A Multi-center, 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: PHASE3
Conditions: Epilepsy, Partial-onset Seizures
Sponsor: UCB Pharma SA

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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UCB
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.
EDACTE
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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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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
REDACTED COPY 
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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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UCB
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 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

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
-
Visit window (days)d
-
±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
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.
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
LCM 0mg/day
Visit 1
Visit 2
Visit 3
Visit 4
 End-of-Study
End-of-Studyc/
Final Visit
(Week 0)
(Week 4)
(Week 8)
(Week 12)
Visitc
Withdrawal
(2 weeks 
Visit
after final
At 4-week intervals
At 12-week intervals
LCM dose)
LCM=lacosamide 
a
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
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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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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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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) 
•
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•
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•
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•
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AE assessment
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Withdrawal criteria
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•
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
•
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•
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•
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UCB
13 Mar 2013
Clinical Study Protocol
Lacosamide
EP0009
Confidential
Page 32 of 70
•
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•
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 
chemistry, and urinalysis) 
•
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•
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 
•
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)
•
IMP return/review
•
Subject diary return/review
•
AE assessment
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) 
•
IMP review
•
Subject diary review
•
AE assessment
•
Withdrawal criteria
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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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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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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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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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
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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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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
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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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UCB
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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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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UCB
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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UCB
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 
This document cannot be used to support any marketing authorization application and any extensions or variations 
nd d 
thereof. 

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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UCB
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. 
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UCB
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 
___
__
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