Clinical trial NCT01832038
Conditions: Epilepsy Partial-onset Seizures
Keywords: Lacosamide Epilepsy Partial-onset Seizures
Sponsor: UCB Pharma SA
Start date: 2013-03-26; Completion date: 2019-07-31
Enrollment: 473 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this trial is to evaluate the safety and tolerability of long-term administration of Lacosamide at doses up to 400 mg/day in Japanese and Chinese adults with Epilepsy who have completed the Treatment and Transition Period of EP0008 \[NCT01710657\]

Detailed description:

Arms: arm 1: Lacosamide treatment of 100 - 400 mg/day for long-term
Interventions: intervention 1: Lacosamide
Intervention descriptions: intervention 1: Strength: Lacosamide (LCM) 50 mg, LCM 100 mg

Formulation: Tablet

Frequency: twice daily during the study period (until the date of approval)

At the completion of EP0008 \[NCT01710657\], all subjects who choose to enroll in EP0009 will be taking a dose of Lacosamide 200 mg/day. At the beginning of EP0009, the investigator may maintain the LCM dose or increase or decrease the dose. During the Treatment Period, the investigator will be allowed to increase or decrease the dose of LCM to optimize tolerability and seizure reduction. The LCM dose may be decreased to 100 mg/day or increased, no faster than 100 mg/day per week, up to 400 mg/day.

