A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study to Investigate the Efficacy and Safety of Lacosamide as Adjunctive Therapy in Subjects With Epilepsy >=1 Month to <4 Years of Age With Partial-Onset Seizures
Phase: PHASE3
Conditions: Epilepsy With Partial-onset Seizures
Sponsor: UCB BIOSCIENCES, Inc.

UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 1 of 144
PROTOCOL SP0967 AMENDMENT 3
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF 
LACOSAMIDE AS ADJUNCTIVE THERAPY IN SUBJECTS 
WITH EPILEPSY ≥1 MONTH TO <4 YEARS OF AGE WITH 
PARTIAL-ONSET SEIZURES
PHASE 3
EudraCT Number: 2013-000717-20
IND Number: 73809
Sponsor:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Protocol/Amendment 
number
Date
Type of amendment
Final Protocol
29 May 2014
Not applicable
Protocol Amendment 1
14 Jan 2015
Substantial
Protocol Amendment 2
09 Aug 2016
Substantial
Protocol Amendment 3
05 Apr 2018
Substantial
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.
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 2 of 144
STUDY CONTACT INFORMATION
Sponsor
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Principal/Coordinating Investigator
Will be listed separately.
Sponsor Study Physician
Name:
, MD
Address:
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Clinical Project Manager
Name:
Address:
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim
GERMANY
Phone:
Fax:
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 3 of 144
Clinical Trial Biostatistician
Name:
Address:
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES
Phone:
Fax:
Clinical Monitoring Contract Research Organization
Name:
Pharmaceutical Research Associates, Inc.
Address:
4130 Park Lake Avenue, Suite 400
Raleigh, NC 27612
UNITED STATES
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 4 of 144
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 24 21
USA or Canada: +1 800 880 6949 or +1 866 890 3175
Email
DS_ICT@ucb.com (for all regions)
REDACTED COPY 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 5 of 144
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................5 
LIST OF TABLES...................................................................................................................10 
LIST OF FIGURES .................................................................................................................10 
LIST OF ABBREVIATIONS..................................................................................................11 
1 
SUMMARY.....................................................................................................................14 
2 
INTRODUCTION ...........................................................................................................15 
3 
STUDY OBJECTIVE(S).................................................................................................17 
4 
STUDY VARIABLES.....................................................................................................18 
4.1 
Efficacy variables...................................................................................................18 
4.1.1 
Primary efficacy variable.............................................................................18 
4.1.2 
Secondary efficacy variables .......................................................................18 
4.1.3 
Other efficacy variables...............................................................................19 
4.2 
Pharmacokinetic and pharmacodynamic variables................................................19 
4.3 
Safety variables......................................................................................................19 
4.3.1 
Primary safety variables...............................................................................19 
4.3.2 
Other safety variables ..................................................................................19 
5 
STUDY DESIGN.............................................................................................................19 
5.1 
Study description ...................................................................................................19 
5.1.1 
Study duration per subject ...........................................................................21 
5.1.2 
Planned number of subjects and sites ..........................................................21 
5.1.3 
Anticipated regions and countries................................................................22 
5.2 
Schedule of study assessments...............................................................................22 
5.3 
Schematic diagram.................................................................................................29 
5.4 
Rationale for study design and selection of dose...................................................32 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................33 
6.1 
Inclusion criteria ....................................................................................................33 
6.2 
Exclusion criteria ...................................................................................................33 
6.3 
Withdrawal criteria ................................................................................................35 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria................36 
7 
STUDY TREATMENTS.................................................................................................37 
7.1 
Description of investigational medicinal products ................................................37 
7.2 
Treatment(s) to be administered ............................................................................37 
7.2.1 
Titration Period............................................................................................37 
7.2.2 
Maintenance Period .....................................................................................38 
7.2.3 
Transition Period..........................................................................................39 
7.2.4 
Taper Period.................................................................................................39 
7.3 
Packaging...............................................................................................................40 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
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Page 6 of 144
7.4 
Labeling .................................................................................................................40 
7.5 
Handling and storage requirements .......................................................................40 
7.6 
Drug accountability................................................................................................40 
7.7 
Procedures for monitoring subject compliance......................................................41 
7.8 
Concomitant medications/treatments.....................................................................41 
7.8.1 
Permitted and prohibited concomitant treatments (medications and 
therapies)......................................................................................................41 
7.8.2 
Rescue medication .......................................................................................42 
7.9 
Blinding..................................................................................................................42 
7.9.1 
Procedures for maintaining and breaking the treatment blind.....................42 
7.9.1.1 
Maintenance of study treatment blind................................................42 
7.9.1.2 
Breaking the treatment blind in an emergency situation....................42 
7.10 
Randomization and numbering of subjects............................................................43 
8 
STUDY PROCEDURES BY VISIT ...............................................................................43 
8.1 
Baseline Period: Visit 1 (Day -7) to Visit 2 (Day -3 to Day -1)............................43 
8.1.1 
Baseline Period: Visit 1 (Day -7).................................................................43 
8.1.2 
Baseline Period: Visit 2 (Day -3 to Day -1).................................................44 
8.2 
Titration Period: Visit 3 (Day 1) to Telephone Contact 3 (Day 20) ......................45 
8.2.1 
Titration Period: Visit 3 (Day 1)..................................................................45 
8.2.2 
Titration Period: Telephone Contact 1 (Day 5), Telephone Contact 2 
(Day 13), and Telephone Contact 3 (Day 20)..............................................46 
8.2.3 
Titration Period: Visit 4 (Day 9)..................................................................46 
8.2.4 
Titration Period: Visit 5 (Day 17)................................................................47 
8.3 
Maintenance Period: Visit 6/Early Termination (Day 24 to Day 27)....................48 
8.3.1 
Maintenance Period: Visit 6/Early Termination (Day 24, Day 25, and 
Day 26) ........................................................................................................48 
8.3.2 
Maintenance Period: Visit 6/Early Termination (Day 27)...........................49 
8.4 
Transition Period: Transition Visit 1 (Day 32) to Transition Visit 2 (Day 40) .....50 
8.4.1 
Transition Period: Transition Visit 1 (Day 32)............................................50 
8.4.2 
Transition Period: Transition Telephone Contact 1 (Day 36) .....................50 
8.4.3 
Transition Period: Transition Visit 2 (Day 40)............................................51 
8.5 
Taper Period: Telephone Contact 4 (Day 32) and Taper Visit (Day 36, Day 40, or 
Day 44)...................................................................................................................51 
8.5.1 
Taper Period: Telephone Contact 4 (Day 32)..............................................51 
8.5.2 
Taper Period: Taper Visit (Day 36, Day 40, or Day 44) .............................52 
8.6 
Safety Follow-Up Period .......................................................................................52 
8.6.1 
Safety Follow-Up Period: Safety Follow-Up Clinic Visit (Day 50, Day 54,
or Day 58) ....................................................................................................52 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 7 of 144
8.6.2 
Safety Follow-Up Period: Safety Follow-Up Telephone Contact (Day 66,
Day 70, Day 74, or Day 93).........................................................................53 
8.7 
Unscheduled Visit..................................................................................................53 
9 
ASSESSMENT OF EFFICACY......................................................................................54 
9.1 
Primary and secondary efficacy variables .............................................................54 
9.2 
Other efficacy assessments ....................................................................................54 
9.2.1 
Global Impression of Change ......................................................................54 
9.2.2 
PedsQL.........................................................................................................54 
9.2.3 
Healthcare resource use ...............................................................................55 
10 ASSESSMENT OF PHARMACOKINETIC AND PHARMACODYNAMIC 
VARIABLES ...................................................................................................................55 
11 ASSESSMENT OF SAFETY..........................................................................................55 
11.1 
Adverse events.......................................................................................................55 
11.1.1 
Definition of adverse event..........................................................................55 
11.1.1.1 
Signs and symptoms of depression ....................................................56 
11.1.2 
Procedures for reporting and recording adverse events...............................56 
11.1.3 
Description of adverse events......................................................................56 
11.1.4 
Follow up of adverse events ........................................................................56 
11.1.5 
Rule for repetition of an adverse event........................................................56 
