Abstracts

Rationale: Excessive daytime sleepiness (EDS) is one of the most common complaints in epilepsy and a negative predictor of quality of life (QOL), typically attributed to seizures and AEDs. We performed a Phase IV randomized single-center clinical trial to investigate the effect of lacosamide (LCM) on daytime sleepiness using the Epworth Sleepiness Scale (ESS) and other patient- reported outcomes (PROs) in adults with focal epilepsy.Methods: Subjects >18 yrs with focal epilepsy on 1 or 2 marketed AEDs for at least 4 weeks were eligible. Subjects with sleep apnea, narcolepsy, habitual sleep duration <4 hrs, and unquantifiable seizures were excluded. A randomized double-blind clinical trial was conducted comparing LCM 400 mg/day versus placebo (4:1 schema) with the former titrated over 4 weeks beginning with 50 mg bid and increasing weekly to a target dose of 200 mg bid. The primary endpoint was change in ESS from baseline (Visit 1; V1) to 4 weeks (Visit 4; V4). Subjects underwent overnight ambulatory EEG/Polysomnography and Maintenance of Wakefulness tests and completed the ESS, Adverse Event Profile (AEP), Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Inventory (PSQI), Functional Outcomes in Sleep Questionnaire (FOSQ), Patient Health Questionnaire (PHQ-9) and Quality of Life in Epilepsy (QOLIE-31) at baseline, LCM 200 mg/day (Visit 2) and LCM 400 mg/day (V4). Within each group, change from baseline to V4 was tested by paired t-test. The non-inferiority test on ESS was performed by one-sided t-test based on the hypothesis that the difference in change between groups (LCM minus placebo) was no more than 4 points. Superiority test used two-sided t-test to investigate whether there was difference in change in the ESS and other PROs between groups. 55 subjects provided 80% power to show non-inferiority of LCM to placebo assuming a drop-out rate of 10%.Results: 52 subjects (mean age 43.5±13.2 yr, 69.2% female, monthly seizure frequency 5.7±8.5, AED standardized dose 1.9±1.1) were included. LCM and placebo groups were similar at baseline in age, gender, ethnicity, AED standardized dose, monthly seizure frequency, ESS (9.3±5.8 vs. 6.8±4.8, p=0.24), AEP, FSS and PSQI. The non-inferiority test (see figure) found a no more than 4 point increase in ESS change (mean [95%CI]) between LCM and placebo groups (-1.2 [-2.9, 0.53] vs. -1.1 [-5.2, 3.0], p=0.027). No significant difference in change in ESS, FSS, FOSQ, PHQ-9, PSQI, AEP, QOLIE-31 or AED standardized dose was observed between groups (superiority test, see table). However, the change in global PSQI was significant (-1.6 [-2.9, 0.00]) in LCM subjects representing an improvement in sleep quality and daytime functioning at V4 relative to baseline.Conclusions: Compared to placebo, LCM was not associated with increased daytime sleepiness as measured by the ESS. This work suggests the lack of adverse impact of LCM on subjective sleep and wakefulness in adults with epilepsy. Analyses incorporating objective measurements are underway. This work is an investigator-initiated study supported by UCB.