Protocol documents:
Prot_000.pdf: 
UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 1 of 70
PROTOCOL EP0009 AMENDMENT 2
A MULTICENTER, OPEN-LABEL, UNCONTROLLED,      
LONG-TERM, EXTENSION STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF LACOSAMIDE AS 
ADJUNCTIVE THERAPY IN JAPANESE AND CHINESE 
ADULTS WITH PARTIAL-ONSET SEIZURES WITH OR 
WITHOUT SECONDARY GENERALIZATION
PHASE 3
Sponsor:
UCB Pharma SA
Allée de la Recherche 60
B-1070 Brussels
BELGIUM
UCB Japan Co. Ltd.
Shinjuku Grand Tower 
8-17-1 Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023
JAPAN
Protocol/Amendment number
Date
Type of 
amendment
Final Protocol
06 Mar 2012
Not applicable
Protocol Amendment 1
12 Sep 2012
Nonsubstantial
Protocol Amendment 2
13 Mar 2013
Nonsubstantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed 
on, reproduced, published, or otherwise used without the express permission of 
UCB.
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 2 of 70
SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 3 of 70
STUDY CONTACT INFORMATION
Sponsor
UCB Pharma SA
Allée de la Recherche 60
B-1070 Brussels
BELGIUM
UCB Japan Co. Ltd.
Shinjuku Grand Tower 
8-17-1 Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023
JAPAN
Local Regulatory Representative of UCB Pharma SA
Name:
UCB Trading (Shanghai) Co. Ltd., Beijing Liaison Office
Address:
Suite 806, No. 4 Tower, 38 East 3rd Ring North Rd., 
Chaoyang District, Beijing, 100026, PRC
Phone:
+86 10 8587 9231
Fax:
+86 10 8587 9239
National Principal Investigator (China)
Name:
, MD
Address:
Huashan Hospital Fudan University
No.12 Middle Urumqi Road, Shanghai, 200040, PRC
Phone:
Fax:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 4 of 70
Medical Expert (Japan)
Name:
 MD, PhD
Address:
National Epilepsy Center Shizuoka Institute of Epilepsy and 
Neurological Disorders
886 Urushiyama, Aoi-Ku, Shizuoka-Shi, Shizuoka 420-8688, 
JAPAN
Phone:
Fax:
Sponsor Study Physician
Name:
 MD
Address:
UCB Trading (Shanghai) Co. Ltd., Shanghai office 
Suite 3905, Raffles City Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001, PRC
Phone:
Fax:
Clinical Project Manager 
Name:
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Associate Clinical Project Manager (China)
Name:
Address:
UCB Trading (Shanghai) Co. Ltd., Shanghai office
Suite 3905, Raffles City Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001, PRC
Phone:
Fax:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 5 of 70
Associate Clinical Project Manager (Japan)
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Clinical Monitoring Contract Research Organization (China)
Name:
PAREXEL China Co., Ltd.
Address:
Taiping Finance Tower, No. 488, Middle Yincheng Rd., 
Pudong, Shanghai, 200120, PRC
Phone:
+86 21 5111 8000
Fax:
+86 21 6160 9196
Clinical Monitoring Contract Research Organization (Japan)
Name:
PAREXEL International Inc.
Address:
Kayaba-Cho First Building 1-17-21, Shinkawa, Chuo-Ku, 
Tokyo, 104-0033, JAPAN
Phone:
+81 3 3537 5512
Fax:
+81 3 3552 0451
Other study contact information will be provided in separate documents.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 6 of 70
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
UCB Japan: +81 3 6864 7400
Email
UCB Japan: UCBJ-Safety@ucb.com
Safety related issues
Phone
PAREXEL International Inc. : +1 978 805 7613
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 7 of 70
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................11
1
SUMMARY.....................................................................................................................13
2
INTRODUCTION ...........................................................................................................13
3
STUDY OBJECTIVE(S).................................................................................................15
3.1
Primary objectives .................................................................................................15
3.2
Secondary objective...............................................................................................15
4
STUDY VARIABLES.....................................................................................................16
4.1
Safety variables......................................................................................................16
4.1.1
Primary safety variables...............................................................................16
4.1.2
Other safety variables ..................................................................................16
4.2
Efficacy variables...................................................................................................16
4.2.1
Primary efficacy variables ...........................................................................16
4.2.2
Secondary efficacy variables .......................................................................16
4.2.3
Other efficacy variables...............................................................................16
5
STUDY DESIGN.............................................................................................................17
5.1
Study description ...................................................................................................17
5.1.1
Study duration per subject ...........................................................................18
5.1.2
Dates of the planned study duration ............................................................18
5.1.3
Planned number of subjects.........................................................................18
5.1.4
Anticipated regions and countries................................................................18
5.2
Schedule of study assessments...............................................................................18
5.3
Schematic diagram.................................................................................................22
5.4
Rationale for study design and selection of dose...................................................24
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................24
6.1
Inclusion criteria ....................................................................................................24
6.2
Exclusion criteria ...................................................................................................24
6.3
Withdrawal criteria ................................................................................................24
7
STUDY TREATMENT(S) ..............................................................................................26
7.1
Description of investigational medicinal product..................................................26
7.2
Treatments to be administered...............................................................................26
7.3
Packaging...............................................................................................................26
7.4
Labeling .................................................................................................................27
7.5
Handling and storage requirements .......................................................................27
7.6
Drug accountability................................................................................................27
7.7
Procedures for monitoring subject compliance......................................................27
7.8
Concomitant medications/treatments.....................................................................28
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 8 of 70
7.8.1
Permitted concomitant AED(s)....................................................................28
7.8.2
Prohibited concomitant treatments (medications and therapies) .................28
7.8.3
Rescue medication.......................................................................................29
7.9
Blinding..................................................................................................................29
7.10
Randomization and numbering of subjects............................................................29
7.11
Allowance for entering an additional study (EP0024)...........................................29
8
STUDY PROCEDURES BY VISIT ...............................................................................29
8.1
Treatment Period....................................................................................................30
8.1.1
Visit 1 (Week 0)...........................................................................................30
8.1.2
Visits 2 through 4 (Weeks 4 through 12).....................................................31
8.1.3
From Visit 5 until End-of-Study/Withdrawal Visit (Week 24 or later).......31
8.1.4
End-of-Study Visit.......................................................................................32
8.1.5
Withdrawal Visit..........................................................................................33
8.2
Taper Period...........................................................................................................33
8.2.1
Final Visit (2 weeks after final LCM dose) .................................................33
8.3
Unscheduled Visit..................................................................................................34
9
ASSESSMENT OF SAFETY..........................................................................................35
9.1
Adverse events.......................................................................................................35
9.1.1
Definition of adverse event..........................................................................35
9.1.2
Procedures for reporting and recording adverse events...............................35
9.1.3
Description of adverse events......................................................................35
9.1.4
Follow up of adverse events ........................................................................35
9.1.5
Rule for repetition of an adverse event........................................................36
9.1.6
Pregnancy.....................................................................................................36
9.1.7
Overdose of investigational medicinal product ...........................................36
9.1.8
Safety signal detection.................................................................................37
9.2
Serious adverse events...........................................................................................37
9.2.1
Definition of serious adverse event .............................................................37
9.2.2
Procedures for reporting serious adverse events..........................................38
9.2.3
Follow up of serious adverse events............................................................38
9.3
Adverse events of special interest..........................................................................38
9.4
Immediate reporting of adverse events..................................................................39
9.5
Anticipated serious adverse events........................................................................39
9.6
Other safety assessments........................................................................................40
9.6.1
Assessment of suicidality.............................................................................40
9.6.2
Laboratory measurements............................................................................40
9.6.3
Liver function tests ......................................................................................41
9.6.4
Pregnancy testing.........................................................................................42
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 9 of 70
9.6.5
Vital signs and body weight.........................................................................42
9.6.6
Complete physical examination...................................................................42
9.6.7
Brief neurological examination ...................................................................42
9.6.8
12-lead ECG ................................................................................................42
9.6.8.1
Overall ECG interpretation................................................................42
9.6.8.2
Central ECG laboratory .....................................................................43
10
ASSESSMENT OF EFFICACY......................................................................................43
10.1
Methods for assessing efficacy variables...............................................................43
11
STUDY MANAGEMENT AND ADMINISTRATION.................................................44
11.1
Adherence to protocol............................................................................................44
11.2
Monitoring .............................................................................................................44
11.2.1
Definition of source data..............................................................................44
11.2.2
Source data verification ...............................................................................45
11.3
Data handling.........................................................................................................45
11.3.1
Case Report form completion......................................................................45
11.3.2
Database entry and reconciliation................................................................45
11.3.3
Subject Screening and Enrollment log/Subject Identification Code list......45
11.4
Termination of the study........................................................................................45
11.5
Archiving and data retention..................................................................................46
11.6
Audit and inspection ..............................................................................................46
11.7
Good Clinical Practice...........................................................................................46
12
STATISTICS ...................................................................................................................46
12.1
Definition of analysis sets......................................................................................46
12.2
General statistical considerations...........................................................................47
12.3
Planned safety analyses..........................................................................................47
12.3.1
Analysis of the primary safety variable .......................................................47
12.3.2
Other safety analyses ...................................................................................47
12.4
Planned efficacy analyses ......................................................................................47
12.4.1
Analysis of primary efficacy variables ........................................................47
12.4.2
Analysis of secondary efficacy variables.....................................................47
12.4.3
Other efficacy analyses................................................................................48
12.5
Handling of protocol deviations.............................................................................48
12.6
Handling of dropouts or missing data....................................................................48
12.7
Planned interim analysis and data monitoring.......................................................48
12.8
Determination of sample size.................................................................................48
13
ETHICS AND REGULATORY REQUIREMENTS......................................................49
13.1
Informed consent ...................................................................................................49
13.2
Subject identification cards....................................................................................49
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 10 of 70
13.3
Institutional Review Boards and Independent Ethics Committees........................49
13.4
Subject privacy.......................................................................................................50
13.5
Protocol amendments.............................................................................................50
14
FINANCE, INSURANCE, AND PUBLICATION.........................................................50
14.1
Insurance................................................................................................................51
14.2
Publication .............................................................................................................51
15
REFERENCES ................................................................................................................52
16
APPENDICES .................................................................................................................53
16.1
International Classification of Epileptic Seizures (1981)......................................53
16.2
International Classification of Epilepsies and Epileptic Syndromes (1989) .........56
16.3
Protocol Amendment 1 ..........................................................................................58
16.4
Protocol Amendment 2 ..........................................................................................68
17
DECLARATION AND SIGNATURE OF INVESTIGATOR .......................................70
LIST OF TABLES
Table 5-1
Schedule of study assessments .............................................................................19
Table 7-1
Recommended LCM dose reduction (Taper Period)............................................26
Table 9-1
Anticipated SAEs for the adult epileptic population............................................40
Table 9-2
Laboratory measurements.....................................................................................41
LIST OF FIGURES
Figure 5‒1: Schematic diagram................................................................................................23
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 11 of 70
LIST OF ABBREVIATIONS
AE(s)
adverse event(s)
AED(s)
antiepileptic drug(s)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
CDMS
clinical data management system
CPM
Clinical Project Manager
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
Electronic Case Report form
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IVRS
interactive voice response system
IWRS
interactive web response system
LCM
lacosamide
LFT
liver function test
MedDRA®
Medical Dictionary for Regulatory Activities
PCH
the percent change in seizure frequency per 28 days
PK
pharmacokinetics
PRC
People’s Republic of China
SAE
serious adverse event
SD
standard deviation
SOP(s)
Standard Operating Procedure(s)
SS
Safety Set
TEAE(s)
treatment-emergent adverse event(s)
ULN
upper limit of normal
VNS
vagus nerve stimulation
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 12 of 70
WHO
World Health Organization
REDACTED COPY 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 13 of 70
1
SUMMARY
EP0009 is a Phase 3, multicenter, open-label, uncontrolled, extension study designed to 
evaluate the safety, tolerability, and efficacy of long-term administration of lacosamide 
(LCM; SPM 927; previously referred to as harkoseride; 
(R)-2-acetamido-N-benzyl-3-methoxypropionamide, ADD 234037) as adjunctive therapy at 
doses up to LCM 400mg/day in Japanese and Chinese adults with partial-onset seizures with 
or without secondary generalization who have completed the Treatment and Transition 
Periods of EP0008 and chose to enroll in EP0009.
The duration of EP0009 will be until the date of approval in each country or until the time 
when the sponsor decides to discontinue the development of LCM for the partial-onset 
seizure indication. The expected duration of subject participation is approximately 3 years 
following Visit 1. 
EP0009 consists of a Treatment Period and, if applicable, a Taper Period. Visit 1 of EP0009 
is the same as the Final Visit of EP0008. Visits 2 through 4 of EP0009 will occur at 4-week 
intervals relative to the date of Visit 1. Beginning with Visit 5, each visit will occur at        
12-week intervals relative to the date of Visit 1 until the End-of-Study/Withdrawal Visit. At 
the end of Treatment Period, an End-of-Study Visit will be required. If subjects prematurely 
withdraw from the study, a Withdrawal Visit will be required. Subjects who complete the 
Treatment Period and choose not to continue on to commercial LCM treatment or subjects 
who withdraw during the study will enter the Taper Period and will be required to taper off 
LCM. These subjects will return 2 weeks after the final LCM dose for a Final Visit. Subjects 
who complete the Treatment Period and choose to continue on to commercial LCM treatment 
are not required to enter the Taper Period to taper off LCM or to return for a Final Visit; the 
End-of-Study Visit will be the last visit for these subjects. If LCM is not commercially 
available in a subject’s country at the time the study closes, access to LCM will be provided 
according to local laws.
At the completion of EP0008, all subjects who choose to enroll in EP0009 will be taking a 
dose of LCM 200mg/day. During the EP0009 Treatment Period, the investigator will be 
allowed to increase or decrease the doses of LCM and/or up to 3 concomitant antiepileptic 
drugs (AEDs) to optimize tolerability and seizure reduction for each subject. The LCM dose 
may be decreased to 100mg/day or increased up to 400mg/day. Changes in concomitant 
AED(s) will be allowed only if the LCM dose has been stable for the previous 4 weeks; LCM 
dose must remain stable during changes to concomitant AED(s).
The primary safety variables include adverse events (AEs), reported spontaneously by the 
subject or observed by the investigator, and subject withdrawals due to AEs. Other variables 
to be assessed include efficacy (Section 4.2) and additional measures of safety               
(Section 4.1.2).
2
INTRODUCTION
Epilepsy remains the second most prevalent neurological disorder in the world that affects 
people of all ages. According to the World Health Organization (WHO), it is estimated that 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 14 of 70
approximately 50 million people worldwide were diagnosed with epilepsy in 2009 (WHO, 
2009). 
In Japan, the number of patients with epilepsy is estimated to be approximately 219,000 
(Ministry of Health, Labour and Welfare, Patient Survey, 2009). In addition, 
epidemiologically, epilepsy accounts for 0.5% to 1% of the population (Inoue, 2005). There 
also is a report that the total number of patients with epilepsy in Japan is estimated to be 
approximately 1 million people (Ueda, 2007). In China, the prevalence of epilepsy is around 
700/100,000, with an annual incidence of 28.8/100,000. It is estimated that there are currently 
around 9,000,000 patients with epilepsy in China, with approximately 400,000 new patients 
every year (Chinese Medical Association, 2007).
Most patients with epilepsy require appropriate pharmacological therapy (Perucca, 1996). In 
the past decade, several new options for the treatment of epilepsy have been introduced, 
including novel AEDs, vagus nerve stimulation (VNS), and surgical intervention. The newer 
AEDs differ from older agents in several important ways, including mechanism of action, 
spectrum of activity, and pharmacokinetic (PK) characteristics (Herman and Pedley, 1998). 
However, more than 30% of patients have inadequate seizure control on currently available 
AEDs or experience significant adverse drug effects (Beghi and Sander, 2008). Therefore, a 
need remains for AEDs with improved effectiveness and tolerability (Shorvon, 2009).
Lacosamide belongs to a novel class of functionalized amino acids. It was first approved by 
the European Medicines Agency in 2008 and is indicated as adjunctive therapy in the 
treatment of partial-onset seizures with or without secondary generalization patients with 
epilepsy aged 16 years and older. Lacosamide has also been approved as adjunctive therapy 
for patients with uncontrolled partial-onset seizures in other countries, including the US, 
Australia, and Canada. The specific indication statement and approved formulation(s) for 
LCM slightly differ based on the country; thus, local labels should be consulted for further 
information.
Lacosamide is rapidly and completely absorbed after oral administration and has minimal 
protein-binding properties; thus, there is a low risk of displacement drug-drug interactions. 
Peak plasma concentrations occur between 0.5 and 4 hours after dosing. Pharmacokinetic 
parameters are proportional to dose, with low intra- and inter-subject variability. The terminal 
half-life of the unchanged drug in plasma is approximately 13 hours, allowing for a        
twice-daily dose regimen. The O-desmethyl metabolite (referred to as SPM 12809) is 
excreted in the urine and represents about 30% of the dose. This metabolite has no known 
pharmacological activity.
The clinical development program for LCM includes clinical studies that evaluate efficacy 
and safety of LCM as adjunctive oral (tablet) therapy in adult subjects with partial-onset 
seizures. This includes 3 completed primary double-blind, placebo-controlled studies (SP667, 
SP754, and SP755), 1 completed supporting study (SP607), 3 completed long-term safety and 
efficacy studies (SP615, SP756, and SP774), and 1 completed long-term safety study 
(SP926).
Three double-blind, placebo-controlled, multicenter studies (SP667, SP754, and SP755) 
established the efficacy of oral tablet LCM 200mg/day (SP667 and SP755 only),             
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 15 of 70
LCM 400mg/day, and LCM 600mg/day (SP667 and SP754 only) as adjunctive therapy (1 to 
3 concomitant AEDs) in subjects with uncontrolled partial-onset seizures. In pooled analyses 
of these 3 studies, the most frequently reported AEs were central nervous system- and 
gastrointestinal-related events. The onset of these occurred commonly during the Titration 
Period, and the frequency of these AEs was dose-related. Comprehensive evaluation of 
clinical laboratory results and vital signs measurements did not reveal any issues of clinical 
concern. There was no increase in QTc interval on the ECG, however an important identified 
risk was a small dose-related increase in PR interval. Thus, LCM should be used with caution 
in patients with known conduction problems or severe cardiac disease such as a history of 
myocardial infarction or heart failure. Subjects randomized to LCM 600mg/day were less 
likely to tolerate this dose (compared with subjects randomized to LCM 400mg/day) because 
of central nervous system- and gastrointestinal-related AEs.
The pooled analyses of the clinical studies that evaluated the efficacy and safety of LCM as 
adjunctive oral (tablet) therapy in adult subjects with partial-onset seizures (SP607, SP615, 
SP667, SP754, SP755, SP756, and SP774) show that LCM is an effective long-term (>12 
months) adjunctive treatment for subjects with partial-onset seizures, and no new types of 
treatment-emergent adverse events (TEAEs), considered related to LCM, emerged with 
chronic therapy. In addition, the TEAEs associated with LCM decreased in incidence with 
chronic therapy. 
Further information on LCM preclinical results, as well as the pharmacokinetic, efficacy, and 
safety profiles, can be obtained from the current version of the LCM Investigator Brochure.
To support the development of LCM for the adult partial-onset seizure indication in Japan 
and China, EP0009 is being conducted to evaluate long-term safety, tolerability, and efficacy 
of LCM in Japanese and Chinese subjects. In addition, this study will provide the subjects 
who previously participated in EP0008, a Phase 3, multicenter, double-blind               
placebo-controlled study, the opportunity to continue to receive LCM treatment.
3
STUDY OBJECTIVE(S)
3.1
Primary objectives
The primary objectives of this study are the following:
•
To evaluate the safety and tolerability of long-term administration of LCM at doses up to 
400mg/day in Japanese and Chinese adults with epilepsy who have completed the 
Treatment and Transition Period of EP0008
•
To allow subjects who had completed the Treatment and Transition Periods of EP0008 to 
receive LCM 
3.2
Secondary objective
The secondary objective of this study is the following:
•
To evaluate the efficacy of long-term administration of LCM at doses up to 400mg/day in 
Japanese and Chinese adults with epilepsy who have completed the Treatment and 
Transition Periods of EP0008.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 16 of 70
4
STUDY VARIABLES
4.1
Safety variables
4.1.1
Primary safety variables
The primary safety variables are the following:
•
AEs reported spontaneously by the subject or observed by the investigator
•
Subject withdrawals due to AEs
4.1.2
Other safety variables
The other safety variables are the following:
•
Changes in hematology, clinical chemistry, and urinalysis parameters
•
Changes in 12-lead ECGs
•
Changes in vital sign measurements (ie, blood pressure, pulse rate)
•
Changes in body weight
4.2
Efficacy variables
4.2.1
Primary efficacy variables
No primary efficacy variables are defined for EP0009. 
4.2.2
Secondary efficacy variables
The secondary efficacy variables are the following:
•
Percent change from Baseline in partial-onset seizure frequency per 28 days, where 
Baseline is defined as the Baseline Period of EP0008
•
50% response, where a responder is a subject experiencing a ≥50% reduction from 
Baseline in partial-onset seizure frequency per 28 days, and Baseline is defined as the 
Baseline Period of EP0008
4.2.3
Other efficacy variables
Other efficacy variables are the following:
•
75% response, where a responder is a subject experiencing a ≥75% reduction from 
Baseline in partial-onset seizure frequency per 28 days and Baseline is defined as the 
Baseline Period of EP0008
•
Subjects who achieved “seizure-free” status (yes/no)
•
Percentage of seizure-free days 
•
Subjects who are changed to LCM monotherapy for at least 6 months
•
Subjects who are changed to LCM monotherapy for at least 12 months
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 17 of 70
5
STUDY DESIGN
5.1
Study description
EP0009 is a Phase 3, multicenter, open-label, uncontrolled, extension study designed to 
evaluate the safety, tolerability, and efficacy of long-term administration of LCM as 
adjunctive therapy at doses up to 400mg/day in Japanese and Chinese adults with            
partial-onset seizures with or without secondary generalization who have completed the 
Treatment and Transition Periods of EP0008 and chose to enroll in EP0009. 
EP0009 consists of a Treatment Period and, if applicable, a Taper Period. 
Visit 1 of EP0009 is the same as the Final Visit of EP0008. Visits 2 through 4 of EP0009 will 
occur at 4-week intervals relative to the date of Visit 1. Beginning with Visit 5, each visit will 
occur at 12-week intervals relative to the date of Visit 1 until the End-of-Study/Withdrawal 
Visit. 
At the completion of EP0008, all subjects who choose to enroll in EP0009 will be taking a 
dose of LCM 200mg/day. During the EP0009 Treatment Period, the investigator will be 
allowed to increase or decrease the doses of LCM and/or up to 3 concomitant AEDs to 
optimize tolerability and seizure reduction for each subject. The LCM dose may be decreased 
to 100mg/day or increased, no faster than 100mg/day per week, up to 400mg/day. Changes in 
concomitant AED(s) will be allowed only if the LCM dose has been stable for the previous 
4 weeks; LCM dose must remain stable during changes to concomitant AED(s). Subjects may 
take no more than 3 concomitant AEDs except when temporary (≤12 weeks) use of an 
additional AED is required to switch to a new AED (ie, taper from old AED during titration 
of a new AED). New AED(s) may be added only when the subject has not optimally or 
adequately responded to a maximum tolerated dose of LCM. The concomitant AED(s) can be 
carefully tapered or discontinued at the discretion of the investigator. Monotherapy with 
LCM is permitted. Increasing the dose of LCM and/or concomitant AED(s), as well as the 
addition of a new AED, should be done at a visit (scheduled or unscheduled).
At the end of the Treatment Period, an End-of-Study Visit will be required. If subjects 
prematurely withdraw from the study, a Withdrawal Visit will be required. Subjects who 
complete the Treatment Period and choose not to continue on to commercial LCM treatment, 
and subjects who prematurely withdraw from the study, will enter a Taper Period. During the 
Taper Period, subjects receiving doses greater than LCM 200mg/day at the                        
End-of-Study/Withdrawal Visit should be tapered off gradually at a recommended decrease 
rate of LCM 200mg/day per week, unless the investigator feels that safety concerns require 
more rapid withdrawal of LCM. UCB (or designee) should be contacted if a more rapid 
withdrawal is required. A slower taper (eg, LCM 100mg/day per week) is permitted, if 
medically necessary. Subjects receiving doses of LCM 200mg/day or lower at the                    
End-of-Study/Withdrawal Visit are not required to taper off LCM. A Final Visit will be 
required 2 weeks after final LCM dose. Subjects who complete the Treatment Period and 
choose to continue on to commercial LCM treatment are not required to enter the Taper 
Period to taper off LCM or to return for a Final Visit; the End-of-Study Visit will be the last 
visit for these subjects. If LCM is not commercially available in a subject’s country at the 
time the study closes, access to LCM will be provided according to local laws. 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 18 of 70
The Schedule of study assessments and the schematic diagram of the study are provided in 
Section 5.2 (Table 5-1) and Section 5.3 (Figure 5‒1), respectively.
5.1.1
Study duration per subject
EP0009 will continue until the date of the market approval of LCM in each participating 
country or until the time when the sponsor decides to discontinue the development of LCM 
for the partial-onset seizure indication. The expected duration of subject participation is 
approximately 3 years following Visit 1.
The end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Dates of the planned study duration 
The study duration is planned from third quarter of 2012 to second quarter of 2017.
5.1.3
Planned number of subjects 
No formal sample size determination has been performed because EP0009 is an extension 
study. Approximately 378 subjects, ie, 70% of subjects who are randomized in EP0008, are 
anticipated to participate in this extension study.
5.1.4
Anticipated regions and countries
All sites will be in Japan and China.
5.2
Schedule of study assessments
The schedule of study assessments is provided in Table 5-1.
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UCB
13 Mar  2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 19 of 70
Table 5-1
Schedule of study assessments
Study Period
Treatment Period
Taper 
Period
Visit
1
2
3
4
5a
6
7
8
9
10
11
12
13
14
15
≥16
ESVb
/WVb
Final 
Visit
Unscheduled 
Visitc
Weeks in study
0
4
8
12
24
36
48
60
72
84
96
108
120
132
144
≥156
-
2 weeks 
after final
LCM 
dose
-
Visit window (days)d
-
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
-
-
-
Informed Consente
X
Inclusion/exclusion 
Criteria
X
Concomitant AED(s)
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication(s)/
medical procedure(s)
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical 
examinationf
Xe
X
X
X
X
Xf
X
X
Xg
Brief neurological 
examinationf
Xe
X
X
X
X
Xf
X
X
Xg
Vital signs and weight
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
(the “Since Last Visit” 
version)
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
Laboratory testsh:
  Clinical chemistry/
  hematology
Xe
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
X
X
  Urinalysis
Xe
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
X
X
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UCB
13 Mar  2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 20 of 70
Table 5-1
Schedule of study assessments
Study Period
Treatment Period
Taper 
Period
Visit
1
2
3
4
5a
6
7
8
9
10
11
12
13
14
15
≥16
ESVb
/WVb
Final 
Visit
Unscheduled 
Visitc
Weeks in study
0
4
8
12
24
36
48
60
72
84
96
108
120
132
144
≥156
-
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after final
LCM 
dose
-
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-
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
-
-
-
Pregnancy testi
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Xi
Xg
12-lead ECGj
Xe
X
X
X
X
X
X
Xj
X
X
Xg
Contact IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
Dispense IMP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xg
IMP return/review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Dispense subject diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Subject diary 
return/review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
AE assessment
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ESV=End-of-Study Visit; IMP=investigational 
medicinal product; IVRS=Interactive Voice Response System; IWRS=Interactive Web Response System; LCM=lacosamide; WV=Withdrawal Visit 
a
Beginning with Visit 5, visits will be performed at 12-week intervals.
b
At the time of study completion, or if subjects withdraw from the study prematurely, an End-of-Study Visit or Withdrawal Visit will be required. The End-of-Study Visit is 
the last visit for the subjects who choose to continue on to commercial LCM treatment. Subjects receiving doses greater than LCM 200mg/day at the Withdrawal/End-of-
Study Visit should be tapered off gradually at a recommended decrease rate of LCM 200mg/day per week, unless safety concerns require a more rapid withdrawal of LCM. 
The sponsor should be contacted if a more rapid withdrawal is required. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically necessary.
c
An Unscheduled Visit may be performed at the investigator’s discretion. The investigator should use an Unscheduled Visit to increase a subject’s LCM /concomitant AED(s) 
dose(s) or to add a new AED.
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UCB
13 Mar  2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 21 of 70
d
A visit window ±7 day relative to Visit 1 is applicable.
e
The Informed Consent form must be signed and dated at any time between Visit 7 and Visit 8 of EP0008. Visit 1 of EP0009 is the same as the Final Visit of EP0008. All other 
assessments marked “e” should be completed during the Final Visit of EP0008.
f
After Week 48, physical and neurological (brief) examinations will be performed every 48 weeks until ESV/WV.
g
These assessments may be performed as needed at the discretion of the investigator. 
h
After Week 108, the laboratory assessments will be performed every 24 weeks until ESV/WV. 
i
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j
After Visit 4, a 12-lead ECG will subsequently be performed every 24 weeks until ESV/WV. 
k
At an ESV, the subject diary and IMP will not be dispensed for subjects who complete the Treatment Period and choose to continue on to commercial LCM treatment. If 
LCM is not commercially available in a subject’s country at the time, access to LCM will be provided according to local laws.
l
Subjects should bring the subject diary and IMP to the clinic for review.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 22 of 70
5.3
Schematic diagram
The schematic diagram for EP0009 is provided in Figure 5‒1.
REDACTED COPY 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 23 of 70
Figure 5‒1: Schematic diagram
Open-label
Treatment Perioda
Taper Periodb
LCM 400mg/day
LCM 400mg/day
LCM 300mg/day
LCM 200mg/day
LCM 100mg/day
LCM 100mg/day
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 End-of-Study
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At the completion of EP0008, all subjects will be taking LCM 200mg/day. During the Treatment Period of EP0009, the LCM dose may be decreased to 
100mg/day or increased, no faster than 100mg/day per week, up to 400mg/day.
b
Subjects receiving doses greater than LCM 200mg/day at the End-of Study/Withdrawal Visit should be tapered off gradually at a recommended decrease 
rate of LCM 200mg/day per week (see Table 7-1), unless the investigator feels that safety concerns require more rapid withdrawal of LCM. A slower taper 
(eg, LCM 100mg/day per week) is permitted, if medically necessary. Subjects receiving doses of LCM 200mg/day or lower at the End-of-Study/Withdrawal 
Visit are not required to taper off LCM.
c
The End-of-Study Visit is the last visit for the subjects who choose to continue on to commercial LCM treatment. The subjects who complete the Treatment 
Period and choose not to continue on to commercial LCM treatment will enter a Taper Period.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 24 of 70
5.4
Rationale for study design and selection of dose
EP0009 is designed to evaluate the safety, tolerability, and efficacy of long-term administration 
of LCM as adjunctive therapy in Japanese and Chinese adults with partial-onset seizures with or 
without secondary generalization who have completed the Treatment and Transition Periods of 
EP0008. This design will allow the subjects who completed the Treatment and Transition 
Periods of EP0008 to continue with the treatment of LCM.
The doses in this study were selected to obtain long-term safety information of LCM within the 
approved doses and to give investigators the flexibility to optimize seizure control and
tolerability in study subjects..
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent is signed and dated by the subject or by the parent(s) or legal 
representative. The Informed Consent form or a specific Assent form, where required, will be 
signed and dated by minors (Japanese subjects under 20 years of age and Chinese subjects 
under 18 years of age).
2. Subject has completed the Treatment and Transition Periods of EP0008.
3. Subject is expected to benefit from participation, in the opinion of the investigator.
4. Subject is willing and able to comply with all study requirements.
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria are met:
1. Subject is receiving an investigational medicinal product (IMP) or unapproved medication, or 
using an experimental medical device in each respective country.
2. Subject who withdrew from EP0008.
3. Female subject who is pregnant or nursing. Female subjects of childbearing potential 
(without a history of hysterectomy or bilateral oophorectomy) are eligible, if they use a 
medically accepted contraceptive method for the duration of the study participation. They 
must understand and accept that pregnancy should be avoided during participation in the 
study. Female subjects without childbearing potential (who have been surgically sterilized or 
who are at least 2 years postmenopausal) are eligible.
4. Subject is experiencing an ongoing serious adverse event, unless approved by the sponsor.
6.3
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Investigators should contact the sponsor whenever possible to discuss the withdrawal of a 
subject in advance. All subjects receiving a LCM dose greater than 200mg/day and discontinuing 
treatment with LCM for any reason should taper LCM. All subjects who withdraw due to an AE 
must be followed until resolution of the event or until the event is considered stable.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 25 of 70
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject develops second- or third-degree AV (atrioventricular) block.
2. Confirmation of a pregnancy during the study, as evidenced by a positive pregnancy test.
3. The subject is unwilling or unable to continue and withdraws consent.
4. Request of the sponsor or a regulatory agency.
5. The subject develops an AE that would interfere with his/her continued participation.
6. In the case of liver function test (LFT) results of transaminases (aspartate aminotransferase 
[AST] and/or alanine aminotransferase [ALT]) ≥3x upper limit of normal (ULN) to <5xULN 
and total bilirubin ≥2xULN or transaminases (AST and/or ALT) ≥5xULN, LCM must be 
immediately discontinued and the subject withdrawn from the study. The LFTs will be 
repeated as soon as possible, and in no case more than 1 week later (See Section 9.6.3).
7. Subject has actual suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide Severity 
Rating Scale (C-SSRS). The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study.
Subjects may be withdrawn from the study if any of the following events occur:
8. Subject requires a medication that is not permitted.
9. The subject is noncompliant with the study procedures or medications in the opinion of the 
investigator.
10. Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the IMP (See Section 9.6.3).
11. Subject develops a clinically relevant change in medical condition (or ECG or laboratory 
parameter) as determined by the investigator, and the investigator feels it is in the interest of 
the subject to withdraw.
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. For subjects considered as lost to follow up, the investigator should make an 
effort (at least 1 phone call and 1 written message to the subject), and document his/her effort 
(date and summary of the phone call and copy of the written message in the source documents), 
to complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The electronic Case Report form (eCRF) must document the primary reason for 
withdrawal or discontinuation.
Investigators should contact UCB (or designee), whenever possible, to discuss the withdrawal of 
a subject in advance.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 26 of 70
7
STUDY TREATMENT(S)
7.1
Description of investigational medicinal product
Lacosamide will be supplied as immediate-release, film-coated, tablets in strengths of 50mg 
(pinkish) and 100mg (dark yellow). 
7.2
Treatments to be administered
Lacosamide will be orally administered twice daily (once in the morning and once in the 
evening) in 2 equally divided doses. At the completion of EP0008, all subjects who choose to 
enroll in EP0009 will be taking a dose of LCM 200mg/day. At the beginning of EP0009, the 
investigator may maintain the LCM dose or increase or decrease the dose. During the Treatment 
Period, the investigator will be allowed to increase or decrease the dose of LCM to optimize 
tolerability and seizure reduction. The LCM dose may be decreased to 100mg/day or increased, 
no faster than 100mg/day per week, up to 400mg/day. Increasing the dose of LCM should be 
done at a visit (scheduled or unscheduled). Lacosamide dose must remain stable during changes 
to concomitant AED(s).
Subjects who complete the Treatment Period and choose not to continue on to commercial LCM 
treatment, and who withdraw from the study prematurely, will enter a Taper Period. During the 
Taper Period, subjects receiving doses greater than LCM 200mg/day at the 
End-of-Study/Withdrawal Visit should be tapered off gradually at a recommended decrease rate 
of LCM 200mg/day per week (See Table 7-1), unless the investigator feels that safety concerns 
require more rapid withdrawal of LCM. UCB (or designee) should be contacted if a more rapid 
withdrawal is required. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically 
necessary. Subjects receiving doses of LCM 200mg/day or lower at the 
End-of-Study/Withdrawal Visit are not required to taper off LCM.
The details of concomitant AED(s) to be administered are described in Section 7.8.1.
Table 7-1
Recommended LCM dose reduction (Taper Period)
Dose of LCM at
End-of-Study/
Withdrawal Visit
Taper Schedule
Week 1
Week 2
LCM 400mg/day
LCM 200mg/day
n/a
LCM 300mg/day
LCM 100mg/day
n/a
LCM 200mg/day
n/a
n/a
LCM 100mg/day
n/a
n/a
LCM=lacosamide; n/a=not applicable (ie, no investigational medicinal product will be administered)
7.3
Packaging
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing Practice 
guidelines and applicable laws or regulations. The IMP is suitably packaged in such a way as to 
protect it from deterioration during transport and storage. The IMP will be packaged in bottles.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 27 of 70
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. Labels will be translated into the local 
language.
7.5
Handling and storage requirements
The person in charge of the IMP is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the person in charge of the IMP is to be kept in a 
secured area with limited access.
Investigational medicinal product is to be stored according to the instructions on the label. 