11.1.6 
Suspected transmission of an infectious agent via a medicinal product......57 
11.1.7 
Overdose of investigational medicinal product ...........................................57 
11.1.8 
Safety signal detection.................................................................................57 
11.2 
Serious adverse events ...........................................................................................57 
11.2.1 
Definition of serious adverse event .............................................................57 
11.2.2 
Procedures for reporting serious adverse events..........................................58 
11.2.3 
Follow up of serious adverse events............................................................59 
11.3 
Adverse events of special interest..........................................................................59 
11.4 
Immediate reporting of adverse events..................................................................60 
11.5 
Anticipated serious adverse events ........................................................................60 
11.6 
Laboratory measurements......................................................................................61 
11.6.1 
Liver function tests and evaluation of PDILI ..............................................62 
11.6.1.1 
Consultation with Medical Monitor and local hepatologist...............66 
11.6.1.2 
Immediate action: determination of IMP discontinuation .................66 
11.6.1.3 
Testing: identification/exclusion of alternative etiology ...................66 
11.6.1.4 
Follow-up evaluation .........................................................................68 
11.7 
Other safety measurements....................................................................................69 
11.7.1 
Physical examination ...................................................................................69 
11.7.1.1 
Complete physical examination.........................................................69 
11.7.1.2 
Brief physical examination ................................................................69 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 8 of 144
11.7.2 
Neurological examination............................................................................69 
11.7.2.1 
Complete neurological examination ..................................................69 
11.7.2.2 
Brief neurological examination..........................................................69 
11.7.3 
Vital signs, body weight, and height............................................................69 
11.7.4 
12-lead ECG ................................................................................................70 
11.7.5 
Overall ECG interpretation..........................................................................70 
11.7.6 
Achenbach CBCL........................................................................................70 
11.7.7 
BRIEF-P.......................................................................................................71 
11.7.8 
Bayley Scales of Infant and Toddler Development, Third Edition .............71 
12 STUDY MANAGEMENT AND ADMINISTRATION.................................................72 
12.1 
Adherence to protocol............................................................................................72 
12.2 
Monitoring .............................................................................................................72 
12.2.1 
Definition of source data..............................................................................72 
12.2.2 
Source data verification ...............................................................................73 
12.3 
Data handling.........................................................................................................73 
12.3.1 
Case Report form completion......................................................................73 
12.3.2 
Database entry and reconciliation................................................................73 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list......74 
12.4 
Termination of the study........................................................................................74 
12.5 
Archiving and data retention..................................................................................74 
12.6 
Audit and inspection ..............................................................................................74 
12.7 
Good Clinical Practice ...........................................................................................75 
13 STATISTICS ...................................................................................................................75 
13.1 
Definition of analysis sets......................................................................................75 
13.1.1 
Analysis of the primary efficacy variable....................................................75 
13.1.1.1 
Analysis of the primary efficacy variable for the US ........................76 
13.1.1.2 
Analysis of the primary efficacy variable for the EU ........................77 
13.1.2 
Analysis of secondary efficacy variables.....................................................78 
13.1.3 
Other efficacy analyses................................................................................78 
13.2 
Planned safety and other analyses..........................................................................78 
13.2.1 
Safety analyses.............................................................................................78 
13.2.2 
Pharmacokinetics and pharmacodynamics ..................................................79 
13.2.2.1 
Descriptive statistics of LCM and AED plasma concentrations........79 
13.2.2.2 
Population pharmacokinetics.............................................................79 
13.3 
Handling of protocol deviations.............................................................................79 
13.4 
Handling of dropouts or missing data....................................................................79 
13.5 
Planned interim analysis and data monitoring.......................................................80 
13.6 
Determination of sample size.................................................................................80 
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Clinical Study Protocol
Lacosamide
SP0967
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Page 9 of 144
14 ETHICS AND REGULATORY REQUIREMENTS......................................................81 
14.1 
Informed consent ...................................................................................................81 
14.2 
Subject identification cards....................................................................................81 
14.3 
Institutional Review Boards and Independent Ethics Committees........................82 
14.4 
Subject privacy.......................................................................................................82 
14.5 
Protocol amendments.............................................................................................83 
15 FINANCE, INSURANCE, AND PUBLICATION.........................................................83 
16 REFERENCES ................................................................................................................84 
17 APPENDICES .................................................................................................................86 
17.1 
AMENDMENT 1...................................................................................................86 
17.2 
AMENDMENT 2.................................................................................................111 
17.3 
AMENDMENT 3.................................................................................................136 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................143 
19 SPONSOR DECLARATION ........................................................................................144 
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05 Apr 2018
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Lacosamide
SP0967
Confidential
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LIST OF TABLES
Table 5‒1: Schedule of study assessments (Baseline and Treatment Periods).......................23 
Table 5‒2: Schedule of study assessments (Transition Period)..............................................27 
Table 5‒3: Schedule of study assessments (Taper and Safety Follow-Up Periods)...............28 
Table 7‒1: Recommended dosing schedule for LCM (or matching PBO) during the 
Titration Period.....................................................................................................38 
Table 7‒2: Transition Period LCM dosing schedule for subjects randomized to PBO..........39 
Table 7-3: Dosing of LCM (or matching PBO) during the Taper Period..............................39 
Table 11‒1: 
Anticipated SAEs for the pediatric epilepsy population..............................61 
Table 11‒2: 
Laboratory measurements............................................................................62 
Table 11‒3: 
Required investigations and follow up of PDILI.........................................64 
Table 11‒4: 
PDILI laboratory measurements..................................................................67 
Table 11‒5: 
PDILI information to be collected...............................................................68 
Appendix Table 1: 
Summary of changes in SP0967 Amendment 2 ..............................112 
Appendix Table 2: 
Summary of changes in SP0967 Amendment 3 ..............................137 
LIST OF FIGURES
Figure 5‒1:  
Subjects entering EP0034 open-label extension study ................................30 
Figure 5‒2:  
Subjects not entering EP0034 open-label extension study..........................31 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 11 of 144
LIST OF ABBREVIATIONS
ADF
average daily frequency
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
bid
twice daily
BMI
body mass index
BP
blood pressure
BRIEF®-P
Behavior Rating Inventory of Executive Function®-Preschool Version
BZD
benzodiazepine
CBCL
Childhood Behavior Checklist
CDMS
clinical data management system
CPM
Clinical Project Manager
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
DAP 
Data Analysis Plan
eCRF
electronic Case Report form
ECG
electrocardiogram
EEG
electroencephalogram
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
Food and Drug Administration
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 12 of 144
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
iv
intravenous
IXRS
interactive voice/web response system
LCM
lacosamide
LFT
liver function test
LSM
least square means 
MedDRA®
Medical Dictionary for Regulatory Activities®
PBO
placebo
PDILI
potential drug-induced liver injury
PedsQLTM
Pediatric Quality of Life InventoryTM
PET
polyethylene terephthalate
PK
pharmacokinetic(s)
PK-PPS
Pharmacokinetic Per Protocol Set
PPS
Per Protocol Set
PT
preferred term
QTc
corrected QT interval
RDC
remote data capture
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 13 of 144
SAE
serious adverse event
SAP
Statistical Analysis Plan
SOC
system organ class
SOP
Standard Operating Procedure
SS
Safety Set
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VNS
vagus nerve stimulation
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 14 of 144
1
SUMMARY
SP0967 is a Phase 3, multicenter, double-blind, randomized, placebo (PBO)-controlled, 
parallel-group study to evaluate the efficacy and safety of lacosamide (LCM) (VIMPAT®; SPM 
927; previously referred to as harkoseride; [R]-2-acetamido-N-benzyl-3-methoxypropionamide, 
ADD 234037) 8mg/kg/day to LCM 12mg/kg/day as adjunctive therapy in subjects with epilepsy 
≥1 month to <4 years of age with uncontrolled partial-onset seizures. This study is 1 of 2 pivotal 
studies in a pediatric partial-onset seizure population. In addition to SP0967, SP0969 is a 
Phase 3, multicenter, double-blind, randomized, PBO-controlled, parallel-group study to evaluate 
the efficacy and safety of LCM as an adjunctive therapy in subjects with epilepsy ≥4 years to 
<17 years of age with partial-onset seizures. 
