG) is the first AED to reduce neuronal hyperexcitability by directly activating (opening) neuronal KCNQ channels to enhance M-current. A phase 2 dose-ranging study demonstrated that RTG is effective as adjunctive therapy in adults with partial-onset seizures, identifying 600-1200 mg/day as a potential therapeutic dosage range. This Phase 3 study (RESTORE 1) was to confirm the efficacy and safety of RTG 1200 mg/day as adjunctive therapy in adults with refractory partial-onset seizures. Methods: Multicenter, randomized, double-blind, placebo-controlled trial in adults (18-75 yrs old) with ≥4 partial-onset seizures/month despite 1-3 AEDs, with or without VNS, during an 8-wk prospective baseline. RTG administered t.i.d. as immediate-release tablets was force-titrated to 1200 mg/day over a 6-wk titration period. The only study drug reduction allowed was at the start of the maintenance phase (minimum, RTG 1050 mg/day). Study drug and concomitant AED dosages remained stable for 12-wk maintenance phase. Results: Intent-to-treat population comprised 301 (RTG, n=151; placebo, n=150) patients; 256 patients (RTG, 119; placebo, 137) entered maintenance phase. Baseline characteristics: females, 54%; age (mean), 27 yrs; epilepsy duration (mean), 23 yrs; ≥2 background AEDs, 82%; previous AED failures (median), 3; previous VNS use, 11%. Most common AEDs at baseline: CBZ/OXC, 54%; LTG, 34%; PHT, 22%; LEV, 21%; VPA, 19%; TPM, 18%. Among patients entering maintenance phase, 8% of RTG-treated patients vs. 2% of placebo patients were seizure-free during maintenance (p<0.03). Adverse events (AEs) as cause for study discontinuation: RTG, 27%; placebo, 9%, with most discontinuations occurring during forced titration. Most common treatment-limiting AEs: dizziness (RTG, 8%; placebo, 2%; confusion (6%, 1%); fatigue (3%, 0). AEs were generally mild-to-moderate severity. Most common AEs (>10% incidence in RTG group and substantially higher than placebo): dizziness, somnolence, fatigue, confusion, dysarthria, ataxia, tremor, blurred vision, and nausea. Conclusions: RTG 1200 mg is effective and generally well-tolerated in adults with refractory partial-onset seizures, confirming findings from a Phase 2 dose-ranging study. These results validate the therapeutic usefulness of neuron-specific potassium (KCNQ/M-current) channel openers. Funded by Valeant Pharmaceuticals International.