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Clinical Project Manager (CPM) (or designee) before further use of the IMP.
The CPM (or designee) will transmit the out-of-range temperature (copy of the temperature log 
and duration of the out-of-range temperature, if available) to the Drug Supply Coordinator. 
Based on discussion with a UCB Quality Assurance representative, the Drug Supply Coordinator 
will then provide the CPM (or designee) with instructions for the site regarding use of the IMP.
The investigator (or designee) will instruct the subject to store IMP following the instructions on 
the label.
7.6
Drug accountability
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or returned to 
the sponsor or designee must also be recorded on the appropriate forms. All supplies and 
pharmacy documentation must be made available throughout the study for UCB (or designee) to 
review.
The person in charge of the IMP is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed.
The investigator or the head of the participating study site (Japan only) may assign some of the 
investigator’s duties for drug accountability at the study site to an appropriate 
pharmacist/designee.
The investigator must ensure that the IMP is used only in accordance with the protocol.
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) and unused IMP containers must be reconciled and returned to UCB (or designee), 
preferably in their original package. Investigational medicinal product intended for the study 
cannot be used for any other purpose than that described in this protocol.
7.7
Procedures for monitoring subject compliance
At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP 
containers. Drug accountability must be done in the subject’s presence in order to obtain 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 28 of 70
explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form.
If a subject is found to be persistently noncompliant (less than 75% or more than 125%), the 
sponsor, in conjunction with the investigator, will make a decision as to whether the subject 
should be withdrawn from the study.
7.8
Concomitant medications/treatments
7.8.1
Permitted concomitant AED(s) 
At the beginning of EP0009, the concomitant AED(s) that were used in EP0008 are permitted. 
The investigator (or designee) will be allowed to change the type, dosage and administration, or 
discontinuation/resumption of concomitant AEDs to optimize tolerability and seizure reduction 
for each subject. Antiepileptic drugs approved for epilepsy in the subject’s country (ie, Japan or 
China) are permitted during the study. Changes in concomitant AED(s) will be allowed only if 
the dose of LCM has been stable for the previous 4 weeks; LCM dose must remain stable during 
changes to concomitant AED(s). Subjects may take no more than 3 concomitant AEDs except 
when temporary (≤12 weeks) use of an additional AED is required to switch to a new AED (ie, 
taper from old AED during titration of new AED). New AED(s) may be added only when the 
subject has not optimally or adequately responded to a maximum tolerated dose of LCM. The 
concomitant AED(s) can be carefully tapered or discontinued at the discretion of the investigator. 
Monotherapy with LCM is permitted. Increasing the dose of LCM and/or concomitant AED(s), 
as well as addition of a new AED should be done at a visit (scheduled or unscheduled). There are
no restrictions for concomitant AED(s) during the Taper Period, considering subject safety.
7.8.2
Prohibited concomitant treatments (medications and therapies)
The following concomitant medications/treatments are prohibited during the study:
•
Antischizophrenic agents 
•
Monoamine oxidase inhibitors
•
Barbiturates (except for an epilepsy indication or a single administration at the time when 
examinations such as an EEG are performed)
•
Narcotic analgesics (except for short-term use for things such as a broken bone, a tooth 
extraction, etc)
•
Psychostimulants
•
AEDs given by a route other than oral (except benzodiazepine for rescue medication)
•
Herbal medicines approved for epilepsy
•
Potassium bromide, sodium bromide, and calcium bromide
•
Bemegride
•
Pregabalin
•
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 29 of 70
•
Brain surgery (minimally invasive brain surgery, such as brain mapping, may be permitted 
with the approval of the Study Physician)
•
VNS, except for the subjects who used VNS in EP0008
•
Other investigational medicinal products, and drugs and medical devices that have not been 
approved in Japan and China
•
The drugs which contain the contraindication for epilepsy patients in their package insert
7.8.3
Rescue medication
The use of benzodiazepines, which have the indication for epilepsy for the control of 
uncountable seizures due to clustering, is restricted to rescue therapy.
7.9
Blinding
EP0009 is an open-label study; thus, there will be no blinding.
7.10
Randomization and numbering of subjects
Subjects will not be randomized in this study. The unique identification number assigned to 
subjects during EP0008 will be used to identify subjects and to maintain subject confidentiality 
throughout EP0009. An interactive voice response system (IVRS) or interactive web response 
system (IWRS) will be used to assign the applicable LCM bottle number(s). Further instructions 
will be provide in the IVRS/IWRS manual.
7.11
Allowance for entering an additional study (EP0024)
At selected sites, Japanese subjects may participate in an additional study (EP0024) with an 
intravenous formulation of LCM without withdrawing from EP0009. The study period of 
EP0024 will be included in that of EP0009. Subjects will continue to receive their current dose 
of LCM at the time of entry and remain stable for the duration of EP0024. Subjects who 
complete or withdraw from EP0024 will be given the opportunity to resume their participation in 
EP0009 with oral LCM treatment. In the event that a subject withdraws from EP0024 and is 
required to taper off LCM, the subject will return to EP0009 and taper using LCM tablets. 
Adverse events and concomitant treatment(s)/medication(s) that occur or administered during 
EP0024 will be recorded in EP0024. Ongoing AEs and concomitant medication(s)/medical 
procedure(s) originating from the EP0024 will be followed in EP0009 until resolution or until 
stable. Where possible, data updates related to the resolution of ongoing AEs and concomitant 
medication(s)/medical procedure(s) from EP0024 will be reported in the EP0024 database (eg, 
updates are made in the EP0024 databases until the database is locked). All other data reported 
for EP0024 will be captured in the EP0024 database. Per the EP0024 protocol, the study 
(EP0024) will require hospitalization. Hospitalization for study participation does not need to be 
reported as an SAE as outlined in section 9.4.
8
STUDY PROCEDURES BY VISIT 
A window of ±7 days relative to Visit 1 is applicable for all scheduled visits.
A detailed tabular schedule of study procedures is provided in Section 5.2.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 30 of 70
8.1
Treatment Period
8.1.1
Visit 1 (Week 0)
For subjects completing the Transition Period of EP0008 and choosing to enroll in EP0009, the 
Final Visit (Week 18) of EP0008 will serve as Visit 1 of EP0009. Prior to the conduct of any 
study-related procedures, a complete verbal and written explanation of the nature and purpose of 
the study will be given to the subject by the investigator (or designee). The subject/legal 
representative is required to sign and date the IRB/IEC approved Informed Consent if he/she 
decides to participate in the study.
The subject’s eligibility for the study will be determined on the basis of the inclusion/exclusion 
criteria, signature of an Informed Consent prior to any study-related procedures or evaluations, 
and the results of the following assessments (for further details of the assessments and the 
required procedures and methods, see Section 9 and Section 10).
The following will be performed prior to the first dose of IMP in EP0009:
•
Inclusion/exclusion criteria
•
Contact IVRS/IWRS
•
Dispense IMP
•
Dispense subject diary 
•
Withdrawal criteria
The following should have already been completed during the previous EP0008 Final Visit:
•
Concomitant AED(s)
•
Concomitant medication(s)/medical procedure(s)
•
Complete physical examination
•
Brief neurological examination
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version)
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical 
chemistry, and urinalysis) 
•
Blood sample for pregnancy test (for women of childbearing potential) 
•
12-lead ECG (1 assessment at any time after intake of IMP)
•
AE assessment
The following information collected in EP0008 will be used for EP0009: demographic 
information, medical/procedure history, epilepsy information (diagnosis of epilepsy, etiology of 
epilepsy, ILAE seizure classification, focus localization, classification of epileptic syndrome
[See Section 16.2], treatment history).
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 31 of 70
8.1.2
Visits 2 through 4 (Weeks 4 through 12)
Visits 2 through 4 will occur at 4-week intervals ±7 days relative to the date of Visit 1.
The following will be performed at every visit:
•
Concomitant AED(s)
•
Concomitant medication(s)/medical procedure(s)
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version) 
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical 
chemistry, and urinalysis
•
Urine sample for pregnancy test
•
Contact IVRS/IWRS
•
Dispense IMP
•
IMP return/review
•
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•
Subject diary return/review
•
AE assessment
•
Withdrawal criteria
The following will be performed at Visit 4 (Week 12) only:
•
12-lead ECG (Visit 4 only)(1 assessment at any time after intake of IMP)
8.1.3
From Visit 5 until End-of-Study/Withdrawal Visit (Week 24 or later)
Beginning with Visit 5, each visit will occur at 12-week intervals ±7 days relative to the date of 
Visit 1.
The following will be performed at every visit:
•
Concomitant AED(s)
•
Concomitant medication(s)/medical procedure(s)
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version)
•
Urine sample for pregnancy test (for women of childbearing potential) 
•
Contact IVRS/IWRS
•
Dispense IMP
•
IMP return/review
•
Dispense subject diary 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 32 of 70
•
Subject diary return/review
•
AE assessment
•
Withdrawal criteria
The following will be performed at Visit 5, Visit 7, and every 48 weeks after Visit 7 
•
Complete physical examination
•
Brief neurological examination
The following will be performed at every 24 weeks after Visit 4:
•
12-lead ECG (1 assessment at any time after intake of IMP)
The following will be performed at every visit through Visit 12 (Week 108) and every 24 weeks 
after Visit 12.
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical 
chemistry and urinalysis)
8.1.4
End-of-Study Visit
At the end of the Treatment Period, an End-of-Study Visit will be required. For the subjects who 
choose to continue on to commercial LCM treatment, the End-of-Study Visit is the last visit. 
Subjects who choose not to continue on to commercial LCM treatment will enter the Taper 
Period after the End-of-Study Visit.
The following will be performed:
•
Concomitant AED(s)
•
Concomitant medication(s)/medical procedure(s)
•
Complete physical examination
•
Brief neurological examination
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version)
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical 
chemistry, and urinalysis) 
•
Blood sample for pregnancy test (for women of childbearing potential)
•
12-lead ECG (1 assessment at any time after intake of IMP)
•
Contact IVRS/IWRS
•
Dispense IMP for taper (if applicable, See Section 7.2)
•
IMP return/review
•
Dispense subject diary (if applicable)
•
Subject diary return/review
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 33 of 70
•
AE assessment
•
Withdrawal criteria
8.1.5
Withdrawal Visit
Subjects who prematurely withdraw from the study must complete a Withdrawal Visit. All those 
subjects will enter the Taper Period after the Withdrawal Visit.
The following will be performed:
•
Concomitant AED(s)
•
Concomitant medications(s)/treatment(s)
•
Complete physical examination
•
Brief neurological examination
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version)
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical 
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•
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•
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•
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•
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•
IMP return/review
•
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•
Subject diary return/review
•
AE assessment
•
Withdrawal criteria
8.2
Taper Period
8.2.1
Final Visit (2 weeks after final LCM dose)
For subjects who withdraw during the study and receive doses greater than LCM 200mg/day, 
and subjects who complete the Treatment Period and choose not to continue on to commercial 
LCM treatment and receive doses greater than LCM 200mg/day, LCM should be tapered off 
gradually at a recommended decrease rate or 200mg/day per week (See Section 7.2).
For Subjects who withdraw during the study or complete the Treatment Period and receive doses 
of LCM 200mg/day or lower are not required to taper LCM. 
For all the above subjects, a Final Visit must be performed 2 weeks after the final LCM dose.
The following will be performed:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 34 of 70
•
Concomitant AED(s)
•
Concomitant medication(s)/treatment(s)
•
Complete physical examination
•
Brief neurological examination
•
Vital signs and weight
•
C-SSRS (the "Since Last Visit" version)
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chemistry, and urinalysis) 
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•
12-lead ECG (1 assessment at any time)
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8.3
Unscheduled Visit
An Unscheduled Visit may be performed at the investigator’s discretion. Increasing the dose of 
LCM and/or concomitant AED(s), as well as addition of a new AED should be done at an 
Unscheduled Visit.
The following will be performed:
•
Concomitant AED(s)
•
Concomitant medication(s)/treatment(s)
•
Vital signs and weight
•
Blood and urine samples for clinical laboratory values (includes hematology, clinical
chemistry, and urinalysis) 
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IMP review
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Further assessments/procedures may be performed as needed at the discretion of the investigator 
(See Section 5.2).
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 35 of 70
9
ASSESSMENT OF SAFETY
9.1
Adverse events
9.1.1
Definition of adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
In order to ensure complete safety data collection, all AEs occurring during the study, including 
any posttreatment period required by the protocol must be reported in the eCRF even if no IMP 
was taken but specific study procedures were conducted. This includes all AEs not present prior 
to the initial visit and all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
investigator from the subject’s history or the Baseline.
9.1.2
Procedures for reporting and recording adverse events
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
In addition, the investigator should review any self-assessment procedures (eg, subject diary) 
employed in the study.
9.1.3
Description of adverse events
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, subject diary) and the corresponding medical terminology should be 
clarified in the source documentation.
Details for completion of the Adverse Event eCRF (including judgment of relationship to study 
drug) are described in the eCRF Instructions.
9.1.4
Follow up of adverse events
An AE should be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up. 
If an AE is still ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. The follow up will usually be continued for 30 days 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 36 of 70
after the subject has discontinued his/her IMP. If necessary, UCB may request that the 
investigators perform examinations to obtain supplementary measurements and/or evaluations.
9.1.5
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:
•
The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”
•
The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one
9.1.6
Pregnancy
Should a subject become pregnant after the first intake of any IMP, UCB (or designee) 
department should be informed immediately. The subject should be withdrawn from the study as 
soon as pregnancy is known, and the following should be completed:
•
The subject should return for a Withdrawal Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the Withdrawal Visit.
•
A Safety Follow-Up Visit should be scheduled 14 days after the subject has discontinued her 
IMP.
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, UCB 
(or designee) will ask the investigator or designee to contact the subject and his partner to request 
consent via the Partner Pregnancy Consent form. If the partner agrees to provide additional 
information, the Pregnancy Report and Outcome form will be forwarded to the subject’s partner 
for completion.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed-up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. The health of the child must be followed for 
30 days after birth for any significant medical issues.
In certain circumstances, UCB (or designee) may request that follow up is continued for a period 
longer than 30 days.
A pregnancy becomes a serious adverse event (SAE) in the following circumstances: 
miscarriage, abortion, or anomaly/birth defect of the child. Those SAEs must be additionally 
reported using the Investigator SAE Report form.
9.1.7
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the Study Drug Dosing module of the eCRF. Any SAE or nonserious AE associated 
with excessive dosing must be followed as any other SAE or nonserious AE. These events are 
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 37 of 70
only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of 
taking the excess medicine itself is an AE or SAE (eg, suicide attempt).
9.1.8
Safety signal detection
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Drug Safety 
representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study.
9.2
Serious adverse events
9.2.1
Definition of serious adverse event
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
•
Death
•
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)
•
Significant or persistent disability/incapacity
•
Congenital anomaly/birth defect (including that occurring in a fetus)
•
Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious
(Important medical events may include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.)
•
Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 38 of 70
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.)
9.2.2
Procedures for reporting serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database.
An Investigator SAE report form will be provided to the investigator. 
It is important for the investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form.
The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the investigator of any SAE within this period. Serious AEs that the 
investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study.
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure.
9.2.3
Follow up of serious adverse events
An SAE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time.
9.3
Adverse events of special interest
An AE of special interest is any AE that the US Food and Drug Administration has mandated be 
reported on an expedited basis, regardless of the seriousness, expectedness, or relatedness of the 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 39 of 70
AE to the administration of a UCB product/compound. The procedure for reporting AEs of 
special interest is the same as that of SAEs (see Section 9.2.2).
The following are AEs of special interest:
•
The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV (second degree, Type I and II, and third degree), and marked bradycardia 
(<45 beats/min)
•
Syncope or loss of consciousness (other than seizure related)
•
Serious suspected multiorgan hypersensitivity reactions
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US Food and 
Drug Administration:
An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, 
encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) combined 
with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia.
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia:
•
Eosinophils % ≥10%
•
Eosinophils absolute ≥0.5G/L
•
Neutrophils absolute <1.5G/L
•
Platelets ≤100G/L
•
ALT ≥2×ULN
•
AST ≥2×ULN
9.4
Immediate reporting of adverse events
The following AEs must be reported immediately:
•
SAE: AE that the investigator classifies as serious by the above definitions regardless of 
causality
•
Suspected transmission of an infectious agent via a medicinal product
•
AE of special interest (see Section 9.3)
9.5
Anticipated serious adverse events
The following list of anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure. This original list will remain in effect for the duration of the protocol.
This list does not change the investigator’s obligation to report all SAEs (including anticipated 
SAEs) as detailed in Section 9.2.2.
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 40 of 70
Table 9-1
Anticipated SAEs for the adult epileptic population 
MedDRA® SOC
MedDRA® PT
Congenital, Familial and Genetic disorders
Teratogenicity
General disorders and Administration Site 
Conditions
Sudden unexplained death in epilepsy
Nervous System Disorders
Convulsion
Incontinence
Status epilepticus
Pregnancy, Puerperium and Perinatal disorders
Abortion spontaneous
Psychiatric Disorders
Psychotic behavior
Abnormal behavior
Anxiety
Sleep disorder
Reproductive System and Breast Disorders
Menstrual disorder
Impotence
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; 
SOC=system organ class
9.6
Other safety assessments
9.6.1
Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The Japanese and Chinese translations of the       
C-SSRS will be listed in a separate document. The C-SSRS will be completed according to the 
tabular schedule of study procedures, See Section 5.2. Suicidal ideation and behavior are to be 
reported as AEs.
9.6.2
Laboratory measurements
Blood and urine specimens for routine assay of hematology, clinical chemistry, and urinalysis 
testing will be collected according to the tabular schedule of study procedures, see Section 5.2. A 
central laboratory will perform the routine analysis of blood and urine specimens. The 
procedures for handling and shipping these specimens will be provided to the sites.
The laboratory tests to be performed are presented in Table 9-2.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 41 of 70
Table 9-2
Laboratory measurements
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count 
RBC 
WBC
Differential count 
Calcium
Phosphorus
Serum electrolytes (sodium, 
potassium, chloride, 
bicarbonate)
Glucose
Albumin
Total serum protein
BUN
Creatinine
Uric acid 
Alkaline phosphatase
AST
ALT
GGT
Total bilirubin
Specific gravity
pH
Albumin
Glucose
Ketones
Microscopic exam for 
blood cells or casts/hpf
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; GGT=gamma 
glutamyltransferase; hpf=high power field; RBC=red blood cell; WBC=white blood cell
9.6.3
Liver function tests
Refer to Section 6.3 for LFT withdrawal criteria.
Transaminases (AST, ALT, or both) ≥3xULN but <5xULN, in the presence of total bilirubin 
≥2xULN, or transaminases (AST, ALT, or both) ≥5xULN will result in immediate 
discontinuation of LCM and withdrawal of the subject from the study. The LFTs will be repeated 
as soon as possible, and in no case more than 1 week later.
Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality (ie, 
transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring of LFTs 
should continue until resolved (ie, <3xULN or stable condition). The investigator is to decide 
whether or not to stop the IMP. 
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C will 
be done.
Referral to a specialist (ie, hepatologist or gastroenterologist) is at the discretion of the 
investigator. This is recommended especially if the transaminase abnormalities >3xULN persist 
after discontinuation of the IMP.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 42 of 70
9.6.4
Pregnancy testing
Females of childbearing potential (who have not been surgically sterilized or who are not at least 
2-years postmenopausal) will have serum and urine dipstick pregnancy testing performed 
according to the tabular schedule of study procedures, Section 5.2. Serum pregnancy testing will 
be performed by the central laboratory, and urine pregnancy testing will be performed at the 
study site.
9.6.5
Vital signs and body weight
Noninvasive pulse rate, systolic blood pressure, and diastolic blood pressure will be measured at 
clinic visits with the subject in a sitting position after at least 3 minutes at rest, according to the 
tabular schedule of study procedures, Section 5.2. Body weight will be determined without shoes 
and wearing light clothing. Body weight will be assessed according to the tabular schedule of 
study procedures, Section 5.2.
9.6.6
Complete physical examination
The complete physical examination will be performed by a medically qualified clinician licensed 
to perform the examination, according to the tabular schedule of study procedures, Section 5.2. 
The complete physical examination includes cardiac and respiratory function via auscultation, 
temperature, and review of all body systems. Clinically significant physical examination findings 
are to be reported as AEs.
9.6.7
Brief neurological examination
Brief neurological examination should be performed by a medically qualified clinician with 
documented training in the conduct of neurological examinations, according to the tabular 
schedule of study procedures, Section 5.2. If possible, the same clinician should conduct all 
neurological examinations for the same subject during the study.
The brief neurological examination will include assessment of consciousness and mental status, 
muscle strength, reflexes (knee jerk and biceps only), and coordination/cerebellar function.
Clinically significant neurological examination findings are to be reported as AEs.
9.6.8
12-lead ECG
A standard 12-lead ECG will be recorded according to the tabular schedule of study procedures, 
Section 5.2.
9.6.8.1
Overall ECG interpretation
Electrocardiograms will be initially reviewed locally by the investigator, subinvestigator, or 
qualified designated reader. If this reading identifies abnormal ECG findings that are assessed by 
the investigator or subinvestigator to be clinically significant, then the ECG should be repeated 
in 1 hour. If the clinically significant abnormality is confirmed by the repeat ECG, then the 
subject must be withdrawn from the study (Withdrawal Criteria, Section 6.3). The investigator 
may consult with the cardiologist at the central ECG lab (see Section 9.6.8.2) as needed to 
confirm the presence of a clinically significant ECG abnormality. It remains the responsibility of 
the investigator to decide whether an ECG finding is of clinical significance on the basis of the 
complete clinical picture and whether this finding influences the subject’s participation in the
study.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 43 of 70
9.6.8.2
Central ECG laboratory
All ECGs will be transmitted to and evaluated by a central ECG laboratory. Each ECG will be 
interpreted and reviewed by a qualified cardiologist who is blinded to the treatment. The results 
of this over-read will be entered into the study database and a report will be transmitted to the 
study investigator. The cardiologist at the central ECG laboratory will be available to consult 
with study investigators on the interpretation of individual subject ECG recordings as needed.
10
ASSESSMENT OF EFFICACY
10.1
Methods for assessing efficacy variables
The efficacy variables will be measured based on Seizure Records.
Seizure Records
Diagnosis of partial-onset seizures will be based on the International Classification of Epileptic 
Seizures of the International League Against Epilepsy (See Section 16.1). Each subject will keep 
a diary to note the daily seizure activity from Visit 1 until the last visit will record the following 
information:
•
Seizure type
•
Seizure frequency
•
Any AEs, including physical injury that occurred and any concomitant medication(s)/medical 
procedure(s) that was applied, if applicable.
Appropriate subject diaries will be provided to the subject for this purpose.
Medication Records
Each subject will be asked to record in their diary their daily intake of IMP and concomitant 
AED(s) from Visit 1 until the last visit. The following information should be completed on a 
daily basis:
•
Record whether IMP tablet was taken
•
Record any concomitant AED(s) taken
Any changes in concomitant AED(s) and other medication(s) must be recorded in the diary.
Assessment of Compliance
Subjects must bring their diary containing the seizure and medication records to each visit. The 
investigator or designee should check the medication record against the returned IMP and 
packaging. The investigator or designee should record the quantity of IMP returned in the 
appropriate logs and discrepancies should be addressed. Subject’s noncompliance is defined as 
less than 75% or more than 125% compliant with the dosage schedule, according to tablet 
counts.
The seizure records will be checked by the investigator or designee with regards to correct and 
thorough daily completion by the subject. The investigator must be confident that the subject is 
able to manage seizure records completion.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 44 of 70
11
STUDY MANAGEMENT AND ADMINISTRATION 
11.1
Adherence to protocol
The investigator should not deviate from the protocol. In medical emergencies, the investigator 
may use his/her medical judgment and may remove a study participant from immediate hazard 
before notifying UCB (or its representative) and the IRB/IEC in writing regarding the type of 
emergency and the course of action taken.
11.2
Monitoring
UCB (or designee) will monitor the study to meet the monitoring Standard Operating Procedures 
(SOPs), ICH-GCP guideline(s), and applicable regulatory requirements, and to ensure that study 
initiation, conduct, and closure are adequate. Monitoring of the study may be delegated by UCB 
to a contract research organization (CRO) or a contract monitor.
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s).
The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and investigator’s obligations are being fulfilled, 
and resolve any inconsistencies in the study records.
11.2.1
Definition of source data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies of eCRFs are not considered acceptable source 
documents. 
Source documents are original records in which raw data are first recorded. These may include 
source data documentation for the eCRF, hospital/clinic/general practitioner records(including a 
copy of the record), subject diaries, laboratory results, pharmacy records, or ECGs, for example. 
Source documents should be kept in a secure, limited access area.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the subject’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent.
Electronic data records, such as ECG records, must be saved and stored as instructed by UCB (or 
designee).
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 45 of 70
11.2.2
Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 11.2.1.
11.3
Data handling
11.3.1
Case Report form completion
In the event that the study is performed using electronic data capture, the investigator is 
responsible for prompt reporting of accurate, complete, and legible data in the eCRFs and in all 
required reports.
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change.
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator.
The investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF Instructions.
11.3.2
Database entry and reconciliation
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed.
11.3.3
Subject Screening and Enrollment log/Subject Identification Code list
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log.
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation.
11.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 46 of 70
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused study drug and other material in accordance with UCB procedures for the study.
11.5
Archiving and data retention
The record retainer at the study site and the IRB/IEC will retain the GCP defined essential 
document until at least 10 years after the discontinuation or completion of the study conduct. If
UCB requires retention of these documents for longer period, the duration and method of 
retention will be decided upon discussion between UCB and study site.
It is responsibility of UCB (or designee) to inform the record retainer as to when the documents 
should no longer to be retained.
11.6
Audit and inspection
The investigator and head of the participating study site (Japan only) will permit study-related 
audits mandated by UCB, after reasonable notice, and inspections by domestic or foreign 
regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH-GCP, and applicable regulatory 
requirements.
The investigator and head of the participating study site (Japan only) will provide direct access to 
all study documents, source records, and source data. If an inspection by a regulatory authority is 
announced, the investigator will immediately inform UCB (or designee).
11.7
Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study.
12
STATISTICS
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan.
12.1
Definition of analysis sets
The primary analysis set will be the Safety Set (SS) and will include all enrolled subjects who 
took at least 1 dose of LCM. The analysis set for the efficacy-related data will be the Full 
Analysis Set and will include all subjects in the SS having at least 1 day with available seizure 
diary data in EP0009.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 47 of 70
12.2
General statistical considerations
Descriptive statistics will be used to provide an overview of the safety and efficacy results. For 
categorical parameters, the number and percentages of subjects in each category will be 
presented. The denominator for percentage will be based on the number of subjects appropriate 
for the purpose of analysis. For continuous parameters, descriptive statistics will include n, 
mean, standard deviation (SD), median, minimum, and maximum.
Unless otherwise specified, baseline will be determined from the Baseline values of EP0008. 
Subjects who prematurely withdraw from the study will be evaluated based on the data collected 
at each visit attended.
12.3
Planned safety analyses
All safety analyses will be performed on the SS. 
12.3.1
Analysis of the primary safety variable
Treatment-emergent AEs will be defined as those events starting on or after the date of first dose 
of IMP, or whose severity worsen on or after the date of first IMP dosing. Adverse events 
occurring within 30 days after final IMP dose will be considered treatment-emergent. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) and tabulated by System Organ Class and preferred term. 
Summary tables for number and percentage of subjects reporting at least 1 TEAE, tabulated by 
MedDRA® System Organ Class and preferred term, will be presented. In addition, a summary 
table of TEAEs by intensity may be generated. Treatment-emergent AEs that lead to early 
withdrawal from the study as well as treatment-emergent SAEs will also be tabulated.
12.3.2
Other safety analyses
Other variables assessing safety are laboratory parameters, ECGs (12-lead), vital signs, and body 
weight.
Measurements and changes from Baseline in continuous laboratory parameters in hematology, 
clinical chemistry, and urinalysis, ECGs (12-lead), vital signs (blood pressures and pulse rate), 
and body weight will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum and maximum). When analyzing categorical data, the number and percentage 
of subjects in each category will be presented. In addition, shift tables may be used to evaluate 
the number and percentage of subjects having a different post-Baseline status when compared to 
their Baseline status.
12.4
Planned efficacy analyses
All efficacy variables are to be evaluated descriptively.
12.4.1
Analysis of primary efficacy variables
No primary efficacy variables are defined for EP0009.
12.4.2
Analysis of secondary efficacy variables
Partial-onset seizure frequency per 28 days will be calculated as ([number of seizures over the 
specified analysis interval] divided by [number of days in the interval]) multiplied by 28. The 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 48 of 70
percent change in seizure frequency per 28 days (PCH) from the Baseline Period of EP0008 (B) 
to the appropriate analysis period (P) is defined as:
PCH=[(SFP-SFB)/SFB]x100
where SFP corresponds to the seizure frequency during the analysis period and SFB corresponds 
to the Baseline Period seizure frequency. 
Descriptive statistics (ie, mean, SD, median, minimum and maximum) for the percent change in 
partial-onset seizure frequency per 28 days from the Baseline Period of EP0008 will be 
summarized. The number and percentage of subjects with a ≥50% reduction from Baseline in 
partial-onset seizure frequency per 28 days will be summarized.
12.4.3
Other efficacy analyses
The number and percentage of subjects with a ≥75% reduction from Baseline in partial-onset 
seizure frequency per 28 days will be summarized. The number and percentage of subjects 
achieving a seizure-free status and descriptive statistics for the percentage of seizure-free days 
will be presented. Additionally, the number and percentage of subjects receiving LCM as 
monotherapy for at least 6 months and at least 12 months will be presented.
12.5
Handling of protocol deviations
After all eCRFs have been retrieved and entered, all queries issued and answered to the extent 
possible, and prior to the database snapshot, a Data Review Meeting will be held. Important 
protocol deviations (ie, those considered to have an impact on, eg, primary safety parameters or 
study conduct) will be identified and reviewed by a panel consisting of the Clinical Project 
Manager, the study biostatistician, study physician, a representative of the monitoring team, and 
other appropriate team members according to the specification of the protocol deviations, which 
will be defined prior to the database snapshot.
12.6
Handling of dropouts or missing data
Subjects who prematurely withdraw from the study will be evaluated based on the data collected 
at each visit attended.
12.7
Planned interim analysis and data monitoring
No formal interim analysis is planned. However, data will be reported prior to the completion of 
this study to support regulatory submissions. At a minimum, 2 interim reports are planned after 
all enrolled Japanese subjects complete through Visit 5 (Week 24) and after all enrolled Japanese 
subjects complete through Visit 7 (Week 48).
12.8
Determination of sample size
No formal sample size determination has been performed because EP0009 is an extension study. 
Approximately 378 subjects, ie, 70% of subjects who were randomized in EP0008, are 
anticipated to participate in this extension study.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 49 of 70
13
ETHICS AND REGULATORY REQUIREMENTS
13.1
Informed consent
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator.
Prior to participation in the study, the written Informed Consent form should be signed and
personally dated by the subject, or his/her legal representative, and by the person who conducted 
the informed consent discussion (investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection.
If the Informed Consent form is amended during the study, the investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form.
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. An eCRF 
must not be started, nor may any study specific procedure be performed for a given subject, 
without having obtained his/her written consent to participate in the study.
13.2
Subject identification cards
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with him/her at all times.
13.3
Institutional Review Boards and Independent Ethics 
Committees
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki.
The investigator/UCB (or designee), and head of the participating study site (Japan only) will 
ensure that an appropriately constituted IRB/IEC that complies with the requirements of the 
current ICH-GCP version or applicable country-specific regulations will be responsible for the 
initial and continuing review and approval of the clinical study. Prior to initiation of the study, 
the investigator/UCB will forward copies of the protocol, Informed Consent form, Investigator’s 
Brochure, investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all 
other subject-related documents to be used for the study to the IRB/IEC for its review and 
approval.
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Clinical Study Protocol
Lacosamide
EP0009
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Page 50 of 70
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol.
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects.
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed.
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification.
13.4
Subject privacy
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening.
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study).
13.5
Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented.
14
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 51 of 70
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable.
14.1
Insurance
If any study-related injuries occur in a subject, the sponsor assumes responsibility for all the 
injuries and makes compensation available to the subject, except for the case that has been 
proved that the injury was caused by intentional tort or serious mistake of the participating 
investigator(s)/study site(s) in a study or intentional tort or serious mistake of the subject 
himself/herself. The sponsor should explain this in advance to the investigator(s)/study site(s) as 
well as taking necessary measures, including joining some insurance to secure the responsibility. 
The sponsor should also tell the subject to inform the investigator(s) immediately if any 
study-related injuries occur. If the investigators receive a report of study-related injuries from the 
subject, the investigator(s) should give necessary treatment immediately, as well as informing the 
sponsor. The compensation/indemnification of the health injuries of the subject will be made in 
accordance with the provisions of the clinical study contract.
14.2
Publication
The investigators should not disclose unpublished data provided by the sponsor to any third party 
without prior written consent of the sponsor.
When disclosing any information about the study (method and results of study, etc) or 
information on the investigational product or development, the investigators should obtain prior 
approval of the sponsor for the contents of a manuscript to be published and other materials. The 
sponsor will respond to requests for permitting publication accordingly and will not postpone the 
permission without any justification.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 52 of 70
15
REFERENCES
Beghi E, Sander JW. The natural history and prognosis of epilepsy. In: Engel J Jr, Pedley TA, 
editors. Epilepsy: A Comprehensive Textbook. 2nd ed. Philadelphia: Lippincott Williams and 
Wilkins; 2008:p.65-70.
Chinese Medical Association. Book for epilepsy in China clinical practice guidelines series,        
-author’s translation. 1st ed. Beijing: People’s Medical Publishing house; 2007. 1-2.
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed 02 Feb 2012.
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4.
Inoue Y. Commission on Treatment Guidelines of the Japan Epilepsy Society. Report from 
Commission on Treatment Guidelines of the Japan Epilepsy Society. Guidelines for Drug 
Therapy in Adult Patients with Epilepsy. Journal of the Japan Epilepsy Society. 2005;23: 249-53.
Perucca E. Established antiepileptic drugs. Baillière’s Clin Neurol. 1996;5:693-722.
Shorvon S, Perucca E, Engel J, editors. Treatment of Epilepsy. 3rd ed. Oxford:                     
Wiley-Blackwell;2009.
Statistics and Information Department, Minister's Secretariat, Health Statistics Office, Vital and 
Health Statistics Division, Ministry of Health, Labour and Welfare. Patient Survey 2008. 
Volume 1, Table 64, Total number of patients, gender and age distribution by subcategory of 
injuries and diseases, 2009. author’s translation.                                                                                
http://www.e-stat.go.jp/SG1/estat/List.do?lid=000001060228. Accessed 02 Feb 2012.
Ueda Y. [A new era of anti-epileptic drug (AED): Expectation for a new-type medicine and 
combination therapy with existing AED]. Folia Pharmacol. Jpn. 2007;129:116-8.
World Health Organization. Epilepsy. http://www.who.int/mediacentre/factsheets/fs999/en/. 
Accessed 02 Feb 2012.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 53 of 70
16
APPENDICES
16.1
International Classification of Epileptic Seizures (1981)
International Classification of Epileptic Seizures (1981)
I.
Partial seizures (focal, local)
A. Simple partial seizures (consciousness not impaired)
1. With motor signs
a) Focal motor without march
b) Focal motor with march (Jacksonian)
c) Versive
d) Postural
e) Phonatory (vocalization or arrest of speech)
2. With somatosensory or special sensory symptoms (simple hallucinations, eg, 
tingling, light flashes, buzzing)
a) Somatosensory
b) Visual
c) Auditory
d) Olfactory
e) Gustatory
f)
Vertiginous
3. With autonomic symptoms or signs (including epigastric sensation, pallor, 
sweating, flushing, piloerection, and pupillary dilatation)
4. With psychic symptoms (disturbance of higher cerebral function). These symptoms 
rarely occur without impairment of consciousness and are much more commonly 
experienced as complex partial seizures.
a) Dysphasic
b) Dysmnesic (eg, déjà-vu)
c) Cognitive (eg, dreamy states, distortions of time sense)
d) Affective (fear, anger, etc.)
e) Illusions (eg, macropsia)
f)
Structured hallucinations (eg, music, scenes)
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
with simple symptomatology)
1. Simple partial onset followed by impairment of consciousness
a) With simple partial features followed by impaired consciousness (A.1. - A.4.)
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 54 of 70
b) With automatisms
2. With impairment of consciousness at onset
a) With impairment of consciousness only
b) With automatisms
C. Partial seizures evolving to secondarily generalized seizures (this may be 
generalized tonic-clonic, tonic, or clonic)
1. Simple partial seizures (A) evolving to generalized seizures
2. Complex partial seizures (B) evolving to generalized seizures
3. Simple partial seizures evolving to complex partial seizures evolving to   
generalized seizures
II. Generalized seizures (convulsive or non-convulsive)
A. 1. Absence seizures
a) Impairment of consciousness only
b) With mild clonic components
c) With atonic components
d) With tonic components
e) With automatisms
f)
With autonomic components
(b through f may be used alone or in combination)
2. Atypical absence
May have:
a) Changes in tone that are more pronounced than in A.1
b) Onset and/or cessation that is not abrupt
B. Myoclonic seizures - Myoclonic jerks (single or multiple)
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures - (Astatic)
(combinations of the above may occur, eg, B and F, B and D)
Ш. Unclassified epileptic seizures
Includes all seizures that cannot be classified because of inadequate or incomplete data 
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 55 of 70
and some that defy classification in hitherto described categories. This includes some
neonatal seizures, eg, rhythmic eye movements, chewing, and swimming movements.
Status epilepticus (prolonged partial or generalized seizures without recovery between 
attacks)
Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:489-501.
REDACTED COPY 
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eptic
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thereof. 


UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 56 of 70
16.2
International Classification of Epilepsies and Epileptic 
Syndromes (1989)
International Classification of Epilepsies and Epileptic Syndromes (1989)
1. Localization-related (focal, local, partial) epilepsies and syndromes
1.1 Idiopathic (with age-related onset)
•
Benign childhood epilepsy with centrotemporal spike
•
Childhood epilepsy with occipital paroxysms
•
Primary reading epilepsy
1.2 Symptomatic
•
Chronic progressive epilepsia partialis continua of childhood (Rasmussen syndrome)
•
Syndromes characterized by seizures with specific modes of precipitation
•
Temporal lobe epilepsy
•
Frontal lobe epilepsy
•
Parietal lobe epilepsy
•
Occipital lobe epilepsy
1.3 Cryptogenic
2. Generalized epilepsies and syndromes
2.1 Idiopathic (with age-related onset − listed in order of age)
•
Benign neonatal familial convulsions
•
Benign neonatal convulsions
•
Benign myoclonic epilepsy in infancy
•
Childhood absence epilepsy (pyknolepsy)
•
Juvenile absence epilepsy
•
Juvenile myoclonic epilepsy (impulsive petit mal)
•
Epilepsy with grand mal (GTCS) seizures on awakening
•
Other generalized idiopathic epilepsies not defined above
•
Epilepsies with seizures precipitated by specific modes of activation
2.2 Cryptogenic or symptomatic (in order of age)
•
West syndrome (infantile spasms, Blitz-Nick-Salaam Krämpfe)
•
Lennox-Gastaut syndrome
•
Epilepsy with myoclonic-astatic seizures
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 57 of 70
•
Epilepsy with myoclonic absences
2.3 Symptomatic
2.3.1 Non-specific etiology
•
Early myoclonic encephalopathy
•
Early infantile epileptic encephalopathy with suppression-burst
•
Other symptomatic generalized epilepsies not defined above
2.3.2 Specific syndromes
3. Epilepsies and syndromes undetermined whether focal or generalized
3.1 With both generalized and focal seizures
•
Neonatal seizures
•
Severe myoclonic epilepsy in infancy
•
Epilepsy with continuous spikes-waves during slow wave sleep
•
Acquired epileptic aphasia (Landau-Kleffner-syndrome)
•
Other undetermined epilepsies not defined above
3.2 Without unequivocal generalized or focal features
4. Special syndromes
4.1 Situation-related seizures (Gelegenheitsanfälle, Occasional seizures)
•
Febrile convulsions
•
Isolated seizures or isolated status epilepticus
•
Seizures occurring only when there is an acute metabolic or toxic event due to factors 
such as alcohol, drugs, eclampsia, nonketotic hyperglycemia
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia.
1989;30:389-99.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 58 of 70
16.3
Protocol Amendment 1
Rationale for the amendment
The primary purpose of this nonsubstantial protocol amendment is to revise the contact 
information regarding SAE reporting. In accordance with the contract with the CRO, SAEs will 
be reported to UCB directly. 
The current estimated number of patients with epilepsy in China has been corrected. Dates of the 
planned study duration are revised.
The remainders of the changes in this amendment are described in detail below.
Modifications and changes
Global changes
The following global changes have been made:
•
The version of the C-SSRS at each visit has been stipulated clearly for the site.
•
The term “active” used in withdrawal criteria related to suicidality has been changed to 
“actual” for keeping the consistency with the term which is used in the C-SSRS. 
•
Contact IVRS/IWRS at the Final Visit has been deleted because there is no drug distribution 
at the Final Visit.
•
Inconsistency between Section 5.2 and Section 8 has been corrected.  
Specific changes
This section displays the modifications compared with the previous Protocol dated                          
06 Mar 2012.
Change #1
Title page
UCB Japan Co. Ltd.
Shinjuku Grand Tower 8-17-1
Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023 
JAPAN
Has been changed to:
UCB Japan Co. Ltd.
Shinjuku Grand Tower 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 59 of 70
8-17-1 Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023 
JAPAN
Change #2
SPONSOR DECLARATION
Study Physician
, MD, PhD
_____________________________
Date/Signature
Clinical Program Director 
, PhD
_____________________________
Date/Signature
Has been changed to:
Study Physician
 MD
_____________________________
Date/Signature
Clinical Program Director
 PhD
_____________________________
Date/Signature
Change #3
STUDY CONTACT INFORMATION
UCB Japan Co. Ltd.
Shinjuku Grand Tower 8-17-1
Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023
JAPAN
REDACTED COPY 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 60 of 70
Medical Expert
Name:
, MD, PhD
Address:
National Epilepsy Center Shizuoka Institute of Epilepsy and 
Neurological Disorders
886 Urushiyama, Aoi-Ku, Shizuoka-Shi, Shizuoka 420-8688, JAPAN
Phone:
Fax:
Sponsor Study Physician
Name:
, MD, PhD
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive, Raleigh, NC 27617, US
Phone:
Fax:
Clinical Project Manager 
Name:
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower 8-17-1, Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Associate Clinical Project Manager (Japan)
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower 8-17-1, Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Associate Clinical Project Manager (China)
Name:
 