The primary objective of SP0967 is to evaluate the efficacy of LCM administered concomitantly 
with 1 to 3 antiepileptic drugs (AEDs) in pediatric subjects (≥1 month to <4 years of age) with 
epilepsy who currently have uncontrolled partial-onset seizures. The secondary objective is to 
evaluate the safety and tolerability of LCM in pediatric subjects with partial-onset seizures. An 
additional objective is to evaluate the pharmacokinetics (PK) of LCM in subjects ≥1 month to <4 
years of age.
A total of approximately 244 subjects (122 subjects per treatment arm) are planned to be 
randomized at approximately 140 sites in North America, Europe, Asia Pacific, and Latin 
America, with possible extension to other countries and regions. Stratification of subjects will be 
done by age category (≥1 month to <6 months of age, ≥6 months to <1 year of age, ≥1 year to 
<2 years of age, and ≥2 years to <4 years of age). A target of 50% of the randomized subjects 
should consist of subjects <2 years of age. The maximum duration of study medication 
administration in SP0967 is 55 days (this includes a 20-day Titration Period, a 7-day 
Maintenance Period, a 12-day Transition Period, and/or up to a 16-day Taper Period), and the 
maximum study duration is 93 days (not withstanding visit windows).
The study is comprised of the following: a 7-day Baseline Period; a 20-day blinded Titration 
Period (with study medication dosing flexibility allowed based on tolerability) to attain the target 
dose of study medication for the 7-day blinded Maintenance Period (LCM 8mg/kg/day to 
LCM 12mg/kg/day, or matching PBO, with no adjustments to study medication dose allowed 
during the Maintenance Period); and a 12-day blinded Transition Period for subjects who 
complete the study and choose to enter the open-label extension study (EP0034) or a Taper 
Period (up to 16 days) followed by a 30-day Safety Follow-Up Period for subjects who are not 
eligible or who choose not to enter EP0034. The Transition Period will be required for eligible 
subjects who complete the Maintenance Period and choose to enter EP0034. The Taper Period 
and Safety Follow-Up Period are required for subjects who complete the study but choose not to 
enroll in EP0034 or for subjects who do not complete the Titration, Maintenance, and Transition 
Periods.
Based on US Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
requirements, 2 (co-) primary efficacy variables have been defined for this study based on 
electrographic partial-onset seizures with or without clinical correlate depending upon subject 
age. The primary efficacy variable will be the change in average daily frequency (ADF) of 
electrographic partial-onset seizures (US) or proportion of subjects experiencing ≥50% reduction 
in their ADF of electrographic partial-onset seizures (EU) as measured on the 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 15 of 144
End-of-Maintenance Period video-electroencephalogram (EEG) compared to the 
End-of-Baseline Period video-EEG. Partial-onset seizures will be counted locally by the 
investigator, subinvestigator, or qualified designated reader based on evaluating the characteristic 
ictal patterns of electrographic seizures. At the request of FDA, a contingent primary efficacy 
variable has also been defined based on the percentage of subjects who discontinue early from 
the study prior to completing the End-of-Maintenance Period video-EEG. Contingent upon 
>10% of subjects discontinuing early from the study, the primary efficacy parameter for the US 
will become identical to the primary efficacy parameter for the EU. The endpoint not designated 
as primary will still be summarized as a secondary efficacy parameter. 
Secondary and other efficacy variables will aid further exploration of the effect of LCM on 
partial-onset seizure frequency, global impressions of change, quality of life assessment 
(Pediatric Quality of Life InventoryTM [PedsQLTM]), and healthcare resource use. Plasma 
concentrations of LCM will be obtained in order to develop a population PK model of LCM, to 
investigate the effect of LCM on the steady-state plasma concentrations of concomitant AEDs, 
and to investigate the correlation between LCM plasma concentrations and efficacy or safety.
Safety and tolerability will be assessed primarily based on the occurrence of adverse events 
(AEs) reported spontaneously by the subject’s parent(s) and/or his/her legal 
representative(s)/caregiver(s) or observed by the investigator, and subject withdrawals due to 
AEs. Other safety variables will include assessment for change in hematology and clinical 
chemistry parameters; results of periodic physical and neurological examination, body mass 
index (BMI), 12-lead electrocardiogram (ECG), and vital sign measurements. Baseline 
behavioral function assessment (Achenbach Childhood Behavior Checklist [CBCL]) and 
cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool 
Version [BRIEF®-P]) will be conducted for analysis in EP0034.
2
INTRODUCTION
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy (Ngugi et al, 2011). Although some forms of 
epilepsy may respond to surgical treatment and others may not require any treatment at all, most 
patients with epilepsy require appropriate pharmacological therapy (Perucca, 1996). The Institute 
of Medicine of the National Academies recently provided a review of the burdens of epilepsy, 
global incidence and prevalence of epilepsy, classification systems for seizure types and 
syndromes, gaps in information about epilepsy, and general recommendations (Institute of 
Medicine, 2012). Several newer options for the medical treatment of epilepsy have been 
introduced, including novel AEDs and vagus nerve stimulation (VNS).
The classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age at onset, and sometimes prognosis.
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
than 30% of patients have inadequate seizure control on currently available AEDs or experience 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 16 of 144
significant adverse drug effects (CHMP/EWP/566/98, 2010). Therefore, a need remains for 
AEDs with improved effectiveness and tolerability (Sander, 1998).
Among the newer AEDs, only 6 (gabapentin, lamotrigine, oxcarbazepine, topiramate, 
levetiracetam, and perampanel) have successfully demonstrated efficacy as adjunctive therapy in 
children with difficult to treat partial-onset seizures (Rheims and Ryvlin, 2013; Glauser et al, 
2006; Glauser et al, 2000; Appleton et al, 1999; Duchowny et al, 1999; Elterman et al, 1999;). 
Despite the availability of new AEDs, more than 25% of pediatric patients have inadequate 
seizure control on currently available AEDs or experience significant adverse drug effects 
(Hadjiloizou and Bourgeois, 2007).
