Randomized Controlled Trial to Assess 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.

2.0 STUDY OBJECTIVES Primary Objective To determine the effect of LCM on wakefulness in adults with focal epilepsy by comparing the change between Visit 4 and baseline in the ESS in subjects randomized to LCM versus placebo.

Secondary Objectives

1. To determine the effect of LCM on wakefulness in adults with focal epilepsy by comparing the change between Visit 4 and baseline in MSL of the Maintenance of Wakefulness Test (MWT) in subjects randomized to LCM versus placebo.
2. To determine the impact of LCM on sleep using ambulatory polysomnography (PSG) by comparing sleep efficiency (SE; total sleep time/total recording time) between Visit 4 and baseline in subjects randomized to LCM versus placebo.
3. To compare change in fatigue using the Fatigue Severity Scale (FSS) between Visit 4 and baseline in subjects randomized to LCM versus placebo.
4. To compare change in health- and sleep-related QOL between Visit 4 and baseline in subjects randomized to LCM versus placebo.

3.0 STUDY DESIGN This is a Phase IV, randomized, single center trial of LCM in adult subjects with focal epilepsy. Subjects who meet the inclusion criteria and are taking stable doses of 1 or 2 marketed AEDs for at least 4 weeks will be randomized in a double-blind, 4:1 scheme to LCM 400 mg/day or placebo, respectively. At the end of the Treatment Phase, subjects will have the option to enter an Extension Phase whereby they will receive LCM titrated to 400 mg/day.

4.0 STUDY DRUG Subjects will be randomized to LCM or identically packaged placebo. A 1-step, back-titration of LCM 100 mg/day or placebo will be allowed in the case of an intolerable adverse event (AE) at the end of the Treatment Phase.

A blocked randomization scheme will be developed and used to allocate subjects to active treatment or placebo in a 4:1 ratio. Blocks will be of random size, not to exceed 10, and will ensure appropriate balance of treatment groups at the midpoint of enrollment and study completion.

5.0 STUDY PROCEDURES

5.1 Study Assessments

5.1.1 Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA/SDQ) As part of the screening process, subjects will complete the SA/SDQ, a validated instrument that assesses the likelihood of having obstructive sleep apnea (OSA) based on variables including loud snoring, age, body mass index, tobacco use, and hypertension. In the original validation, cutoffs of 32 or higher for women and 36 or higher for men correlated well with having a diagnosis of OSA by PSG.

The following procedures (subjective assessments, blood sampling and sleep testing will be performed at baseline (Visit 2- 2 week window) and at Visits 3 (LCM 200 mg/day) and 4 (400 mg/day) at least 11 days but no longer than 21 days after the prior visit (at least 11 days after the previous dose adjustment so as to ensure a steady state).

5.1.2 Ambulatory PSG Overnight ambulatory PSG will be performed using the Sapphire PSG ™, Cleveland Medical Devices, Inc. The system records electroencephalography (EEG; F3/4, C3/4, O1/2), electro-oculography (EOG; E1, E2), chin electromyography (EMG; 3 channels), leg EMG (4 channels), thermister and pressure transducer, respiratory effort (RIP), snore, EKG, pulse oximetry, and body position. Remote PSG monitoring with video will be performed using DreamPort™, Cleveland Medical Devices, Inc.

5.1.3 Maintenance of Wakefulness Test (MWT) The MWT is a modification of the more popular MSLT, the gold standard objective measurement of daytime sleepiness. The MSLT is intended to measure physiological sleep tendency under standardized conditions. It is based on the premise that the degree of sleepiness is reflected by sleep latency. The MWT is intended to measure one's ability to maintain wakefulness under standardized, relatively sedentary conditions.

5.1.4 Subjective Sleep Assessments Epworth Sleepiness Scale (ESS): The ESS is a self-administered eight-item questionnaire that measures a subject's subjective daytime sleep propensity. Subjects are asked how likely they are to doze off or fall asleep in 8 specific situations such as watching television or riding a car (never, slight, moderate, high: 0-3), with total scores ranging from 0-24. It has high test-retest reliability and a high level of internal consistency. An ESS score greater than 10 is considered indicative of EDS.

Self-reported EDS is categorized as a response of Yes or No to the question: Have you been feeling excessively sleepy at least a few days per week over the last 2 weeks?

Fatigue Severity Scale (FSS): The FSS is a validated method for assessing fatigue. It is comprised of 9 items that are rated according to a Likert-type scale from 1 to 7, where 1 indicates no impairment and 7 indicates severe impairment. Responses to individual items are tallied to produce a total score.

5.1.5 Seizure and Sleep Log Subjects will record sleep and wake times and quantify and characterize seizures in logs developed for the trial. Mean daily seizure frequency, excluding auras, between Baseline and Visit 4 will be calculated.

5.1.6 Adverse Events Assessments Adverse Event Profile (AEP): The AEP is an epilepsy-specific, 19-item questionnaire designed to monitor the frequency of common AEs associated with AEDs. Subjects rate the frequency of problems or side effects on a scale from 1 (Never) to 4 (Always or often).

Patient Health Questionnaire (PHQ-9): The PHQ-9 is a 9-item depression scale based on the diagnostic criteria for major depressive disorders in the Diagnostic and Statistical Manual Fourth Edition (DSM-IV). It is used in the diagnosis of depression and monitoring of treatments impacting on depression. A score of 10 and higher is indicative of moderate to severe depression. The PHQ-9 discriminates well between individuals with and without depressive disorders.

5.1.7 Quality of Life Assessments Quality of Life in Epilepsy (QOLIE-31): The QOLIE-31 is a 31-item survey of health-related quality of life for adults with epilepsy. The survey is derived from a longer, 89-item instrument.

Pittsburgh Sleep Quality Inventory (PSQI): The PSQI is a self-rating questionnaire for measuring subjective sleep quality. A global score is produced that represents the sum of seven component scores, each which addresses a specific aspect of subjective sleep quality.

Functional Outcomes of Sleep Questionnaire (FOSQ): The FOSQ is a self-administered 30-item questionnaire that offers a measurement of functional status as it relates to the impact of daytime sleepiness on daily activities. It measures the effect on activity level, vigilance, intimacy and sexual relationships, general productivity and social outcome.

5.2 Subjects will have 5 or 6 visits Visit 1 (Baseline Phase - 2 weeks) Visit 2 (Randomization, Start of Treatment Phase - at least 2 weeks after Visit 1 not to exceed 8 weeks) Visit 3 (Treatment Phase, LCM 200 mg/day - 11 -21 days after Visit 2) Visit 4 (Treatment Phase, LCM 400 mg/day - 11-21 days after Visit 3)

At the completion of all study procedures, subjects will be offered the option of entering a 4-week Extension Phase or a 2-week Taper Phase. In the Extension Phase, the investigators and subjects will remain blinded to the initial group assignment but all subjects will be treated with LCM. Subjects in the LCM arm will continue on 400 mg/day. Those in the placebo arm will undergo a 4-week titration schedule. All subjects will continue to maintain a seizure and sleep diary.

Subjects who decline participation in the Extension Phase will undergo a 2-week Taper Phase whereby LCM will be tapered by 200 mg/day per week.

Visit 5 (Final Visit for Nonextenders, beginning of Extension Phase - 0-21 days after Visit 4) For subjects opting to enter the Extension Phase, subjective assessments only will be performed at least 4 days after initiation of LCM 200mg/day to ensure testing is completed after achieving a steady state.

Visit 6 (Extension Phase Final Visit - 26- 42 days after Visit 5)