Address:
UCB Trading (Shanghai) Co. Ltd., Beijing Liaison Office 
Suite 806, No. 4 Tower, 38 East 3rd Ring North Rd., Chaoyang 
District, Beijing, 100026, PRC
Phone:
Fax:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 61 of 70
Clinical Trial Biostatistician 
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower 8-17-1, Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Has been changed to:
UCB Japan Co. Ltd.
Shinjuku Grand Tower 
8-17-1 Nishi-Shinjuku
Shinjuku-Ku
Tokyo 160-0023
JAPAN
Medical Expert (Japan)
Name:
, MD, PhD
Address:
National Epilepsy Center Shizuoka Institute of Epilepsy and 
Neurological Disorders
886 Urushiyama, Aoi-Ku, Shizuoka-Shi, Shizuoka 420-8688, JAPAN
Phone:
Fax:
Sponsor Study Physician
Name:
 MD
Address:
UCB Trading (Shanghai) Co. Ltd., Shanghai office 
Suite 3905, Raffles City Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001, PRC
Phone:
Fax:
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 62 of 70
Clinical Project Manager 
Name:
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Associate Clinical Project Manager (China)
Name:
 
Address:
UCB Trading (Shanghai) Co. Ltd., Shanghai office
Suite 3905, Raffles City Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001, PRC
Phone:
Fax:
Associate Clinical Project Manager (Japan)
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
, Rph
Address:
UCB Japan Co. Ltd.
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku,
Tokyo, 160-0023, JAPAN
Phone:
Fax:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 63 of 70
Change #4
STUDY CONTACT INFORMATION 
The following study contact information has been added:
National Principal Investigator (China)
Name:
, MD
Address:
Huashan Hospital Fudan University
No.12 Middle Urumqi Road, Shanghai, 200040, PRC
Phone:
Fax:
Change #5
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h), safety related issues
Fax
Japan:
UCB Japan: +81 3 6864 7400
PAREXEL: +81 3 6888 5377
China:
PAREXEL: +86 10 5879 7674
Phone
Japan:
UCB Japan:
+81 3 6864 7410 (during business hours)
+81 80 1100 5372 (outside business hours)
PAREXEL: +81 3 3537 5907
China:
PAREXEL: +65 6221 8582 (Singapore)
Email
Japan:
UCB Japan: JDSO@ucb.com
PAREXEL: +Japan-Medical@parexel.com
China:
PAREXEL: Medical_Beijing@parexel.com
Has been changed to:
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 64 of 70
Serious adverse event reporting (24h)
Fax
UCB Japan: +81 3 6864 7400
Email
UCB Japan: UCBJ-Safety@ucb.com
Safety related issues 
Phone
PAREXEL International Inc. : +1 978 805 7613
Change #6
Section 2 INTRODUCTION
Last sentence in paragraph 2
It is estimated that there are currently around 4,000,000 patients with epilepsy in China, with
approximately 400,000 new patients every year (Chinese Medical Association, 2007).
Has been changed to:
It is estimated that there are currently around 9,000,000 patients with epilepsy in China, with 
approximately 400,000 new patients every year (Chinese Medical Association, 2007).
Change #7
Section 5.1.2 Dates of the planned study duration
The study duration is planned from first quarter of 2013 to second quarter of 2017.
Has been changed to:
The study duration is planned from third quarter of 2012 to second quarter of 2017.
Change #8
Section 5.2 Table 5-1: Schedule of study assessments
C-SSRS
Has been changed to:
C-SSRS (the “Since Last Visit” version)
Change #9
Section 5.2 Table 5-1: Schedule of study assessments
Contact IVRS/IWRS at Final Visit has been deleted.
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 65 of 70
Change #10
Section 5.2 Table 5-1: Schedule of study assessments, footnote i
i Serum pregnancy tests should be performed at Visit 1, ESV and Final Visit. Urine pregnancy 
tests will be performed for all other designed study visits.
Has been changed to: 
i Serum pregnancy tests should be performed at Visit 1, ESV and Final Visit. Urine pregnancy
tests will be performed for all other designated study visits.
Change #11
Section 6.3 Withdrawal criteria, criterion 7
7. Subject has active suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide Severity 
Rating Scale (C-SSRS). The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study.
Has been changed to:
7. Subject has actual suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide Severity 
Rating Scale (C-SSRS). The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study.
Change #12
Section 8.1.1 Visit 1 (Week 0), Section 8.1.2 Visits 2 through 4 (Weeks 4 through 12), 
Section 8.1.3 From Visit 5 until End-of-Study/Withdrawal Visit (Week 24 or later), 
Section 8.1.4 End-of-Study Visit, Section 8.1.5 Withdrawal Visit, and Section 8.2.1 
Final visit (2 weeks after final LCM dose), the following bullet:
•
C-SSRS
Has been changed to:
•
C-SSRS (the “Since Last Visit” version)
Change #13
Section 8.2.1 Final Visit (2 weeks after final LCM dose), the following bullet:
•
Contact IVRS/IWRS 
Has been deleted.
Change #14
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 66 of 70
Section 8.3 Unscheduled Visit, the following bullet:
•
Urine samples for pregnancy test (for women of childbearing potential)
Has been deleted.
Change #15
Section 9.2.2 Procedures for reporting serious adverse events
First sentence in paragraph 1
If an SAE is reported, UCB (or designee) must be informed within 24 hours of receipt of this 
information by the site (see contact information for SAE reporting listed in the Serious Adverse 
Event Reporting section at the front of the protocol).
Has been changed to:
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol).
Change #16
Section 9.2.2 Procedures for reporting serious adverse events
Last sentence in paragraph 5
Serious AEs that the investigator thinks may be associated with the IMP must be reported to 
UCB (or designee) regardless of the time between the event and the end of the study.
Has been changed to:
Serious AEs that the investigator thinks may be associated with the IMP must be reported to 
UCB regardless of the time between the event and the end of the study.
Change #17
Section 9.3 Adverse events of special interest
The following has been added after the first sentence in paragraph 1.
The procedure for reporting AEs of special interest is the same as that of SAEs (see 
Section 9.2.2).
Change #18
Section 9.3 Adverse events of special interest, the following bullet:
•
Serious suspected multiorgan hypersensitivity reactions
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 67 of 70
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor (or designee) by the investigator using the following algorithm as agreed with the US 
Food and Drug Administration:
Has been changed to:
•
Serious suspected multiorgan hypersensitivity reactions
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US Food and 
Drug Administration:
REDACTED COPY 
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nd d 
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 68 of 70
16.4
Protocol Amendment 2
Rationale for the amendment
The primary purpose of this nonsubstantial protocol amendment is to clarify the procedure of 
pregnancy testing. Urine pregnancy testing will be done at each study site. 
Withdrawal criteria have been revised to provide additional clarification based on program 
medical review. Suicidal ideation and behavior and clinically significant neurological 
examination findings observed throughout the study period are clarified as findings to be 
reported as AEs. International classification of epilepsies and epileptic syndromes (1989) has 
been added as an appendix for reference.
Modifications and changes
Global changes
There are no global changes in this amendment.
Specific changes
This section displays the modifications in this amendment compared with the 
Protocol Amendment 1 dated 12 Sep 2012. 
Change #1
Section 6.3 Withdrawal criteria, criterion 1
1. Subject develops second- or third-degree AV (atrioventricular) block, or another clinically 
relevant change in medical condition (or ECG or laboratory parameter), as determined by the 
investigator, or if the investigator feels it is in the interest of the subject to withdraw.
Has been changed to:
1. Subject develops second- or third-degree AV (atrioventricular) block.
Change #2
Section 6.3 Withdrawal criteria, criterion 6 and 10
The following has been added after the last sentence:
(See Section 9.6.3)
Change #3
Section 6.3 Withdrawal criteria
The following criterion has been added as withdrawal criterion 11:
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 69 of 70
11. Subject develops a clinically relevant change in medical condition (or ECG or laboratory 
parameter) as determined by the investigator, and the investigator feels it is in the interest of the 
subject to withdraw.
Change #4
Section 8.1.1 Visit 1 (Week 0)
Last sentence
The following information collected in EP0008 will be used for EP0009: demographic 
information, medical/procedure history, epilepsy information (diagnosis of epilepsy, etiology of 
epilepsy, ILAE seizure classification, focus localization, classification of epileptic syndrome, 
treatment history).
Has been changed to:
The following information collected in EP0008 will be used for EP0009: demographic 
information, medical/procedure history, epilepsy information (diagnosis of epilepsy, etiology of 
epilepsy, ILAE seizure classification, focus localization, classification of epileptic syndrome 
[See Section 16.2], treatment history).
Change #5
Section 9.6.1 Assessment of suicidality
The following sentence has been added after the last sentence:
Suicidal ideation and behavior are to be reported as AEs.
Change #6
Section 9.6.4 Pregnancy testing
The following sentence has been added after the last sentence:
Serum pregnancy testing will be performed by the central laboratory, and urine pregnancy testing 
will be performed at the study site.
Change #7
Section 9.6.7 Brief neurological examination
The following sentence has been added after the last sentence:
Clinically significant neurological examination findings are to be reported as AEs.
Change #8
Section 16.2 International Classification of Epilepsies and Epileptic Syndromes (1989)
The above section and its content have been added. 
REDACTED 
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13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 70 of 70
17
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements.
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract.
Investigator:
__________________________________
Printed name
__________________________________
Date/Signature
REDACTED COPY 
__
__
This document cannot be used to support any marketing authorization 
___
__
Date/
Date
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and any extensions
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SAP_001.pdf: 
UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 1 of 35
STATISTICAL ANALYSIS PLAN
Study: EP0009
Product: Lacosamide
A MULTICENTER, OPEN-LABEL, UNCONTROLLED,
LONG-TERM, EXTENSION STUDY TO EVALUATE THE
SAFETY AND EFFICACY OF LACOSAMIDE AS
ADJUNCTIVE THERAPY IN JAPANESE AND CHINESE
ADULTS WITH PARTIAL-ONSET SEIZURES WITH OR
WITHOUT SECONDARY GENERALIZATION
PHASE 3
SAP/Amendment Number
Date
Final SAP
<12 Sep 2014>
Confidentiality Statement
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, 
published, or otherwise used without the express permission of UCB.
REDACTED COPY 
3
This document 
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12 S
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U
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or variations thereof. 


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12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 2 of 35
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures below indicate that the final version of 
the Statistical Analysis Plan (SAP) or amended SAP is released for execution.
REDACTED COPY 
Y
This document cannot be used to support any marketing authorization applplication and any xtens
nsion
ons 
exte
or 
ons 
variations thereof. 