Lacosamide belongs to a novel class of functionalized amino acids. It has minimal protein 
binding and effect on cytochrome P450 enzyme system function (reducing the risk of drug-drug 
interactions), high oral bioavailability, and a half-life of approximately 13 hours (in adults), 
which allows a twice daily (bid) dose regimen. It also displays dose-proportional PK following 
administration over a range of doses up to 800mg in adults.
In the US, LCM has been approved as monotherapy and adjunctive therapy in the treatment of 
partial-onset seizures in patients 4 years of age and older for tablets and oral solution, and 
17 years of age and older for intravenous [iv] infusion. In the EU, LCM has been approved as 
monotherapy and adjunctive therapy in the treatment of partial-onset seizures with or without 
secondary generalization in adults, adolescents, and children from 4 years of age with epilepsy 
(tablets, oral solution, and solution for iv infusion). The oral solution (also referred to as syrup) is 
a formulation suitable for administration to children. Bioequivalence has been shown between 
the tablet and oral solution formulations, comparing 2 tablets of LCM 100mg and the oral 
solution containing LCM 200mg, after single-dose administration in healthy subjects. The PK of 
LCM and SPM 12809 (major LCM metabolite in humans) in plasma, urine, and saliva were 
identical or very similar after single oral doses of LCM 200mg administered as tablets or as oral 
solution.
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
LCM 400mg bid (LCM 800mg/day) were evaluated in approximately 800 unique volunteers who 
received LCM in Phase 1 studies. The safety and efficacy of LCM has also been evaluated in 
Phase 2/3 studies as adjunctive oral therapy in over 1300 adult subjects with partial-onset 
seizures and as oral monotherapy in over 2400 adult subjects in other indications (neuropathic 
pain, osteoarthritis, fibromyalgia, and migraine prophylaxis). In addition, LCM solution for 
infusion was evaluated as short-term replacement therapy in a subset of subjects with 
partial-onset seizures (220 patients) who were receiving adjunctive LCM tablets.
Three double-blind, PBO-controlled, multicenter studies (SP667, SP754, and SP755) in 
1308 adult subjects, aged 16 to 70 years, established the efficacy of oral LCM as adjunctive 
therapy (1 to 3 concomitant AEDs) in subjects with difficult to control partial-onset seizures. In 
these studies, LCM was initiated at a dose of 100mg/day (in 2 divided doses) and escalated to the 
randomized dose (LCM 200mg/day, LCM 400mg/day, or LCM 600mg/day) in LCM 100mg/day 
per week increments.
When oral LCM was administered as adjunctive therapy at doses up to LCM 600mg/day in the 
3 double-blind, PBO-controlled, multicenter studies in subjects with partial-onset seizures, the 
most frequently reported treatment-emergent adverse events (TEAEs) were central nervous 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 17 of 144
system- and gastrointestinal-associated events. A dose relationship was seen for the most 
frequently reported common TEAEs, including dizziness, nausea, and diplopia. The nature and 
frequency of AEs were comparable to adjunctive therapy with other marketed AEDs. Safety 
evaluations support the further development of LCM as an AED.
Pellock et al have recently conducted a systematic review of AEDs used in the treatment of 
partial-onset seizures (Bourgeois and Goodkin, 2012; Pellock et al, 2012). The AEDs that were 
shown to be superior to PBO for the adjunctive treatment of partial-onset seizures in adult 
clinical studies were also shown to be superior to PBO for adjunctive treatment of partial-onset 
seizures in the pediatric clinical studies (subjects >2 years of age) in which they were 
investigated. The efficacy and safety of LCM observed in clinical studies in adults and 
preclinical data, as well as many additional attributes of LCM, render the drug appropriate to 
investigate in pediatric subjects. These attributes include predictable and linear PK, lack of 
drug-drug interactions, easy bid dosing, and the availability of 3 different types of formulations 
in multiple strengths (allowing for flexibility in dose range and individualizing treatment).
Lacosamide is being evaluated in pediatric subjects 1 month to 17 years of age with partial-onset 
seizures in completed and ongoing studies. The completed pediatric studies include: SP847 
(open-label, safety, tolerability, and PK study) and SP1047 (PK study for subjects prescribed 
LCM). The ongoing pediatric studies include: SP848 and EP0034 (open-label, long-term safety 
studies). In SP847, SP848, and EP0034, subjects with uncontrolled partial-onset seizures have 
received LCM oral solution at doses up to 12mg/kg/day based on tolerability. In SP1047, 
subjects with epilepsy received LCM oral tablets (50mg, 100mg, 150mg, or 200mg), or LCM 
oral solution (syrup; LCM 10mg/mL) that they had been prescribed for epilepsy and brought 
with them to the clinic for dosing. Preliminary data have not demonstrated any clinically relevant 
changes in vital signs, in ECGs, or in clinical laboratory values; or evidence of cardiac related 
TEAEs or body weight changes.
SP0967 is a Phase 3, multicenter, double-blind, randomized, PBO-controlled, parallel-group 
study to evaluate the efficacy and safety of LCM (LCM 8mg/kg/day to 12mg/kg/day, or 
matching PBO) as adjunctive therapy in subjects ≥1 month to <4 years of age with epilepsy with 
uncontrolled partial-onset seizures.
3
STUDY OBJECTIVE(S)
The primary objective of this study is to evaluate the efficacy of LCM administered 
concomitantly with 1 to 3 AEDs in subjects ≥1 month to <4 years of age with epilepsy who 
currently have uncontrolled partial-onset seizures.
The secondary objective is to evaluate the safety and tolerability of LCM in subjects ≥1 month to 
<4 years of age with epilepsy who currently have uncontrolled partial-onset seizures.
An additional objective is to evaluate the PK of LCM in children ≥1 month to <4 years of age. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 18 of 144
4
STUDY VARIABLES
4.1
Efficacy variables
Primary and secondary efficacy variables will be based on video-EEGs (up to 72 hours of 
continuous recording with every attempt to obtain at least 48 hours of interpretable recording). 
4.1.1
Primary efficacy variable
For the US, the primary efficacy variable will be contingent on the percentage of subjects that 
discontinue from the study after the first dose of study medication but prior to performance of the 
End-of-Maintenance Period video-EEG (ie, early discontinuation).
The following variable will be considered primary for the US given that ≤10% of subjects 
discontinue early from the study:
x The change in ADF of electrographic partial-onset seizures as measured on the End-of-
Maintenance Period video-EEG compared to the End-of-Baseline Period video-EEG. 
If >10% of subjects discontinue early from the study, the following contingency endpoint will be 
considered primary for the US (same as the primary efficacy variable for the EU):
x The proportion of responders where a responder is a subject experiencing a 50% or greater 
reduction in their ADF of electrographic partial-onset seizures recorded on the End-of-
Maintenance Period video-EEG compared to the End-of-Baseline Period video-EEG.
For the EU:
The primary efficacy variable will be the proportion of responders where a responder is a subject 
experiencing a 50% or greater reduction in their ADF of electrographic partial-onset seizures 
recorded on the End-of-Maintenance Period video-EEG compared to the End-of-Baseline Period 
video-EEG.
