Abstracts

Rationale: Lacosamide is a recently-approved antiepileptic drug (AED) for the adjunctive treatment of partial-onset seizures in adults and is available in oral and IV formulations. Based on results of preclinical testing, the efficacy and safety of oral lacosamide monotherapy for nonepilepsy indications of migraine prophylaxis (Trial SP906; NCT00440518), fibromyalgia (Trial SP887; NCT00401830), and osteoarthritis (Trial SP905; NCT00485472) were evaluated in three randomized, placebo-controlled, proof-of-concept trials. Lacosamide doses of 100, 300, and 400 mg/day were evaluated depending on indication. Though efficacy assessments did not show significant differences for the primary variable using the study designs chosen, safety assessments from the individual trials provide a placebo-controlled evaluation of the safety profile of lacosamide AED monotherapy up to 17 weeks. Methods: After a baseline phase of up to 6 weeks depending on indication, subjects were randomized to placebo or lacosamide in 2 equally divided doses. Subjects were titrated to their target dose in weekly increments of 100 mg/day, then maintained at that dose for 8 weeks (fibromyalgia and osteoarthritis) or 14 weeks (migraine), followed by taper and discontinuation of trial medication. Safety and tolerability were evaluated by adverse event (AE), clinical laboratory, ECG, and vital signs (including body weight) data. Results: A total of 525 subjects were randomized and received treatment (migraine: n=72 placebo, n=72 lacosamide 100 mg/day, n=74 lacosamide 300 mg/day; fibromyalgia: n=81 placebo; n=78 lacosamide 400 mg/day; osteoarthritis n=76 placebo; n=72 lacosamide 400 mg/day). There was a similar gender distribution across all indications, with a higher percentage of females (85%) enrolled than males. The osteoarthritis trials had the largest number of subjects ?65 years of age (~40% placebo; ~45% lacosamide). More subjects in the lacosamide 400 mg/day groups for fibromyalgia (6.4%) and osteoarthritis (11.0%) withdrew due to an AE than in the respective placebo groups (2.5%) and (6.6%). Fewer subjects in the lacosamide 300 mg/day group for migraine (2.7%) withdrew due to an AE than in the placebo group (6.9%) or the lacosamide 100 mg/day group (9.7%). The most common AE leading to lacosamide discontinuation was vertigo (4.2%) for osteoarthritis, dizziness and headache (3.8% each) for fibromyalgia, and chest pain (2.8 %) for migraine (100 mg/day). The most common AE leading to discontinuation in a placebo group was nausea (2.8%) in the migraine trial. No clinically relevant influence of lacosamide on laboratory values (including cholesterol and triglycerides) or vital signs was observed. Lacosamide was associated with a small increase in mean PR interval. Lacosamide had no effect on heart rate or QRS duration and did not prolong QT/QTc interval. Conclusions: Safety data from randomized, placebo-controlled trials for migraine prophylaxis, fibromyalgia, and osteoarthritis demonstrated that lacosamide as AED monotherapy for up to 17 weeks was well-tolerated in these predominately female populations.