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 3 of 35
TABLE OF CONTENTS
LIST OF ABBREVIATIONS....................................................................................................5
1
INTRODUCTION .............................................................................................................6
2
PROTOCOL SUMMARY.................................................................................................6
2.1
Study objectives.......................................................................................................6
2.1.1
Primary objectives .........................................................................................6
2.1.2
Secondary objective.......................................................................................6
2.2
Study variables.........................................................................................................6
2.2.1
Safety variables..............................................................................................6
2.2.1.1
Primary safety variables.......................................................................6
2.2.1.2
Other safety variables...........................................................................6
2.2.2
Efficacy variables ..........................................................................................7
2.2.2.1
Primary efficacy variables ...................................................................7
2.2.2.2
Secondary efficacy variables ...............................................................7
2.2.2.3
Other efficacy variables .......................................................................7
2.3
Study design and conduct ........................................................................................7
2.4
Determination of sample size...................................................................................8
3
DATA ANALYSIS CONSIDERATIONS........................................................................9
3.1
General presentation of summaries and analyses ....................................................9
3.2
General study level definition..................................................................................9
3.2.1
Relative day ...................................................................................................9
3.2.2
Analysis time point ........................................................................................9
3.2.3
Completer cohort .........................................................................................10
3.3
Definition of Baseline values.................................................................................10
3.4
Protocol deviations.................................................................................................10
3.5
Analysis sets...........................................................................................................11
3.5.1
All Subjects Screened ..................................................................................11
3.5.2
Safety Set .....................................................................................................11
3.5.3
Full Analysis Set..........................................................................................11
3.6
Treatment assignment and treatment group...........................................................11
3.7
Center pooling strategy..........................................................................................11
3.8
Coding dictionaries................................................................................................11
4
STATISTICAL/ANALYTICAL ISSUES.......................................................................11
4.1
Adjustments for covariates ....................................................................................11
4.2
Handling of dropouts or missing data....................................................................11
4.3
Interim analyses and data monitoring....................................................................13
4.4
Multicenter studies.................................................................................................13
4.5
Multiple comparisons/multiplicity.........................................................................13
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 4 of 35
4.6
Use of an efficacy subset of subjects .....................................................................13
4.7
Examination of subgroups .....................................................................................13
5
STUDY POPULATION CHARACTERISTICS.............................................................13
5.1
Subject disposition.................................................................................................13
5.2
Protocol deviations.................................................................................................14
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................14
6.1
Demographics ........................................................................................................14
6.2
Other Baseline characteristics................................................................................14
6.3
Medical history and concomitant disease ..............................................................15
6.4
Concomitant medications.......................................................................................15
7
MEASUREMENTS OF TREATMENT COMPLIANCE...............................................16
8
SAFETY ANALYSES.....................................................................................................16
8.1
Extent of exposure .................................................................................................16
8.2
Adverse events.......................................................................................................17
8.3
Clinical laboratory evaluations ..............................................................................18
8.4
Vital signs, physical findings, and other observations related to safety................19
8.4.1
Vital signs ....................................................................................................19
8.4.2
Electrocardiograms ......................................................................................19
8.4.3
Other safety variables ..................................................................................20
9
EFFICACY ANALYSES ................................................................................................21
9.1
Statistical analysis of the primary efficacy variables.............................................21
9.2
Statistical analysis of the secondary efficacy variables .........................................21
9.3
Analysis of other efficacy variables.......................................................................22
10
PHARMACOKINETICS AND PHARMACODYNAMICS..........................................24
11
OTHER ANALYSES ......................................................................................................24
12
REFERENCES ................................................................................................................25
13
APPENDICES .................................................................................................................26
13.1
List of Other Significant AEs ................................................................................26
13.2
Marked lab abnormalities ......................................................................................28
13.2.1
Hematology..................................................................................................28
13.2.2
Chemistry.....................................................................................................30
13.3
Vital sign assessments - abnormal .........................................................................33
13.4
Electrocardiogram (ECG) – abnormal...................................................................35
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 5 of 35
LIST OF ABBREVIATIONS
AE(s) 
Adverse event(s)
AED(s) 
Antiepileptic drug(s)
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CRF
Case Report Form
ECG(s) 
Electrocardiogram(s)
eCRF 
Electronic Case Report form
EEG
Electroencephalogram
FAS 
Full Analysis Set
ICF
Informed consent form
ILAE
International League Against Epilepsy 
LCM
Lacosamide
LFT
Lever function test
MedDRA
Medical Dictionary for Regulatory Activities
PT
Preferred term
SAE(s) 
Serious adverse event(s)
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
QTcP
QT interval corrected using the population
SAP
Statistical analysis plan 
SD 
Standard deviation
SOC
System organ class
SS
Safety Set
TEAE 
Treatment-emergent adverse event
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
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12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 6 of 35
1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the statistical principals that are applied for the 
analyses as well as tables and listings that are foreseen for this study. Tables or listings might be 
added or slightly modified for the purpose of readability or clarification of results that might 
have been seen during the process of analyzing the data. Changes in the statistical methodology 
result in an SAP amendment.
This SAP should be read in conjunction with the following documents that provide all necessary 
background information and rationale for the current study and its design.
1) Finalized Study Protocol Amendment
2) Electronic Case Report Form (eCRF)
2
PROTOCOL SUMMARY
2.1
Study objectives
2.1.1
Primary objectives
The primary objectives of this study are the following:
•
To evaluate the safety and tolerability of long-term administration of lacosamide (LCM) at 
doses up to 400mg/day in Japanese and Chinese adults with epilepsy who have completed the 
Treatment and Transition Period of EP0008
•
To allow subjects who had completed the Treatment and Transition Periods of EP0008 to 
receive LCM 
2.1.2
Secondary objective
The secondary objective of this study is the following:
•
To evaluate the efficacy of long-term administration of LCM at doses up to 400mg/day in 
Japanese and Chinese adults with epilepsy who have completed the Treatment and Transition 
Periods of EP0008
2.2
Study variables
2.2.1
Safety variables
2.2.1.1
Primary safety variables
The primary safety variables are the following:
•
Adverse events (AEs) reported spontaneously by the subject or observed by the investigator
•
Subject withdrawals due to AEs
2.2.1.2
Other safety variables
The other safety variables are the following:
•
Changes in hematology, clinical chemistry, and urinalysis parameters
•
Changes in 12-lead electrocardiograms (ECGs)
•
Changes in vital sign measurements (ie, blood pressure, pulse rate)
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 7 of 35
•
Changes in body weight
2.2.2
Efficacy variables
2.2.2.1
Primary efficacy variables
No primary efficacy variables are defined for EP0009. 
2.2.2.2
Secondary efficacy variables
The secondary efficacy variables are the following:
•
Percent change from Baseline in partial-onset seizure frequency per 28 days, where Baseline 
is defined as the Baseline Period of EP0008
•
50% response, where a responder is a subject experiencing a ≥50% reduction from Baseline 
in partial-onset seizure frequency per 28 days, and Baseline is defined as the Baseline Period 
of EP0008
2.2.2.3
Other efficacy variables
Other efficacy variables are the following:
•
75% response, where a responder is a subject experiencing a ≥75% reduction from Baseline 
in partial-onset seizure frequency per 28 days and Baseline is defined as the Baseline Period 
of EP0008
•
Subjects who achieved “seizure-free” status (yes/no)
•
Percentage of seizure-free days 
•
Subjects who are changed to LCM monotherapy for at least 6 months
•
Subjects who are changed to LCM monotherapy for at least 12 months
2.3
Study design and conduct
EP0009 is a Phase 3, multicenter, open-label, uncontrolled, extension study designed to evaluate 
the safety, tolerability, and efficacy of long-term administration of LCM as adjunctive therapy at 
doses up to 400mg/day in Japanese and Chinese adults with partial-onset seizures with or 
without secondary generalization who have completed the Treatment and Transition Periods of 
EP0008 and chose to enroll in EP0009. 
Visit 1 of EP0009 is the same as the Final Visit of EP0008. Visits 2 through 4 of EP0009 will 
occur at 4-week intervals relative to the date of Visit 1. Beginning with Visit 5, each visit will 
occur at 12-week intervals relative to the date of Visit 1 until the End-of-Study/Withdrawal Visit. 
At the completion of EP0008, all subjects who choose to enroll in EP0009 will be taking a dose 
of LCM 200mg/day. During the EP0009 Treatment Period, the investigator will be allowed to 
increase or decrease the doses of LCM and/or up to 3 concomitant antiepileptic drug(s) (AED[s])
to optimize tolerability and seizure reduction for each subject. The LCM dose may be decreased 
to 100mg/day or increased, no faster than 100mg/day per week, up to 400mg/day. Changes in 
concomitant AED(s) will be allowed only if the LCM dose has been stable for the previous 
4 weeks; LCM dose must remain stable during changes to concomitant AED(s). Subjects may 
take no more than 3 concomitant AEDs except when temporary (≤12 weeks) use of an additional 
AED is required to switch to a new AED (ie, taper from old AED during titration of a new 
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 8 of 35
AED). New AED(s) may be added only when the subject has not optimally or adequately 
responded to a maximum tolerated dose of LCM. The concomitant AED(s) can be carefully 
tapered or discontinued at the discretion of the investigator. Monotherapy with LCM is 
permitted. Increasing the dose of LCM and/or concomitant AED(s), as well as the addition of a 
new AED, should be done at a visit (scheduled or unscheduled).
At the end of the Treatment Period, an End-of-Study Visit will be required. If subjects 
prematurely withdraw from the study, a Withdrawal Visit will be required. Subjects who
complete the Treatment Period and choose not to continue on to commercial LCM treatment, and 
subjects who prematurely withdraw from the study, will enter a Taper Period. During the Taper 
Period, subjects receiving doses greater than LCM 200mg/day at the End-of-Study/Withdrawal 
Visit should be tapered off gradually at a recommended decrease rate of LCM 200mg/day per 
week, unless the investigator feels that safety concerns require more rapid withdrawal of LCM. 
UCB (or designee) should be contacted if a more rapid withdrawal is required. A slower taper 
(e.g., LCM 100mg/day per week) is permitted, if medically necessary. Subjects receiving doses 
of LCM 200mg/day or lower at the End-of-Study/Withdrawal Visit are not required to taper off 
LCM. A Final Visit will be required 2 weeks after final LCM dose. Subjects who complete the 
Treatment Period and choose to continue on to commercial LCM treatment are not required to 
enter the Taper Period to taper off LCM or to return for a Final Visit; the End-of-Study Visit will 
be the last visit for these subjects. If LCM is not commercially available in a subject’s country at 
the time the study closes, access to LCM will be provided according to local laws. 
At selected sites, Japanese subjects may participate in an additional study (EP0024) with the
intravenous formulation of LCM without withdrawing from EP0009. The study period of
EP0024 will be included in that of EP0009. Subjects will continue to receive their current dose
of LCM at the time of entry and remain stable for the duration of EP0024. Subjects who
complete or withdraw from EP0024 will be given the opportunity to resume their participation in
EP0009 with oral LCM treatment. In the event that a subject withdraws from EP0024 and is
required to taper off LCM, the subject will return to EP0009 and taper using LCM tablets.
Adverse events and concomitant treatment(s)/medication(s) that occur or were administered 
during EP0024 will be recorded in EP0024. Ongoing AEs and concomitant
medication(s)/medical procedure(s) originating from the EP0024 will be followed in EP0009 
until resolution or until stable. Where possible, data updates related to the resolution of ongoing 
AEs and concomitant medication(s)/medical procedure(s) from EP0024 will be reported in the 
EP0024 database (eg, updates are made in the EP0024 databases until the database is locked). 
All other data reported for EP0024 will be captured in the EP0024 database. Per the EP0024 
protocol, the study (EP0024) will require hospitalization. Hospitalization for study participation 
does not need to be reported as an SAE.
2.4
Determination of sample size
No formal sample size determination has been performed because EP0009 is an extension study. 
Approximately 378 subjects, ie, 70% of subjects who were randomized in EP0008, are
anticipated to participate in this extension study.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 9 of 35
3
DATA ANALYSIS CONSIDERATIONS
3.1
General presentation of summaries and analyses
Datasets will be analyzed using SAS version 9.1.3 or higher. All tables and listings will use 
Courier New font size 9.
Descriptive statistics will be displayed to provide an overview of the safety and efficacy results.
For categorical parameters, the number and percentages of subjects in each category will be 
presented at the relevant time point. The denominator for percentages will be based on the 
number of subjects appropriate for the purpose of analysis. Percentages will be presented to one 
decimal place. Percentages will not be presented for zero counts and 100% will be presented as
an integer.  
For continuous parameters, descriptive statistics will include number of the subjects, mean, 
standard deviation (SD), median, minimum, and maximum. The minimum and maximum will be 
reported to the same number of decimal places as the raw data recorded in the CRF.  The mean, 
SD, median will be reported to one more decimal place, than the raw data recorded in the CRF.  
In general, the maximum number of decimal places reported should be 4 for any summary 
statistics. 
Subjects who withdraw early from the study will be evaluated based on the data collected at each 
visit attended or period entered. Data summaries will be presented overall and by randomized 
dose in EP0008 unless otherwise specified. Additionally, summaries will be presented separately 
by country.
3.2
General study level definition
3.2.1
Relative day
Relative day is defined as the day relative to the first dose in EP0009 of LCM. 
•
If the start date of an event occurred prior to the first dose of LCM in EP0009, the relative
day is calculated as start date minus first LCM dose date. In subject data listings, relative 
days based on this situation will be preceded by a “-“.
•
If the start date of an event occurred on or after the first dose of LCM but prior to or on the 
last dose of LCM in EP0009, the relative day is calculated as start date minus first LCM dose 
date + 1.
•
If the start date of an event occurred after the date of last dose of LCM in EP0009, the 
relative day is calculated as start date minus last dose date. In subject data listings, relative 
days based on this situation will be preceded by a “+”.
3.2.2
Analysis time point
For analysis purposes, the Treatment Period is defined as the period of time from the first dose of 
study drug during the EP0009 study to the date of last dose of study drug or the date of 
ESV/WV, whichever occurs later. The Treatment Period includes time while treated with LCM 
during the protocol-defined Taper Period if the subject enters the Taper Period.
The Post-Treatment Period is defined as the treatment-free observational period after the 
Treatment Period. It starts one day after the end date of the Treatment Period and ends on the 
date of the final clinic visit or date of last contact with the subject, whichever is later. Data for 
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 10 of 35
safety parameters evaluated at clinic visits (ie, laboratory, ECG, vital signs, weight, physical 
exam, and neurological exam) will be summarized for each visit during the Treatment Period. 
Additionally, the minimum and maximum values during the Treatment Period will be 
summarized. Repeated or unscheduled assessments will not be included in the by-visit 
summaries but will be considered when determining the minimum and maximum Treatment 
Period values.
Data from the Final Visit (2 weeks after final LCM dose) will be reported separately on by-visit
summaries of safety parameters evaluated at clinic visits. It should be noted that all subjects will 
not have completed a Final Visit. Subjects completing the study and continuing on commercially 
available LCM do not require a Final Visit per the protocol.
3.2.3
Completer cohort
A completer cohort will be defined as the subset of subjects in the FAS that were enrolled and 
treated with LCM for a specified duration of time and have seizure diary data available for the 
duration of the cohort. For example, a 6-month completer cohort consists of subjects enrolled 
and treated with LCM for at least 6 months and have efficacy data through at least 1-year 
exposure where a month is defined as 28 days. EP0009 will last 3 years, so 6-month completer 
cohort, 12-month completer cohort, 18- month completer cohort, 24-month completer cohort, 30-
month completer cohort, and 36-month completer cohort will be defined in this study.
3.3
Definition of Baseline values
Unless otherwise specified, Baseline will be defined from the Baseline values of EP0008and will 
be taken directly from EP0008 data sets (ie, not reprogrammed in EP0009).
For Baseline seizure frequencies, the partial-onset seizures per 28-days derived during the 
Baseline Period in EP0008 will be used. The number of lifetime AEDs from EP0008 and the 
number of concomitant AEDs taken during EP0008 will also be used.
For quantitative ECGs, Baseline was defined as the average of the 3 ECG measurements taken at 
Visit 3 of EP0008. If a subject had less than 3 ECG measurements on the day of Visit 3 of 
EP0008, Baseline was to be defined as the average of the available ECGs on the day of Visit 3 of 
EP0008. If no ECGs were available on the day of Visit 3 of EP0008, Baseline was not defined 
for ECG assessments.
For laboratory and vital sign data, Baseline was the last non-missing evaluation prior to the first 
dose of intake of the study drug in EP0008.
3.4
Protocol deviations
The data will be reviewed to identify important protocol deviations. Important protocol 
deviations will be identified and documented prior to database snapshot for interim reports and 
database lock for the final analysis based on predefined criteria. Important deviations will be 
categorized as follows: 
•
Inclusion criteria
•
Exclusion criteria
•
Withdrawal criteria
•
Prohibited medications
•
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 11 of 35
•
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A list of subjects with important protocol deviations will be agreed upon and documented prior 
to database lock.
3.5
Analysis sets
3.5.1
All Subjects Screened
All subjects screened will consist of all subjects who signed the informed consent form (ICF).
3.5.2
Safety Set
The Safety Set (SS) will include all enrolled subjects in EP0009 who took at least 1 dose of LCM
in EP0009.
3.5.3
Full Analysis Set
The analysis set for the efficacy variables will be the Full Analysis Set (FAS) and will include all 
subjects in the SS having at least 1 day with available seizure diary data in EP0009.
3.6
Treatment assignment and treatment group
All subjects treated in EP0009 received LCM at doses ranging between 100mg/day to 
400mg/day. A subject’s LCM dose may be decreased to 100mg/day or increased, no faster than 
100mg/day per week, up to 400mg/day. In terms of results presentation, summaries will present 
subjects overall and by randomized dose in EP0008: placebo, LCM 200mg/day, or LCM 
400mg/day, unless otherwise specified.
3.7
Center pooling strategy
For the purpose of the summaries and analyses, the term ‘Center’ will be used to define each site.
All centers will be pooled by country for the purpose of analysis.
Descriptive summaries will not be presented by individual center. Subject data listing will 
provide data sorted by country and individual center.
3.8
Coding dictionaries
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
version 16.1.
All medications will be coded using the World Health Organization Drug Dictionary (WHO-DD)
version SEP/2013.
All coding will be performed prior to database lock.
4
STATISTICAL/ANALYTICAL ISSUES
4.1
Adjustments for covariates
This section is not applicable.
4.2
Handling of dropouts or missing data
For by-visit analyses, data from the Withdrawal Visit will be presented with data corresponding 
to the next scheduled visit for the subject.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 12 of 35
Due to the potential for missing number of seizures for a given diary date, seizure frequency will 
be calculated using only the number of days for which seizure data is provided.
For analyses of treatment-emergent AEs (TEAEs) and concomitant medications, a complete 
date must be established in order to correctly identify the TEAE or medication as occurring 
during treatment or not. For purposes of imputing missing components of partially reported start 
and stop dates for adverse events and for medications, the algorithms listed below will be 
followed. Start and stop dates of AEs or concomitant medication will be displayed as reported in 
the subject data listings (ie, no imputed values will be displayed in data listing).
•
Missing start day, but month and year present: If the start date of study treatment occurred in 
the same month and year as the occurrence of the event/medication, the start day of the 
event/concomitant medication will be assigned to the day of first intake of study treatment in 
order to treat the adverse event and medication as treatment-emergent and concomitant, 
respectively. Otherwise the start day will be set to the 1st day of the month.
•
Missing start day and month, but year present: If the start date of trial medication occurred in 
the same year as the occurrence of the event/medication, the start day and month will be 
assigned to the date of first intake of study treatment in order to treat the adverse event and 
medication as treatment-emergent and concomitant, respectively. Otherwise the start day and 
month will be set to January 1st.
•
Start date is completely unknown: The start date of the event/concomitant medication will be 
assigned to the date of first intake of study treatment.
•
Missing end day, but month and year present: The end day will be set to the last day of the 
month.
•
Missing end day and month, but year present: The end day and month will be set to the 
maximum of the date of study or the date equivalent to 30 days after last intake of study 
treatment.
•
End date is completely unknown: The end date will not be imputed.
However, if the study termination year and year for the date which is 30 days after last intake of 
study treatment are greater than the event/concomitant medication year, the day and month are to 
be set to December 31st.
Relative day is not calculated for partial dates in cases where relative day is shown in a subject 
listing. In such cases, relative day should be left blank in the subject data listings.
Subjects participating in EP0024 while also enrolled in EP0009 will have missing data for 
seizure frequency and drug dosing while participating in the EP0024 trial. As the duration of the 
EP0024 study will be short (3-7 days), no imputation for data missing due to participation in 
EP0024 will be performed. Subjects will be assigned the same dose in EP0024 as that assigned 
in EP0009 for the two weeks prior to the start of EP0024. As such, time during the EP0024 study
will not be subtracted from the exposure calculations (eg, exposure will be from the start of LCM 
treatment in the EP0009 study until the date of last dose of LCM in EP0009). 
For the calculation of variables related to seizure frequency, the dates during participation in
EP0024 will be considered as not done for the purpose of efficacy analyses for trial EP0009 (eg,
these dates will not be considered as days evaluated for seizure frequency). Due to the short
nature of the EP0024 study, only a few days of seizure frequency data are expected to be missing
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 13 of 35
due to participation in EP0024 unless otherwise specified (eg, for the evaluation of seizure 
freedom).
4.3
Interim analyses and data monitoring
No formal interim analysis is planned. However, data will be reported prior to the completion of 
this study to support regulatory submissions. At a minimum, 2 interim reports are planned after 
all enrolled Japanese subjects complete through Visit 5 (Week 24) and after all enrolled Japanese 
subjects complete through Visit 7 (Week 48). All analyses described in this SAP will be 
presented at each interim analysis for regulatory reporting.
4.4
Multicenter studies
Descriptive summaries for individual sites will not be presented due to the low number of
expected subjects per site. However, subject data listings will provide data grouped by country 
and individual site.
4.5
Multiple comparisons/multiplicity
This section is not applicable.
4.6
Use of an efficacy subset of subjects
Selected efficacy analyses will be performed for the completer cohorts defined in Section 3.2.3.
4.7
Examination of subgroups
Unless otherwise noted, all tabular data summaries will be presented overall and by country
(Japan, China).
5
STUDY POPULATION CHARACTERISTICS
5.1
Subject disposition
Summary tables of subject disposition will be provided overall, by EP0008 randomized dose and 
by country separately as follows:
•
The number of subjects in the SS, and in the FAS will be presented. The date of the first visit 
for the first subject, date of the last visit for the last subject, and the number of subjects 
screened will also be included. (Analysis population: All Subjects Screened)
•
The number and percentage of subjects entering, completing, ongoing, and discontinuing the 
study with associated reasons for discontinuation. The number and percentage of ongoing 
subjects will be displayed at the interim analyses only. (Analysis population: SS and FAS)
•
A by-subject listing of analysis population classification (Analysis population: SS)
The following listing will be provided: 
•
Subject disposition status, including the date of informed consent, screening result, date of 
study completing/discontinuation, and reason for premature discontinuation. (Analysis 
population: SS)
•
A by-subject listing of subjects who did not meet study eligibility criteria (Analysis 
population: All Subjects Screened)
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 14 of 35
•
A by-subject listing of analysis population classification (Analysis population: SS)
5.2
Protocol deviations
A summary table and listing of important protocol deviations will be provided for the SS as 
follows:
•
The number and percentage of subjects with no important protocol deviations and with at 
least 1 important protocol deviation in each of the categories defined in Section 3.4 will be 
summarized overall, by EP0008 randomized treatment group, and by country separately. 
•
A by-subject listing of important protocol deviations will be presented.
6
DEMOGRAPHICS AND OTHER BASELINE
CHARACTERISTICS
Unless otherwise specified, demographics, baseline characteristics, medical history, concomitant 
disease, and concomitant medications will be summarized for the SS and FAS overall, by
EP0008 randomized treatment group, and by country separately.
Subject listings of demographics, baseline characteristics, medical history, concomitant diseases,
and concomitant medication will be displayed for the SS. 
6.1
Demographics
Summary statistics or the number and percentage for each category of demographic information 
will be presented as follows:
•
A summary of demographics data including gender, age (years), age category (≤18, >18 to 
<65, ≥65 years) (<16, ≥16 to <65, ≥65 years), ethnicity (Hispanic or Latino, and not Hispanic 
or Latino), race group (American Indian/ Alaskan native, Asian, Black, Native Hawaiian or 
other Pacific Islander, White, and Other/mixed), race, racial subgroup (Chinese or Japanese), 
height, weight, body mass index (BMI, kg/m2), BMI category (<18.5, ≥18.5 to <25, ≥25 to 
<30, and ≥30 kg/m2), number of lifetime AEDs, number of concomitant AEDs during 
EP0008, and Baseline partial-onset seizure frequencies per 28 days will be provided overall, 
by EP0008 randomized treatment group, and by country separately.
•
A by-subject listing of demographic data.
Gender, race, ethnicity, racial subgroup, height, weight, and BMI will betaken directly from 
EP0008 datasets and not programmed. Age will be relative to the date of informed consent for 
EP0009.
6.2
Other Baseline characteristics
Summary statistics or the number and percentage for each category of baseline characteristics as 
reported at Visit 1 of EP0008 will be provided as follows:
•
A summary of the diagnoses of primary disease, including time since diagnosis of epilepsy 
(in years) and etiology of epilepsy taken from EP0008 will be provided.
In EP0008, time since first diagnosis was calculated using all available information; partial 
dates was completed using the earliest calendar date based on the partial date provided.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 15 of 35
In EP0008, time since the first diagnosis (years) was calculated as (year and month of 
informed consent date – year and month of the first diagnosis) / 365.25. Month and year of 
the first epilepsy diagnosis are collected on the CRF. To calculate the time since first 
epilepsy diagnosis at Visit 1 of EP0008, a complete date will be imputed as follows:
-
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of the first seizure, whichever is later in the month.
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birthday, or the date of the first seizure, whichever is later in the year.
-
Both month and year are missing, no imputation will be done.
•
A summary of International League Against Epilepsy (ILAE) seizure classification will be 
provided.
The types of partial seizures experienced will be summarized using the ILAE classification 
system.
•
A summary of classification of epileptic syndromes.
•
A by-subject listing of other Baseline characteristics.
6.3
Medical history and concomitant disease
Medical history and concomitant diseases will be as reported as of Visit 1 of EP0008.
Concomitant diseases are medical history events which were ongoing at Visit 1 of EP0008.
Summary tables of medical history and concomitant diseases will be provided for the SS as 
follows:
•
A summary of medical history by MedDRA system organ class (SOC) and preferred term 
(PT) will be presented overall, by EP0008 randomized treatment group, and country
separately.
•
A summary of concomitant disease by MedDRA system organ class (SOC) and preferred 
term (PT) will be presented overall, by EP0008 randomized treatment group, and country
separately.
•
A by-subject listing of medical history.
•
A by-subject listing of concomitant diseases.
•
A by-subject listing of procedure history.
6.4
Concomitant medications
Concomitant medications will be defined as any medications taken concurrent with LCM if the 
start date was prior to the first dose with ongoing status, or the start date was on or after the date 
of first dose of study drug in EP0009. Medications with a missing start date, whose stop date is 
either unknown or after the date of the first dose of study drug, will be considered concomitant. 
Summary tables will be provided for the SS and FAS as follows:
•
A summary of concomitant medications (excluding AEDs) taken during Treatment Period
will be provided by level 1 and level 2 ATC code. The tables will be presented overall, by 
EP0008 randomized treatment group, and by country separately.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 16 of 35
•
A summary of concomitant AEDs taken during the Treatment Period will be provided by 
Level 4 ATC code and preferred medication name. The tables will be presented overall, by 
EP0008 randomized treatment group, and by country separately.
•
A by-subject listing of concomitant AEDs (Analysis population: SS)
•
A by-subject listing of concomitant medications (non-AEDs) (Analysis population: SS)
7
MEASUREMENTS OF TREATMENT COMPLIANCE
LCM dosing compliance will be evaluated through the review of important protocol deviations 
classified under LCM Dosing Regimen.
8
SAFETY ANALYSES
All safety analyses will be performed on the SS. 
8.1
Extent of exposure
Overall exposure to LCM in days is calculated as the date of last administration of LCM minus 
the date of first administration in EP0009 plus 1. Subject-years of exposure will be calculated as 
the number of days of exposure, divided by 365.25. Gaps in LCM treatment or days on the LCM 
dosing log CRF with unknown dosing will not be subtracted from the overall exposure days and 
subject-years of exposure.
The maximum daily dose will be calculated as the highest total daily dose the subject received 
during the treatment period.
LCM modal dose (mg/day) will be defined as the daily LCM dose the subject received for the 
longest duration during the treatment period in EP0009. A modal dose calculated as 50mg/day 
will be presented with 100mg/day. For any modal dose greater than 100mg/day falling between 2
consecutive categories, the modal dose will be presented with the lower of the consecutive
categories. For example, 150mg/day will be presented with the 100mg/day group. The modal
dose calculation is based on the number of days a subject was on a given daily dose. Gaps in
LCM dosing will be excluded from the determination of modal dose (ie, no imputation for days 
with missing dosing log information will be performed).
The following exposure summaries and a listing will be produced:
•
Summary statistics for study treatment duration (days) by modal dose and overall.
•
Number of subjects and subject-years of study treatment duration by cumulative time 
intervals (ie, >0, >6, >12, >18, >24, >30, and >36 months, where one month is defined as 28 
days) and modal dose. 
•
Number and percentage of subjects within each LCM treatment duration category by modal 
dose, maximum daily dose, and overall. LCM treatment duration categories (days) are as 
follows: 1 to 14; 15 to 28; 29 to 56; 57 to 84; 85 to 168; 169to 336; 337 to 672; 673 to 1008; 
≥1009 to 1344; 1345 to 1680; 1681 to 2016; ≥2017; any duration (total of durations).
•
Summary statistics for overall treatment duration (days), modal dose (mg/day), and 
maximum daily dose (mg/day) will be presented by EP0008 randomized treatment group and 
overall.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 17 of 35
•
A by-subject listing of LCM dosing.
8.2
Adverse events
TEAE is defined as an event starting on or after the date of first dose of LCM in this study and 
within 30 days of the last LCM dose, or whose severity worsen on or after the date of first LCM
dosing in this study and within 30 days of the last LCM dose.
TEAEs will be coded using MedDRA and tabulated by SOC and PT. All summaries will be 
sorted alphabetically by SOC and by frequency of events in the overall column within the SOC, 
starting with the most frequent event unless otherwise specified.
The following summary tables of TEAEs will be provided overall, by EP0008 randomized 
treatment group, and by country separately. For the summary tables of TEAEs onset during the 
Treatment Period will be further presented overall, by 6month interval, by EP0008 randomized 
treatment group, by country, and follows as well: 
•
Overview summaries of TEAEs with onset during the Treatment Period and events during 
the Post-Treatmrent Period will be presented. They will include the number and percentage 
of subjects with at least 1 TEAE, at least 1 serious TEAE, at least 1 TEAE leading to early 
withdrawal, drug-related TEAEs, at least 1 severe TEAE, and death.
•
Summary of the incidence of TEAEs with onset during the Treatment Period by SOC and PT.
•
Summary of the incidence of TEAEs with onset during the Treatment Period by SOC, PT, 
and maximum intensity.
•
Summary of the incidence of TEAEs with onset during the Treatment by SOC, PT, and 
relationship.
•
Summary of the incidence of serious TEAEs with onset during the Treatment by SOC and 
PT.
•
Summary of the incidence of non-serious TEAEs by SOC and PT. The occurrence of non-
serious TEAEs is only presented with incidence ≥5%.
•
Summary of the incidence of TEAEs leading to discontinuation with onset during the
Treatment Period by SOC and PT.
•
Summary of the incidence of other significant TEAEs (Section 13.1) with onset during the 
Treatment Period by SOC and PT.
•
Summary of incidence of TEAEs with onset during the Treatment Period per 100 person-
months of exposure.
•
A summary of subject numbers of subjects with TEAEs with an onset during the Treatment 
Period.
•
A summary of subject numbers of serious TEAEs with an onset during the Treatment Period.
•
A summary of subject numbers of TEAEs with an onset during the Treatment Period leading 
to discontinuation.
•
A by-subject listing of all TEAEs; events with onset during the Post-Treatment Period will be 
identified.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 18 of 35
•
A by-subject listing for all deaths
•
Glossary of MedDRA terms and associated investigator’s terms for adverse events.  
8.3
Clinical laboratory evaluations
For continuous laboratory measurements, including hematology, clinical chemistry, and 
urinalysis, a summary using descriptive statistics of the actual values and their change from 
Baseline (where Baseline is from the previous trial as defined in Section 3.3) will be presented at 
each visit, the last visit value, the minimum value, and the maximum value during the Treatment 
Period. For white blood cell differentials, both of absolute values and percentages of the white 
blood cell count will be analyzed. When analyzing categorical data, the number and percentage 
of subjects in each category will be presented. In addition, shift tables will be used to evaluate 
the number and percentage of subjects having a different Treatment Period status (low, normal, 
and high) when compared to their baseline status from EP0008.
Repeated or unscheduled laboratory assessments during the study will not be presented for each 
visit summary, but will be considered when determining the last visit value, minimum value, and 
maximum value during the Treatment Period and when determining treatment emergent marked 
abnormality.
Categorical urinalysis parameters (excluding urine glucose, urine ketones, and urine protein) will
be presented in listings only. 
The number and percentage of subjects with treatment-emergent marked laboratory
abnormalities (hematology and clinical chemistry) as defined in Section 13 will be summarized 
by laboratory parameters. Treatment-emergent is defined as meeting the marked abnormality 
criteria during EP0009 Treatment Period but not meeting the criteria during Baseline of EP0008. 
Subject numbers for subjects meeting the marked abnormality criteria will also be presented.
A subject data listing will be provided for all laboratory data. Values outside the normal range
will be flagged within the listing. A subject data listing will also be provided for all 
treatment-emergent marked laboratory abnormalities and will include all lab values for those 
subjects experiencing the marked abnormality.
The following summaries and listings will be provided:
•
A summary of each laboratory parameter and change from Baseline of EP0008.
•
A shift table based on the normal range for each lab parameter will be presented by
Treatment Period endpoint value relative to Baseline of EP0008.
•
A summary of incidence of treatment-emergent marked abnormalities presented by 
scheduled visit and for the entire Treatment Period (including unscheduled visits) during the 
Treatment Period for the laboratory parameters, hematology and clinical chemistry.
•
A shift table that will cross-tabulate Baseline value of EP0008 by maximum value during the 
Treatment Period (including unscheduled visits) will be presented for liver function tests 
(LFTs) which include alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
GGT, ATL, and total bilirubin based on abnormality.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 19 of 35
The shift table that cross-tabulates Baseline versus maximum values during the Treatment 
Period in categories of <1 x ULN, 1 to <2 x ULN, 2 to <3 x ULN, ≥3 x ULN, and missing 
will be presented for the liver function tests.
•
Subject numbers of treatment-emergent marked abnormalities during the Treatment Period
for each laboratory parameter will be provided.
The summaries above will be provided overall, by EP0008 randomized treatment group, and by
country separately.
•
A by-subject listing of subjects with laboratory values.
•
A by-subject listing of LFTs with pre-defined criteria.
8.4
Vital signs, physical findings, and other observations related to 
safety
8.4.1
Vital signs
Noninvasive pulse rate, systolic blood pressure, and diastolic blood pressure will be measured at 
visits with the subject in a sitting position after at least 3 minutes at rest, according to the tabular 
schedule of study procedures in the protocol. Summary statistics of the actual measurement and 
their changes from Baseline will be presented at each visit, the last visit value, the minimum 
value, and the maximum value during the Treatment Period.
Repeated or unscheduled vital sign assessments during the study will not be presented for each 
visit summary, but will be considered when determining the last visit value, minimum value, and 
maximum value during the Treatment Period and post-Baseline abnormal vital signs during 
Treatment Period.
The following summaries and a listing will be provided:
•
A summary of observed blood pressure and pulse rates and changes from Baseline of EP0008.
•
The number and percentage of subjects with post-Baseline abnormal vital signs during 
Treatment Period as defined in Section 13.
The summaries above will be provided overall, by EP0008 treatment group, and by country
separately.
•
A by-subject listing of vital signs. Abnormal vital signs will be flagged in the listing.
8.4.2
Electrocardiograms
For quantitative ECG measurements (heart rate, RR interval, PR interval, QRS duration, QT 
interval, and corrected QT intervals using Bazett and Fridericia methods), summary statistics of 
the actual measurement collected at Baseline and each Treatment Period visit (as well as change 
from Baseline) will be presented. Baseline is defined as the average of the 3 ECG measurements 
taken at Visit 3 in EP0008. In addition to Baseline and each Treatment Period visit, the last visit, 
minimum, and maximum values during the Treatment Period of EP0009 will be presented. 
Repeated or unscheduled ECG assessments during the study will not be presented for each visit 
summaries, but will be considered when determining the last visit value, minimum value, and 
maximum value during the Treatment Period and abnormal ECG values.
The Bazett corrected QT (QTcB) will be calculated as
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12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 20 of 35
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The following summaries and listings will be provided for the SS:
•
A summary of ECG measurements (heart rate, RR interval, PR interval, QRS duration, QT 
interval, and corrected QT intervals using Bazett and Fridericia methods) and changes from 
Baseline of EP0008.
•
The number and percentage of subjects with a QTc (using Bazett and Fridericia) of ≥500ms 
and an increase from Baseline of <30ms, 30 to <60ms, and ≥60ms will be summarized for 
each visit.
•
The number and percentage of subjects with a maximum QTc of ≥500ms, a maximum 
increase in QTc from Baseline of <30ms, 30 to <60ms, and ≥60ms, a maximum 
post-Baseline QTc of ≥500ms or a maximum increase in QTc of ≥60ms, and a maximum 
post-Baseline QTc of ≥500ms and a maximum increase in QTc of ≥60ms will be summarized 
for each of the corrected QT interval formulas. Subjects with a QTc (Bazett and Fridericia) of 
≥500ms or an increase from Baseline of ≥60ms will be listed.
•
The number and percentage of subjects with PR interval values >200ms, >220ms, or >250ms, 
and the number and percentage of subjects with QRS interval values >100ms, >120ms, and 
>140ms will be presented. For these defined criteria, the number and percentage of subjects 
with treatment-emergent PR interval and/or QRS interval prolongation will also be presented. 
Treatment-emergent is defined as meeting the criteria at any Treatment Period visit 
(including unscheduled visits) during the Treatment Period and not meeting the same criteria 
during Baseline.
•
Subject numbers for subjects with prolonged post-Baseline QTcB will be provided.
•
Subject numbers for subjects with treatment-emergent PR interval prolongation will be 
provided.
•
Subject numbers for subjects with treatment-emergent QRS interval prolongation will be 
provided.
•
A summary of incidence of treatment-emergent abnormality 12-lead ECG findings after start 
of study drug for each visit and during the Treatment Period in EP0009.
The summaries above will be provided overall, by EP0008 randomized treatment group, and by
country separately.
•
A by-subject listing of 12-lead ECG data.
•
A by-subject listing of abnormal 12-lead ECG data as defined in Section 13 .
8.4.3
Other safety variables
Body weight will be determined without shoes when the subject is wearing light clothing, and 
will be assessed according to the tabular schedule of study procedures.
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 21 of 35
The following summaries and listings will be provided:
•
A summary of body weight and change from Baseline for each visit
•
The number and percentage of subjects with Treatment Period abnormal body weight during 
the Treatment Period as defined in Section 13.
The summaries above will be provided overall, by EP0008 randomized treatment group,  and by
country separately.
•
A subject listing of body weight and change from Baseline in body weight
•
A subject listing of abnormal physical examination abnormalities
•
A subject listing of neurological examination findings
•
A subject listing of pregnancy test
•
A subject listing of C-SSRS suicidality
9
EFFICACY ANALYSES
All efficacy variables are to be evaluated descriptively using FAS.
9.1
Statistical analysis of the primary efficacy variables
No primary efficacy variables are defined for EP0009.
9.2
Statistical analysis of the secondary efficacy variables
Partial-onset seizure frequency per 28 days will be calculated as ([number of seizures over the 
specified interval] divided by [number of days in the interval]) multiplied by 28. 
The following table and listing will be provided:
If a seizure cluster is reported, it will be assigned to the correct seizure type and the highest
recorded daily number of seizures of that seizure type during the 28 days prior to the cluster
event will be used as the imputed number of seizures for the day on which the cluster occurred. 
If no other seizures are recorded for that seizure type for the subject in the 28 days prior to the 
cluster event, the frequency will be set to 1 or the number of cluster episodes reported if more 
than 1 cluster event occurred on the same day.
9.2.1
Percent change in seizure frequency from Baseline to the Treatment 
Period
The percent change in partial-onset seizure frequency per 28 days from Baseline to the 
Treatment Period in 6-month interval is calculated by the following formula:
Percent 
Change
(%)
=
[(Seizure frequency per 28 days in 6-month interval during the 
Treatment Period) -
(Seizure frequency per 28 days during Baseline Period)]
x 100
(Seizure frequency per 28 days during Baseline Period)
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 22 of 35
Descriptive statistics will be calculated for the percent change in partial-onset seizure frequency 
per 28 days from Baseline to the Treatment Period in 6-month specified interval during the 
Treatment Period, and overall.
The percent change in 28-day seizure frequency per 28 days from Baseline among each 
completer cohort will also be displayed. A subject must have been treated with LCM and have 
available seizure diary data for the interval for each interval (eg, 6-month completer cohort 
subjects must be enrolled and taking trial medication for at least 6 months and have available 
seizure diary data for the interval) to be included in the 6-month completer cohort (see Section 
3.2.3 for definition of completer cohort).
•
A summary of the percent change in partial-onset seizure frequency per 28 days from 
Baseline will be presented by 6-month interval and overall Treatment Period.
•
A summary of the percent change in partial-onset seizure frequency per 28 days from 
Baseline among each complete cohort will be presented. For each completer cohort, the 
percent change in 28-day seizure frequency per 28 days from Baseline will be presented by 
6-month time interval..
The summaries above will be provided overall, by EP0008 randomized treatment group, and by
country separately.
•
A by-subject listing of number of seizure, seizure frequency per 28 days and percent change 
from Baseline by 6-month interval and overall Treatment Period.
9.2.2
Response to treatment of at least 50% from Baseline to the 
Treatment Period
≥50% responders are defined as subjects who experience a ≥50% reduction in partial-onset 
seizure frequency per 28 days from Baseline to the 6-month interval or the Treatment Period 
which is defined at Section 9.2.1. 
•
The number and percentage of ≥50% responders in the partial-onset seizure frequency per 28 
days from Baseline to the Treatment Period by 6-month interval and overall Treatment 
Period will be presented.
•
The number and percentage of ≥50% responders among each completer cohort will be 
presented in a same way as above. For each completer cohort, the ≥50% response rate will be 
presented by 6-month time interval.
The summaries above will be provided overall, by EP0008 randomized treatment group,  and by
country separately.
•
A by-subject listing of ≥50% responder categories by 6-month interval and overall Treatment 
Period.
9.3
Analysis of other efficacy variables
9.3.1
Response to treatment of at least 75% from Baseline to the 
Treatment  Period
≥75% responders are defined as subjects who experience a ≥75% reduction of in the partial-onset 
seizure frequency per 28 days from Baseline to the 6-month time interval or the Treatment 
Period.  
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 23 of 35
•
≥75% responders will also be summarized by the same manner as ≥50% responders,
described in Section 9.2.2.
•
The number and percentage of ≥75% responders in the partial-onset seizure frequency per 28 
days from Baseline to the Treatment Period by 6-month interval and overall Treatment 
Period will be presented.
•
The number and percentage of ≥75% responders among each completer cohort will be 
presented in a same way as above.
The summaries above will be provided overall, by EP0008 randomized treatment group,  and by
country separately.
•
A by-subject listing of ≥75% responder categories by 6-month interval and overall Treatment 
Period.
9.3.2
Seizure-free status
A seizure-free status will be assessed for the duration of at least consecutive 6 months (182 days) 
and at least consecutive 12 months (365 days). Seizure-free is defined as a report of no seizures
in the seizure diary on the CRF for the consecutive days where the subject was treated with 
LCM. Days in the seizure diary which are marked as “not done” on the CRF will not be counted 
as a seizure free day unless otherwise noted.
When subjects are in EP0024, the days should be treated as "not done" days for EP0009 but they 
should not disqualify a subject from being seizure free if they were in EP0024.
•
The number and percentage of subjects who achieved seizure-free status (yes/no) for the
duration of at least 6 months and at least 12 months will be presented overall, by completer 
cohort, by EP0008 randomized treatment group, and by country separately.
•
A by-subject listing of seizure freedom data.
9.3.3
Percentage of seizure-free days
Percentage of seizure-free days is calculated as:
Percentage of 
seizure free days
=
Seizure free days during time interval in the Treatment
Period
x 100%
Number of days during time interval in the Treatment
Period with available seizure diary data
Time interval is defined as 6-month interval for the first year and yearly intervals thereafter (at 
least 6 months, at least 12 months, at least 24, and at least 36 months).
•
Summaries of the percentage of seizure-free days during the Treatment Period will be 
presented overall, by completer cohorts, EP0008 randomized treatment group, and by
country separately.
•
A summary of change in percentage of seizure-free days and change in percentage from 
Baseline from Baseline during the Treatment Period will be presented overall, by completer 
cohorts, by EP0008 randomized treatment group, and by country separately.
REDACTED 
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 24 of 35
9.3.4
Subjects receiving LCM as monotherapy
Monotherapy is defined as when LCM only is used during the period with no other concomitant 
AEDs. If the subjects had a rescue medications of benzodiazepines which are used for the control 
of uncountable seizures due to clustering are not regarded as AEDs. Other AED rescues where 
an AED was taken for ≤1 day will also not disquality a subject from being on LCM
monotherapy.
•
The number and percentage of subjects achieving continuous LCM monotherapy for at least 
6 months and at least 12 months at any time during the Treatment Period among subjects 
who were exposed to LCM for at least 6 months and at least 12 months during the Treatment 
Period will be presented overall, by EP0008 randomized treatment group, and by country
separately.
10
PHARMACOKINETICS AND PHARMACODYNAMICS
This section is not applicable.
11
OTHER ANALYSES
Not applicable for this study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions
y
s
cou
cou
NAMI
MI
or
reat
rea
variations 
east 
ast 
cts
cts
thereof. 