4.1.2
Secondary efficacy variables
The secondary efficacy variables are described below.
x Percent and absolute change in ADF of electrographic partial-onset seizures from the 
End-of-Baseline Period video-EEG to the End-of-Maintenance Period video-EEG
x Proportion of subjects who achieved “seizure-free” status (yes/no) from all seizure types, and 
from partial-onset seizure types only for subjects who completed at least 48 hours of 
interpretable video-EEG recording during the End-of-Maintenance Period video-EEG
x Proportion of subjects experiencing a ≥25% to <50%, 50% to 75%, or >75% reduction in 
ADF of electrographic partial-onset seizures from the end-of-Baseline Period video-EEG to 
the End-of-Maintenance Period video-EEG
x Proportion of subjects experiencing no change in ADF of electrographic partial-onset 
seizures (between <25% reduction and <25% increase) from the End-of-Baseline Period 
video-EEG to the End-of-Maintenance Period video-EEG
x Proportion of subjects experiencing an increase in ADF of electrographic partial-onset 
seizures of ≥25% from the End-of-Baseline Period video-EEG to the End-of-Maintenance 
Period video-EEG
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 19 of 144
4.1.3
Other efficacy variables
Other efficacy variables to be examined include:
x Clinical Global Impression of Change at the end of the Maintenance Period
x Caregiver’s Global Impression of Change at the end of the Maintenance Period
x Change from Baseline in PedsQL health summary score at the end of the Maintenance Period
x Healthcare resource use: concomitant medications, medical procedures, healthcare provider 
consultations not related to the study, and hospitalizations not related to the study
4.2
Pharmacokinetic and pharmacodynamic variables
Plasma concentrations of LCM will be obtained in order to:
x Develop a population PK model of LCM
x Investigate the correlation between LCM plasma concentrations and efficacy or safety
4.3
Safety variables
4.3.1
Primary safety variables
Safety and tolerability will be assessed using the following primary safety variables:
x Adverse events reported spontaneously by the subject’s parent(s) and/or legal 
representative(s)/caregiver(s) (in accordance with local regulation) or observed by the 
investigator
x Subject withdrawals due to AEs
4.3.2
Other safety variables
x Change in hematology and clinical chemistry parameters
x Change in 12-lead ECGs
x Change in vital signs measurements (ie, blood pressure [BP] and pulse rate)
x Physical and neurological examination findings
x Changes in body weight, height, and calculated BMI
5
STUDY DESIGN
5.1
Study description
SP0967 is a Phase 3, multicenter, double-blind, randomized, PBO-controlled, parallel-group 
study to evaluate the efficacy and safety of LCM 8mg/kg/day to LCM 12mg/kg/day as 
adjunctive therapy in subjects ≥1 month to <4 years of age with epilepsy with partial-onset 
seizures.
Primary and secondary efficacy variables will be based on video-EEGs (up to 72 hours of 
continuous recording with every attempt to obtain at least 48 hours of interpretable recording). 
The video-EEGs will be conducted in an inpatient setting. Assessment of video-EEG seizure 
count will be performed locally by the investigator, subinvestigator, or qualified designated 
reader for the purpose of both assessment of eligibility and study analyses.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 20 of 144
Baseline Period
At Visit 1 (Day -7), subjects who meet the selection criteria will begin a 7-day Baseline Period 
(Day -7 to Day -1). In the event that additional time is needed to access inpatient facilities to 
perform the video-EEG, a maximum of 7 days may be added to the period between Visit 1 and 2.
From Visit 2 (Day -3 to Day -1) to Visit 3 (Day 1), an End-of-Baseline Period video-EEG will be 
performed. 
After completion of the End-of-Baseline video-EEG at Visit 3, subjects who meet the selection 
criteria will be randomized in a double-blind manner to 1 of 2 parallel treatment arms: LCM or 
PBO in a 1:1 ratio.
Titration Period
Subjects will begin a 20-day blinded Titration Period (Day 1 to Day 20) to attain the target dose 
for the Maintenance Period (LCM 8mg/kg/day to LCM 12mg/kg/day, or matching PBO). 
Subjects will be dispensed study medication and will begin treatment with LCM oral solution 
4mg/kg/day or matching PBO for 4 days. Subjects will then be titrated at 4-day intervals as 
recommended in Table 7‒1. The current 4-day titration step approach has been selected as it is 
generally accepted that frequent seizures require a rapid titration of AEDs.
Dosing flexibility during the Titration Period based on tolerability is allowed in SP0967. After 
completion of Day 4, investigators will assess whether a subject would tolerate a further dose 
increase or whether a subject should hold the dose for a longer duration. In addition to holds, 
subjects may have the study medication titrated to a higher dose or back titrated by 
LCM 1mg/kg/day or 2mg/kg/day (or matching PBO) steps. If study medication is titrated to a 
higher dose, the subject should remain on the higher dose for ≥4 days unless a back titration step 
based on tolerability is required.
If study medication is back titrated, the back titrated dose must never be lower than LCM 
4mg/kg/day (or matching PBO) and must be maintained for ≥3 days (in order to reach steady 
state) before a subsequent dose increase. After study medication is back titrated, if a subject 
returns to a higher dose previously administered, the dose must be maintained for ≥3 days before 
subsequent titration to a higher dose. There is no limit to the number of titration steps or dose 
holds allowed and all are at the investigator’s discretion; however, subjects must achieve at least 
the minimum target dose (LCM 8mg/kg/day or matching PBO) for the final 3 days of the 
Titration Period. If it becomes apparent that the subject will not be able to reach the minimum 
target dose, then the subjects should be withdrawn from the Titration Period and enter the Taper 
Period.
No adjustments in dose of study medication will be permitted after Day 20. Subjects who are not 
able to tolerate the study medication during the Titration Period or who will not be able to 
achieve the target dose by the end of the Titration Period will be withdrawn from the Titration 
Period and enter the Taper Period. 
Maintenance Period
Subjects who achieve at least the minimum target study medication (LCM 8mg/kg/day or 
matching PBO) dose for the final 3 days of the Titration Period will enter a 7-day blinded 
Maintenance Period on the dose achieved on the final day of the Titration Period 
(LCM 8mg/kg/day to LCM 12mg/kg/day, or matching PBO). No adjustments to study 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 21 of 144
medication dose will be allowed during the Maintenance Period. Subjects who complete the 
Maintenance Period may be eligible to participate in the open-label extension study (EP0034). 
Transition Period
A 12-day blinded Transition Period will be required for eligible subjects who complete the 
Maintenance Period and who plan to enter EP0034. For subjects randomized to LCM, the 
Maintenance Period dose will be maintained during the Transition Period. Subjects randomized 
to PBO will be transitioned in a double-blind fashion as described in Table 7‒2.
Taper Period
A blinded Taper Period (8 to 16 days, depending on dose level achieved) will be required for 
subjects who discontinue study medication prematurely and for subjects who complete the 
Maintenance Period but will not be entering EP0034. Study medication will be tapered as 
described in Table 7-3.
At the discretion of the investigator, AEDs may be added or adjusted and VNS adjustments may 
be made once the subject enters the Taper Period. 
Safety Follow-Up Period
There will be a 30-day Safety Follow-Up Period for subjects not entering the open-label 
extension study (EP0034). The Safety Follow-Up Period will include a Safety Follow-Up Clinic 
Visit 14 days (±2 days) after the final dose of study medication, and a Safety Follow-Up
Telephone Contact 30 days (-1/+3 days) after the final dose of study medication.
Unscheduled visits can be conducted at the discretion of the investigator.
Detailed schedules of study procedures are provided in Section 5.2, and study schematic 
diagrams are included in Section 5.3.
5.1.1
Study duration per subject
For each subject, the maximum total study duration can be up to 93 days (not withstanding visit 
windows), including the 30-day Safety Follow-Up Period. Each subject’s participation in the 
study begins with a 7-day Baseline Period (no administration of study medication). Each 
subject’s maximum total duration of study medication administration in SP0967 can be up to 55 
days. This includes a 20-day Titration Period, a 7-day Maintenance Period, a 12-day Transition 
Period (for subjects who plan to enter the open-label extension study [EP0034]) and/or up to a 
16-day Taper Period (for subjects who will not be entering EP0034). 
