Epilepsia, 48(7):1308–1317, 2007 Blackwell Publishing, Inc. C  2007 International League Against Epilepsy Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures ∗ Elinor Ben-Menachem, †Victor Biton, ‡Dalius Jatuzis, §Bassel Abou-Khalil, ¶Pamela Doty, and ¶G. David Rudd ∗ Sahlgrenska Academy at G¨ oteborg University, G¨ oteborg, Sweden, †Arkansas Epilepsy Program, Little Rock, Arkansas, U.S.A., ‡Vilnius University Hospital, Vilnius, Lithuania, §Vanderbilt University, Nashville, Tennessee, U.S.A., and ¶ SCHWARZ BIOSCIENCES, Inc., Research Triangle Park, North Carolina, U.S.A. Summary: Purpose: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. Methods: During this multicenter, double-blind, placebo- controlled trial, patients were randomized to placebo or la- cosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. Results: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The me- dian percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The me- dian percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p = 0.0023) and 600 mg/day (p = 0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p = 0.0038) and 600 mg/day (p = 0.0141). Adverse events that appeared dose- related included dizziness, nausea, fatigue, ataxia, vision ab- normal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. Conclusions: In this trial, adjunctive lacosamide signifi- cantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further develop- ment of lacosamide as an AED. Key Words: Epilepsy— Partial-onset seizures—Lacosamide—Antiepileptic drugs— Randomized controlled trials. Lacosamide (SPM 927, formerly harkoseride), the R-enantiomer of 2-acetamido-N-benzyl-3-methoxypro- pionamide, is a new chemical entity being developed as an oral formulation (Bialer et al., 2004) for the treatment of epilepsy and neuropathic pain. In addition, an intravenous formulation is being developed for short-term replacement of oral lacosamide in patients with partial-onset seizures. Based on recent experimental studies, lacosamide ap- pears to have a dual mode of action—enhancement of sodium-channel slow inactivation and modulation of col- lapsin response mediator protein-2 (CRMP-2) (Stoehr et al., 2006)—both of which are novel mechanisms for an antiepileptic drug (AED). Without affecting fast inactiva- tion, lacosamide appears to selectively enhance sodium- Accepted April 23, 2007 Address correspondence and reprint requests to Elinor Ben- Menachem, Institute of Clinical Neurosciences, Division of Neurol- ogy, Sahlgrenska Academy at G¨ oteborg University, G¨ oteborg 413 45, Sweden. E-mail: elinor.ben-menachem@neuro.gu.se doi: 10.1111/j.1528-1167.2007.01188.x channel slow inactivation, which may help normalize ac- tivation thresholds and decrease pathophysiological neu- ronal activity, thus controlling neuronal hyperexcitabil- ity (Errington et al., 2006). Because CRMP-2 is part of the signal transduction cascade of neurotrophic factors and can convey neuroprotective effects, the ability of la- cosamide to modulate CRMP-2 may contribute to the de- creased neuronal loss observed in status epilepticus animal models and its potential antiepileptogenic effects as seen in animal models (Brandt et al., 2006, Beyreuther et al., 2007). Preclinical studies have demonstrated that lacosamide protects against seizures in various anticonvulsant ani- mal models (Bialer et al., 2002). In animal studies of lacosamide, there was no evidence of teratogenicity or adverse effects on male or female reproductive func- tion (Krebsfaenger, unpublished data). Studies in healthy adult volunteers have shown that oral lacosamide is rapidly and almost completely absorbed from the gas- trointestinal tract and has a high oral bioavailability 1308