Searching for "Sleep Friendly" Therapies for a Sleepy Population: A Double-Blind, Placebo-Controlled, Randomized Trial to Assess the Effects of Lacosamide on Sleep and Wake in Adults With Focal Epilepsy

1.1. Background Epilepsy is a common disorder affecting approximately 1% of the population including nearly 2 million people in the United States. Excessive daytime sleepiness (EDS) is the most common complaint of people with epilepsy, reported in as many 50% of cases. EDS has long been attributed to the effects of antiepileptic drugs (AEDs) and seizures, but this assumption has not been adequately tested. In recent years, primary sleep disorders, such as sleep apnea, have been identified as potential contributors. A recent questionnaire-based study of 486 adults with epilepsy found a 2-fold higher prevalence of sleep disturbances in patients compared with age- matched controls (39% vs.18%). The presence of a sleep disturbance adversely affects quality of life (QOL) in people with epilepsy.

Despite the frequency of EDS in people with epilepsy, surprisingly few have attempted to measure this complaint objectively. In a study presented at the 2007 Annual Meeting of the American Academy of Sleep Medicine (AASM) by the investigators of this proposal, the prevalence of EDS among 92 epilepsy patients was assessed using three measures: self-reported EDS, the Epworth Sleepiness Scale (ESS), a subjective screening tool used in sleep clinics, and the multiple sleep latency test (MSLT), the gold standard objective measurement of daytime sleepiness. Seventy-two percent of subjects endorsed EDS (feeling excessively sleepy at least a few days per week over the last 6 months), 37% had abnormal ESS scores (> 10), and 62% had abnormal MSLTs (mean sleep latency [MSL] < 8 min). The MSL was less than 5 minutes, comparable to that of patients with narcolepsy, in 36% of cases. The correlation between self-reported EDS and the MSL was poor. However, as found in previous studies in sleep populations, a better correlation between the ESS and MSL was found. Among larger epilepsy series using the ESS, 11-28% of patients had scores greater than 10, suggesting the presence of EDS.

Excessive daytime sleepiness is a negative predictor of QOL in sleep disorders patients and is likely the most important, overlooked complaint of people with epilepsy. To date, no well-designed trials have explored the impact of specific AED therapy on wakefulness, although the sedating effects of most of the currently available agents have been demonstrated through small series and clinical experience. The current study is proposed to objectively measure the effects of lacosamide (LCM) on sleep and wakefulness in adult patients with focal epilepsy.

1.2. Investigational Agent Lacosamide ([R]-2-acetamido-N-benzyl-3-methoxypropionamide) belongs to a novel class of functionalized amino acids. It has been shown in animal models to have antiepileptic properties possibly by two distinct and novel mechanisms of action. Like many other AEDs, LCM has an effect on voltage-gated sodium channels. But unlike other AEDs, LCM enhances the slow inactivation of these channels. LCM also interacts with collapsin-response mediator protein-2 (CRMP-2) which may represent other novel mechanism, not previously recognized in AED development.

Lacosamide 200-400 mg/day is approved in the US and in Europe in oral and IV formulations as adjunctive therapy in adults with focal seizures.