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 25 of 35
12
REFERENCES
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 26 of 35
13
APPENDICES
13.1
List of Other Significant AEs
MedDRA Preferred Term
HEPATOTOXICITY RELATED TERMS
Hepatitis toxic
Hepatotoxicity
CARDIAC AND ECG RELATED TERMS
Atrioventricular block third degree
Atrioventricular block second degree
Bradyarrhythmia*
Bradycardia*
Cardiac pacemaker insertion
Atrial fibrillation
Atrial flutter
Sinus bradycardia*
Ventricular tachycardia
Ventricular fibrillation
Heart Rate decreased*
Sick sinus syndrome
SUICIDALITY RELATED TERMS
Completed suicide
Depression suicidal
Suicidal behaviour
Suicidal ideation
REDACTED 
D
CT
RE
COPY 
Y
C
This document
Com
om
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cannot 
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 27 of 35
MedDRA Preferred Term
Suicide attempt
Intentional self-injury
Self injurious behaviour
Self-injurious ideation
Intentional overdose
Multiple drug overdose intentional
Poisoning deliberate
ADDITIONAL TERMS
Loss of consciousness
Syncope
*All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia 
(marked reduction in heart rate) with HR <45 bpm will be listed as ‘Other Significant AEs’.
REDACTED
rev
rev
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pm wi
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on
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 28 of 35
13.2
Marked lab abnormalities
13.2.1
Hematology
Abnormality criteria to be applied in the assessment of laboratory parameter values are given 
below.
PARAMETER
AGE 
RANGE
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
(conventional 
unit)
UNIT
(standard)
ABNORMALITY 
CRITERIA 
(standard unit)
Hematocrit
<2y
%
≤27
>45
%
≤27
>45
2y -
<17y
≤29
>47
≤29
>47
≥17y
≤85% of LLN
≥115% of ULN
≤85% of LLN
≥115% of ULN
Hemoglobin
<2y
g/dL
≤9.0
>15.0
g/L
≤90
>150
2y -
<17y
≤9.5
>16.0
≤95
>160
≥17y
≤85% of LLN
≥115% of ULN
≤85% of LLN
≥115% of ULN
WBC/Leukocytes
All
109/L
≤3.0
≥16.0
G/L
≤3.0
≥16.0
Lymphocytes 
Absolute
<2y
109/L
<1.0
>9.8
G/L
<1.0
>9.8
2y - <6y
<0.7
>6.9
<0.7
>6.9
≥6y
<0.6
>5.0
<0.6
>5.0
Basophils
>1m
%
≥5.0
%
≥5.0
Basophils 
Absolute
>1m
109/L
≥0.4
G/L
≥0.4
Eosinophils
>1m
%
≥10
%
≥10
Eosinophils 
Absolute
>1m
109/L
≥1.0
G/L
≥1.0
Monocytes
>1m
%
≥20.0
%
≥20.0
Monocytes 
Absolute
>1m
109/L
≥2.0
G/L
≥2.0
Neutrophils 
Absolute
>1m
109/L
<1.5
G/L
<1.5
Platelets
>1m
109/L
≤100
≥600
G/L
≤100
≥600
≥
ED
TE
L
DA
COPY 
>16
>1
≤85%
≤85%
≥115
≥11
OP
This document 
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 29 of 35
PARAMETER
AGE 
RANGE
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
(conventional 
unit)
UNIT
(standard)
ABNORMALITY 
CRITERIA 
(standard unit)
RBC/ 
Erythrocytes
<2y
1012/L
<3.0
T/L
<3.0
≥2y
<3.5
<3.5
Abbreviations: ANC = absolute neutrophil count. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations
iat
s s thereof. 
t