The end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Planned number of subjects and sites
A total of approximately 244 subjects (122 subjects per treatment arm) are planned to be 
randomized. Approximately 50% of the 244 randomized subjects should be <2 years of age. Of 
these (n=122), every attempt will be made to enroll a minimum target of 20% (n=25) of subjects 
in each of the 3 age categories: ≥1 month to <6 months, ≥6 months to <1 year, and ≥1 year to <2 
years.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 22 of 144
Every attempt will be made to enroll subjects in the following age categories as detailed below:
x ≥1 month to <6 months of age (≥25 subjects)
x ≥6 months to <1 year of age (≥25 subjects)
x ≥1 year to <2 years of age (≥25 subjects)
x ≥2 years to <4 years of age (≥20 subjects)
Approximately 140 sites are planned in order to recruit the required subjects; additional sites will 
be added if deemed necessary. 
5.1.3
Anticipated regions and countries
The study will be conducted in North America, Europe, Asia Pacific, and Latin America with
possible extension to other countries and regions. A target of approximately 30% of the 
randomized subjects should consist of subjects originating from sites in North America and 
Europe.
5.2
Schedule of study assessments
A tabular schedule of study procedures for the Baseline and Treatment Periods is presented in 
Table 5‒1. A tabular schedule of study procedures for the Transition Period is presented in 
Table 5‒2. A tabular schedule of study procedures for the Taper and Safety Follow-Up Periods is 
presented in Table 5‒3.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 23 of 144
Table 5‒1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
Informed consent
X
Demographics
c
X
Inclusion/exclusion criteria
X
X
X
Medical history
X
Seizure history/count
X
Concomitant medications
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant AEDs
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
VNS assessmentf
X
X
X
X
X
X
Physical examination (complete)
X
X
Physical examination (brief)
X
X
X
X
Vital signs (including BP and 
pulse rate)g
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Height
X
X
Head circumference
X
X
Neurological examination 
(complete)
X
X
Neurological examination (brief)
X
X
X
X
ECG (12-lead)h
X
X q
X
X
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 24 of 144
Table 5‒1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
Video-EEGi
X
X
X
X
X
X
X
X
Rescue medicationj
X
X
X
X
X
X
X
X
Clinical chemistry/hematology
X
X
X
LCM plasma concentration
X
X
Clinical GIC 
X
Caregiver’s GIC
X
Contact IXRS
X
X
X
X
X
X
Randomization
Xk
Dispense study medication
Xk
X
X
X
X
Return study medication
X
X
X
X
Dosing instructionsl
X
X
X
AE reporting
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
Healthcare resource use
X
X
Bayley-III scalesm
X
BRIEF-Pn
X
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 25 of 144
Table 5‒1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
PedsQLo
X
X
Achenbach CBCLp
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; 
CBCL=Childhood Behavior Checklist; ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination; GIC=Global Impression of 
Change; IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; T=Telephone Contact; 
UV=Unscheduled Visit; V=Visit; VNS=vagus nerve stimulation.
a If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments may be performed at the investigator’s 
discretion.
b The Day -3 and Day 24 assessments should be conducted prior to the start of video-EEG monitoring. A maximum of 7 days may be added to the 
period between Visit 1 and 2 in the event that additional time is needed to access inpatient facilities to perform the video-EEG. 
c Demographics: date of birth, age group category, age in months and years, race, ethnicity, and gender. In countries where recording of complete 
date of birth is not permitted, only permitted data will be collected.
d The concomitant medications recording will include any current medication intake as well as any medications taken ≤30 days prior to Visit 1.
e The concomitant AED recording will include any current medication intake as well as any previous AED taken prior to Visit 1.
f The VNS setting will be assessed as applicable.
g Orthostatic assessments of BP and pulse rate will be assessed where it is feasible according to investigator judgment.
h A 12-lead ECG (2 interpretable recordings) will be performed prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recording. The second recording will be conducted approximately 20 to 30 minutes after 
the first recording. Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified designated reader and at a central 
ECG laboratory. The investigator may consult with the cardiologist at the central ECG laboratory to confirm the presence of a clinically significant 
ECG abnormality; however, 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.
i The video-EEG (up to 72 hours of continuous recording with every attempt to obtain at least 48 hours of interpretable recording) will be conducted 
in an inpatient setting. Upon completion of the End-of-Baseline video-EEG (Visits 2 and 3), the investigator will assess the electrographic seizure 
count and confirm the selection criteria have been met. If the subject meets all selection criteria, including the requisite number of seizures based 
on the video-EEG data, the subject may be randomized at Visit 3. Assessment of video-EEG seizure count will be performed locally by the 
investigator, subinvestigator, or qualified designated reader for the purpose of both assessment of eligibility and study analyses. The 
End-of-Maintenance Period video-EEG will be done at Visit 6. Subjects who discontinue on or before Day 20 will not require a video-EEG.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 26 of 144
Table 5‒1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
j Additional assessment for changes in VNS or rescue medication taken within 24 hours prior to and until the end of the video-EEG monitoring.
k Randomization and initial dispensing of study medication will occur at Visit 3 and after the completion of the video-EEG and confirmation that the 
subject has met selection criteria. 
l Dosing instructions will be provided to the caregiver(s) during the telephone contacts. At a minimum, AEs and tolerability should be discussed 
with the caregiver(s) in order to determine the next dose for the subject. See Section 7.2.1 for additional details on dosing options. 
m Investigators must make every attempt to administer the Bayley Scales of Infant and Toddler Development, Third Edition, for subjects who are 
<18 months of age who originate in English-speaking countries. The investigators may utilize trained pediatric psychologists or other appropriately 
skilled individuals to administer the scale. 
nThe BRIEF-P will be used only for subjects who are ≥2 years of age at Visits 3. BRIEF-P will be used only in countries where a translated version 
is available.
o The version of the PedsQL used at Visit 3 should be consistent with the subject’s age at Visit 3 and should be maintained for each subject for the 
duration of the study. The PedsQL will be used only in countries where a translated version is available. 
p The Achenbach CBCL/1½-5 will be completed by the parent(s)/legal representative(s)/caregiver(s) of subjects ≥18 months of age at Visit 3. The 
Achenbach CBCL will be administered only in countries where a translated version is available.
q ECG at Visit 3 will be performed at the discretion of the investigator.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 27 of 144
Table 5‒2:
Schedule of study assessments (Transition Period)
Assessments 
Transition Period (12 days)
Visit
TV1
TT1
TV2
a
Study Day 
32
36
40
Concomitant medications
X
X
X
b
Concomitant AEDs
X
X
Xb
VNS assessment
c
X
Xb
Physical examination (brief)
X
Physical examination (complete)
Xb
Vital signs (including BP and pulse rate)
d
X
Xb
Body weight
X
Xb
Neurological examination (brief)
X
Neurological examination (complete)
Xb
ECG (12-lead)e
Xb
Clinical chemistry/hematology
Xb
Contact IXRS
X
X
Dosing instructionsf
X
Dispense study medication
X
Return study medication
X
X
AE reporting
X
X
Xb
Withdrawal criteria
X
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; ECG=electrocardiogram; IXRS=interactive 
voice/web response system; TT=Transition Telephone Contact; TV=Transition Visit; VNS=vagus nerve 
stimulation
a Transition Visit 2 will also serve as Visit 1 for EP0034.
