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)

Inclusion Criteria:

Subjects must meet the following inclusion criteria to be eligible for the study.

- Subject can provide written informed consent and is willing to comply with study
procedures.

- Subject is at least 18 years of age.

- Subject has focal epilepsy with classifiable seizures according to the International
Classification of Epileptic Seizures, 1981.11

- Subject is deemed to be an appropriate candidate for LCM adjunctive therapy.

- Subject has been maintained on a stable dose of 1 or 2 marketed AEDs for at least 4
weeks.

Exclusion Criteria:

Subjects must meet the following exclusion criteria to be eligible for the study.

- Subject has a history of a moderate or severe sleep apnea (apnea-hypopnea index [AHI]
> 15), severe insomnia (habitual sleep duration < 4 hours) or narcolepsy.

- Subject has a score on the Sleep Apnea Scale of the Sleep Disorders Questionnaire
(SA/SDQ) at screening of 32 or higher (female) and 36 or higher (male).

- Subject is currently participating or has participated within the last 2 months in a
trial of an investigational drug or experimental device.

- Subject has seizures or seizures clusters that are not quantifiable.

- Subject has 6 or more seizures (excluding auras) in the 2-week Baseline Phase.

- Subject has a medical condition that could reasonably be expected to interfere with
drug absorption, distribution, metabolism or excretion.

- Subject has any medical or psychiatric condition, which in the opinion of the
investigator, could jeopardize the subject's health or would compromise the - Subject
has a history of alcohol or drug abuse within the previous 2 years.

- Subject has an acute or sub-acutely progressive central nervous system disease.

- Subject is pregnant, breastfeeding or of childbearing age and not surgically sterile
or practicing an acceptable form of contraception (barrier contraception, surgically
sterilized, IUD, abstinence) for the duration of the trial.