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 30 of 35
13.2.2
Chemistry
Abnormality criteria to be applied in the assessment of chemistry parameter values are given 
below.
PARAMETER
AGE 
RANGE
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
(conventional)
UNIT
(standard)
ABNORMALITY 
CRITERIA 
(standard)
AST (SGOT)
All
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
ALT (SGPT)
All
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
Alkaline 
Phosphatase
<4y
U/L
≥690
U/L
≥690
4y -
<10y
≥834
≥834
10y -
<17y
≥1761
≥1761
≥17y
≥3.0 x ULN
≥3.0 x ULN
GGT
<6m
U/L
≥522
U/L
≥522
6m - <1y
≥279
≥279
1y -
<13y
≥66
≥66
13y -
<17y
≥126
≥126
≥17y
≥3.0 x ULN
≥3.0 x ULN
Total Bilirubin
>1m
mg/dL
≥2.0
umol/L
≥34.208
Total Protein
2m-<1y
g/dL
<3.0
>11.9
g/L
<30
>119
1y -
<17y
<4.3
>12.0
<43
>120
≥17y
<4.3
>13.0
<43
>130
Albumin
<1y
g/dL
<1.6
>7.2
g/L
<16
>72
≥1y -
<17y
<2.4
>8.4
<24
>84
≥17y
<2.6
<26
REDACTED 
CT
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 31 of 35
PARAMETER
AGE 
RANGE
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
(conventional)
UNIT
(standard)
ABNORMALITY 
CRITERIA 
(standard)
BUN
<1y
mg/dL
≥24
mmol/L
≥8.568
1y -
<17y
≥36
≥12.852
≥17y
≥40
≥14.28
Urea
<1y
mg/dL
>42
mmol/L
>7.014
≥1y
>60
>10.02
Creatinine
1y -
<10y
mg/dL
>1.2
umol/L
>106.8
10y -
<16y
>1.8
>159.12
≥16y
≥2.0
≥176.8
Creatinine 
Clearance*
All
mL/min
<50
mL/s
<0.835
Bicarbonate
>1m -
<17y
mEq/L
<15
>38
mmol/L
<15
>38
≥17y
<18
>38
<18
>38
Calcium
<1y
mg/dL
<6.9
>12.2
mmol/L
<1.725
>3.05
1y -
<17y
<7.4
>11.7
<1.85
>2.925
≥17y
≤7.6
≥11.0
≤1.9
≥2.75
Chloride
>1m
mEq/L
≤90
≥112
mmol/L
≤90
≥112
Phosphorous
<1y
mg/dL
<1.8
>8.2
mmol/L
<0.5814
>2.6486
1y -
<17y
<1.8
>7.4
<0.5814
>2.3902
≥17y
≤2.0
≥6.0
≤0.646
≥1.938
Potassium
<1y
mEq/L
≤3.0
≥6.5
mmol/L
≤3.0
≥6.5
≥1y
≤3.0
≥6.0
≤3.0
≥6.0
Sodium
>1m
mEq/L
<127
>151
mmol/L
<127
>151
REDACTED 
CT
CT
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CT
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dL
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<5
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 32 of 35
PARAMETER
AGE 
RANGE
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
(conventional)
UNIT
(standard)
ABNORMALITY 
CRITERIA 
(standard)
Glucose
>1m -
<17y
mg/dL
<50
≥180
mmol/L
<2.775
≥9.99
≥17y
<50
≥200
<2.775
≥11.1
Total 
Cholesterol
≥1y
mg/dL
>250
mmol/L
>6.475
LDL 
(calculated)
1y -
<17y
mg/dL
>140
mmol/L
>3.626
≥17y
>200
>5.18
HDL
≤2y
mg/dL
<10
mmol/L
<0.259
>2y
<20
<0.518
Triglycerides
<1y
mg/dL
>750
mmol/L
>8.475
≥1y
>300
>3.39
Uric Acid
<1y
mg/dL
>7.7
umol/L
>457.996
1y -
<13y
>6.5
>386.62
13y -
<17y
>8.6
>511.528
≥17y
>9.5
>565.06
Thyroxine (T4)
<1y
ug/dL
≤4.3
≥18.4
nmol/L
≤55.3453
≥236.8264
≥1y
≤3.8
≥13.5
≤48.9098
≥173.7585
Globulin
<1y
g/dL
<1.0
>4.5
g/L
<10
>45
≥1y
<1.2
>5.3
<12
>53
ALT= alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; dL = 
deciliter; GGT: gamma-glutamyltransferase; HDL = high density lipoprotein; LDL = low density
lipoprotein.
*Schwartz equation (subjects <12): Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine 
  Cockroft equation (subjects >12): Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum 
creatinine); Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85
CT
CT
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CT
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>30
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UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 33 of 35
13.3
Vital sign assessments - abnormal
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below.
PARAMETER
AGE 
RANGE
ABNORMALITY CRITERIA
Pulse Rate 
(beats/minute)
<6m
<100
>180
6m - <3y
<90
>150
3y - <12y
<60
>130
12y - <17y
<50
>120
≥17y
<50 and a decrease from Baseline of ≥15
>120 and an increase from Baseline of ≥15
Systolic Blood 
Pressure (mmHg)
<6m
<60
>100
6m - <3y
<70
>120
3y - <12y
<80
>140
12y - <17y
<90
>160
≥17y
≤ 90 and a decrease from Baseline of ≥20
≥ 180 and an increase from Baseline of ≥20
Diastolic Blood 
Pressure (mmHg)
<6m
<40
>65
6m - <3y
<45
>75
3y - <12y
<50
>80
12y - <17y
<50
>105
≥17y
<50 and a decrease from Baseline of ≥15
>105 and an increase from Baseline of ≥ 15
Respiratory Rate 
(breaths/minute)
<6m
<25
>55
6m - <3y
<20
>45
3y - <12y
<15
>35
≥12y
<10
>25
Temperature
>1m
>101 0F (38.3 0C)
REDACTED 
D
AC
RE
R
COPY 
PY
C
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um
cannot
ato
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be
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ory R
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thereof. 


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 34 of 35
PARAMETER
AGE 
RANGE
ABNORMALITY CRITERIA
Body Weight
1m - <17y
<3% or >97% of the normal body weight growth curve 
ranges based on gender and the age of subject on date of 
weight assessmenta
≥17y
≥ 10% change from Baseline (an increase or a decrease)a
asource: http://www.cdc.gov/growthcharts/
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations 
on
on
on thereof. 


UCB
12Sep2014
Statistical Analysis Plan
Lacosamide
EP0009
Confidential
Page 35 of 35
13.4
Electrocardiogram (ECG) – abnormal
Abnormality criteria to be applied in the assessment of ECG parameter values are given below:
Parameter
Age
Abnormality Criteria
QT interval (ms)
1m-<12y
>500
>12y
>500 or ≥60ms increase from Baseline
QTc(F) (ms)
<6m
>490, or >15% increase from Baseline
6m-<3y
>440, or >15% increase from Baseline
3y-<12y
>440, or >15% increase from Baseline
>12y- <17y
>440, or >15% increase from Baseline
≥17y
>500 or ≥60ms increase from Baseline
QTc(B) (ms)
<6m
>490, or >15% increase from Baseline
6m-<3y
>450, or >15% increase from Baseline
3y-<12y
>450, or >15% increase from Baseline
>12y- <17y
>450, or >15% increase from Baseline
≥17y
>500 or ≥60ms increase from Baseline
PR interval (ms)
<6m
>150, or >25% increase from Baseline
6m-<3y
>170, or >25% increase from Baseline
3y-<12y
>180, or >25% increase from Baseline
>12y - <17y
>200, or >25% increase from Baseline
≥17y
Treatment-emergent value >200, >220, >250
QRS interval (ms)
<6m
>90, or >25% increase from Baseline
6m-<3y
>90, or >25% increase from Baseline
3y-<12y
>100, or >25% increase from Baseline
>12y - <17y
>110, or >25% increase from Baseline
≥17y
Treatment-emergent value >100, >120, >140
Heart rate (bpm)
<6m
<100, >180
6m-<3y
<90, >150
3y-<12y
<60, >130
>12y
<50, >120
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit during the 
Treatment Period (including unscheduled visits) and not meeting the same criteria during Baseline
REDACTED 
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