b The designated procedures will serve as the point of data for both TV2 in SP0967 and Visit 1 for EP0034.
c Vagus nerve stimulation setting will be assessed as applicable.
d Orthostatic assessments of BP and pulse rate will be assessed if it is feasible according to investigator judgment.
e A 12-lead ECG (2 interpretable recordings) will be performed prior to any blood draws and vital signs assessment 
and, if possible, with the subject in the supine position for 5 minutes preceding the ECG recording. The second 
recording will be conducted approximately 20 to 30 minutes after the first recording. 
f Dosing instructions will be provided to the caregiver(s) during the telephone contacts. See Section 7.2.3 for 
additional details on dosing options.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 28 of 144
Table 5‒3:
Schedule of study assessments (Taper and Safety Follow-Up 
Periods)
Assessments 
Taper Period (8 to 16 days)
Safety Follow-Up Period (30 days)
a
Visit
T4
b
Taper Visit
c
Safety Follow-Up
Clinic Visit
Days in Study: 
FSM+14 (±2)
Safety Follow-Up
Telephone Contact
Days in Study: 
FSM+30 (-1/+3)
Study Day 
32
d
36/40/44c,d
50/54/58d
66/70/74/93d
Concomitant medications
X
X
X
X
Concomitant AEDs
X
X
X
X
VNS assessment
e
X
X
Physical examination (brief)
X
Physical examination (complete)
X
Vital signs (including BP and 
pulse rate)
f
X
X
Body weight
X
X
Neurological examination (brief)
X
Neurological examination 
(complete)
X
ECG (12-lead)
g
Xh
X
h
Clinical chemistry/hematology
Xh
Xh
Contact IXRS
X
Dosing instructionsi
X
Return study medication
X
AE reporting
X
X
X
X
Withdrawal criteria
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; ECG=electrocardiogram; FSM=Final Study 
Medication; IXRS=interactive voice/web response system; T=Telephone Contact; VNS=vagus nerve 
stimulation
a The Safety Follow-Up Clinic Visit will be scheduled 14 days (±2 days) after the final dose of study 
medication. The Safety Follow-Up Telephone Contact will occur 30 days (-1/+3 days) after the final dose of 
study medication.
b A telephone contact (T4) will be conducted at the end of the first taper step of the Taper Period.
c Each subject will have only 1 Taper Visit. The Taper Visit will be scheduled at the end of the Taper Period 
(Day 36, 40, or 44), depending on dose level achieved (see Table 7-3).
d The study day numbers provided are for subjects who complete the Maintenance Period and enter the Taper 
Period. The study day numbers provided do not apply to subjects who enter the Taper Period at other times. 
Day 66, 70, or 74 result from the administration of final study medication during the Taper Period whereas 
Day 93 would result from a subject progressing to the end of the Transition Period, but then not entering 
EP0034 and instead entering the Transition Period followed by the Taper Period.
e VNS setting will be assessed as applicable.
f Orthostatic assessments of BP and pulse rate will be assessed where it is feasible according to investigator 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 29 of 144
Table 5‒3:
Schedule of study assessments (Taper and Safety Follow-Up 
Periods)
Assessments 
Taper Period (8 to 16 days)
Safety Follow-Up Period (30 days)
a
Visit
T4
b
Taper Visit
c
Safety Follow-Up
Clinic Visit
Days in Study: 
FSM+14 (±2)
Safety Follow-Up
Telephone Contact
Days in Study: 
FSM+30 (-1/+3)
Study Day 
32
d
36/40/44c,d
50/54/58d
66/70/74/93d
judgment.
g A 12-lead ECG (2 interpretable recordings) will be performed prior to any blood draws and vital signs 
assessment and, if possible, with the subject in the supine position for 5 minutes preceding the ECG 
recording. The recordings should be made approximately 20 to 30 minutes apart.
h The assessment will be required for subjects with a clinically significant abnormal value (clinical chemistry or 
hematology) or reading (ECG) at the previous clinic visit. For non-clinically significant abnormalities, repeat 
of these assessments is at the discretion of the investigator. 
i Dosing instructions will be provided to the caregiver(s). See Section 7.2.3 for additional details on dosing 
options.
5.3
Schematic diagram
An overall schematic diagram for subjects entering EP0034 is provided in Figure 5‒1. An overall 
schematic diagram for subjects not entering EP0034 is provided in Figure 5‒2.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 30 of 144
Figure 5‒1: Subjects entering EP0034 open-label extension study
PBO=placebo; T=Telephone Contact; TT=Transition Telephone Contact; TV=Transition Visit; V=Visit
RED
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 31 of 144
Figure 5‒2:
Subjects not entering EP0034 open-label extension study
a Subjects progressing to the end of the Transition Period, but then not entering EP0034 and instead entering the Transition Period followed by the Taper Period 
would complete the Safety Follow-Up Period at Day 93.
PBO=placebo; T=Telephone Contact; V=Visit
REDACTED COPY 
This document cannot be used to support any marke
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 32 of 144
5.4
Rationale for study design and selection of dose
Epilepsy is a condition for which an improved benefit/risk ratio for medicinal products remains a 
challenge; this is especially true for pediatric patients. Based on the demonstrated efficacy and 
safety of LCM as adjunctive treatment in subjects aged ≥16 years of age, and the experience with 
other AEDs in pediatric subjects, it is likely that LCM will be an efficacious and safe treatment 
in the pediatric population with uncontrolled partial-onset seizures.
SP0967 is a Phase 3, multicenter, double-blind, randomized, PBO-controlled, parallel-group 
study to evaluate the efficacy and safety of LCM as adjunctive therapy in subjects ≥1 month to 
<4 years of age with epilepsy who have uncontrolled partial-onset seizures. 
Based on the currently available LCM pediatric PK, safety, and tolerability data from SP847 and 
SP1047, as well as on information available in the medical literature, the recommendations for 
SP0967 are as follows:
x Subjects must weigh ≥4kg to <30kg at Visit 1.
x Feeding tube administration is permitted for subjects who are unable to swallow the oral 
solution.
x Titration should occur over a 20-day period; with LCM dose increased by 2mg/kg/day every 
4 days until the target dose (LCM 8mg/kg/day to 12mg/kg/day, or matching PBO) is 
achieved. All subjects will start on a dose of LCM 4mg/kg/day or matching PBO at the start 
of the Titration Period.
x During the Titration Period, step-back titration by LCM 1mg/kg/day or LCM 2mg/kg/day 
will be permitted to allow subjects with reduced tolerability to remain in the study depending 
on tolerability (ie, based on investigator judgment and legal representative[s]/caregiver[s] 
feedback). If study medication is back titrated, the dose must never be lower than 
LCM 4mg/kg/day (or matching PBO) and must be maintained for ≥3 days (in order to reach 
steady state) before subsequent titration to a higher dose.
x During the Titration Period, subjects may also have the dose of study medication held steady 
or titrated to a higher dose. If study medication is titrated to a higher dose, the subject must 
remain on that dose for ≥4 days unless a step-back titration based on tolerability is required.
x The LCM dose should remain fixed over the Maintenance Period.
Based on US FDA and EMA requirements, 2 (co-) primary efficacy variables have been defined 
for this study based on electrographic partial-onset seizures with or without clinical correlate 
depending upon subject age. The primary efficacy variable will be the change in ADF of 
electrographic partial-onset seizures (US) or proportion of subjects experiencing ≥50% reduction 
in their ADF of electrographic partial-onset seizures (EU) as measured on the End-of-
Maintenance Period video-EEG compared to the End-of-Baseline Period video-EEG. At the 
request of FDA, a contingent primary efficacy variable has also been defined based on the 
percentage of subjects who discontinue early from the study prior to completing the End-of-
Maintenance Period video-EEG. Contingent upon >10% of subjects discontinuing early from the 
study, the primary efficacy parameter for the US will become identical to the primary efficacy 
parameter for the EU.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 33 of 144
The endpoint not designated as primary will still be summarized as a secondary efficacy 
parameter.
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 form is signed and date by the parent(s) or legal 
representative(s)/caregiver(s) (in accordance with local regulation). 
2.
Subject’s parent(s) or legal representative(s)/caregiver(s) is considered reliable and capable 
of adhering to the protocol visit schedule or medication intake according to the judgment of 
the investigator.
3.
Subject is male or female from ≥1 month (ie, 4 weeks after full term [37 weeks gestational 
age]) to <4 years of age. For preterm infants <1 year old, the corrected gestational age 
should be used when determining eligibility. The generally accepted definition of corrected 
gestational age, which is calculated by subtracting the number of weeks born before 
37 weeks of gestation from the chronological age, will be used for this study. 
4.
Subject has a diagnosis of epilepsy with partial-onset seizures. The results of ≥1 prior EEG 
and ≥1 magnetic resonance imaging/computerized tomography scan should be consistent 
with this diagnosis.
5.
Subject weighs ≥4kg to <30kg at Visit 1.
7.
Subject has experienced ≥2 partial-onset seizures with or without secondary generalization 
during each consecutive 7-day period during the 2 weeks prior to Visit 1.
8a.
Subject has ≥2 partial-onset seizures with or without secondary generalization during the 
End-of-Baseline video-EEG. Electrographic seizures are defined as recognizable ictal
patterns on an EEG involving ≥2 contiguous electrodes. The seizures are initiated as a 
unilateral or strongly asymmetric abnormal epileptiform discharge lasting a total of 
>10 seconds.
9.
Subject is on a stable (concurrently or sequentially) dosage regimen of 1 to 3 AEDs. The 
dosage regimen of concomitant AED therapy must be kept constant for a period of 
≥2 weeks prior to Visit 1. A stable daily dosage regimen of a concomitant benzodiazepine 
(BZD) will be considered as a concomitant AED. 
10.
Vagus nerve stimulation is allowed and will not be counted as a concomitant AED. The 
VNS device must have been implanted for ≥6 months prior to Visit 1; device settings must 
be kept stable for ≥2 weeks prior to Visit 1 and kept stable during the Baseline, Treatment,
and Transition Periods. Use of the VNS device magnet is allowed.
11.
Subject is an acceptable candidate for venipuncture.
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria are met:
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 34 of 144
1a.
Subject has been previously randomized in this study (re-screening for screen-failed 
subjects is only allowed with prior consultation and permission of the medical monitor).
2.
Subject has participated in another study of an investigational medicinal product (IMP) or a 
medical device during the 2 months immediately prior to Visit 1 or is currently 
participating in another study of an IMP or a medical device.
3.
Subject has any medical or psychiatric condition that, in the opinion of the investigator, 
could jeopardize or would compromise the subject’s ability to participate in this study.
4a.
Subject has been previously treated with LCM and the LCM treatment was stopped due to 
lack of efficacy or adverse event(s).
5.
Subject has a known hypersensitivity to any component of the study medication.
6.
Subject has a medical condition that could be expected, in the opinion of the investigator, 
to interfere with study medication absorption, distribution, metabolism, or excretion.
7.
Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures in 
addition to partial-onset seizures is not exclusionary.
8a.
Subject is on a ketogenic diet that has either changed within the 4 weeks prior to Visit 1 or 
is expected to change during the study.
9a.
Subject has creatinine clearance <30mL/minute.
10.
Subject has a clinically relevant ECG abnormality, in the opinion of the investigator (eg, 
second or third degree heart block at rest or a corrected QT interval [QTc] ≥450ms). 
11.
Subject has a hemodynamically significant congenital heart disease. 
12.
Subject has an arrhythmic heart condition requiring medical therapy. 
13.
Subject has a known history of severe anaphylactic reaction secondary to medication intake 
or serious blood dyscrasias. 
14.
Subject has nonepileptic events that could be confused with seizures. Subjects may be 
included if epileptic events can be clearly distinguished and the frequency meets the study 
inclusion criteria. 
15a. Subject has a current diagnosis of Lennox-Gastaut syndrome, epilepsia partialis continua, 
primary generalized epilepsy, Dravet Syndrome, or seizures that are not of partial-onset 
origin. 
16a. Subject has a history of generalized convulsive status epilepticus ≤2 months prior to 
Screening (Visit 1). 
19.
Subject has been treated with felbamate and has experienced any serious toxicity issues 
(defined as liver failure, aplastic anemia) with this treatment. Subjects treated with 
felbamate for <12 months are excluded. Subjects treated with felbamate for ≥12 months 
prior to Visit 1 and who have not experienced serious toxicity issues are eligible.
20.
Subject has an acute or subacutely progressive central nervous system disease. Subject has 
epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease (malignant brain tumor or Rasmussen Syndrome).
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 35 of 144
21a. Subject has a known cardiac sodium channelopathy, such as Brugada syndrome.
22.
Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject 
has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%).
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful elevation must 
be understood and recorded in the electronic Case Report form (eCRF).
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at 
screening, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing 
clinically relevant increase. In case of a clinically relevant increase, inclusion of the subject 
must be discussed with the Medical Monitor.
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be 
repeated once for confirmation.
6.3
Withdrawal criteria
Parent(s)/legal representative(s) are free to withdraw the subject from the study at any time, 
without prejudice to their continued care. The following criteria for subject withdrawal from 
SP0967 are outlined below. Additional discontinuation criteria for potential drug-induced liver 
injury (PDILI) are presented in Section 6.3.1.
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study. 
Subjects who are unable to tolerate study medication will be withdrawn from the study as 
follows:
x Subjects unable to achieve or maintain target dose for the final 3 days of the Titration Period
2. The sponsor or a regulatory agency requests withdrawal of the subject.
3. Subject has QTc interval of ≥500ms that is confirmed by a cardiologist over-read on any 
ECG.
4. Subject develops a second or third degree atrioventricular (AV) block. 
5. Subject is unwilling or unable to continue, or the parent(s)/legal 
representative(s)/caregiver(s) is unwilling or unable to allow the subject to continue in the 
study.
6. Investigator's decision that withdrawal from further participation would be in the subject’s 
best interest.
7. Subject experiences generalized convulsive status epilepticus.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 36 of 144
Subjects may be withdrawn from the study if any of the following events occur:
1. Subject has any clinically relevant change in medical or psychiatric condition and in the 
opinion of the investigator, the condition warrants discontinuation from the study.
2. Subject requires a medication that is not permitted by the protocol.
3. Subject’s legal representative(s)/caregiver(s) (in accordance with local regulation) is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
5. Subject uses BZDs within 24 hours prior to or during video-EEG for any reason other than a
stable daily dosage regimen as a concomitant AED. The Medical Monitor should be 
contacted if withdrawal is being considered. Use of a stable daily dosage regimen of a 
concomitant BZD (ie, 1 of the Baseline concomitant AED[s]) should be maintained for the
video-EEG procedures.
Investigators should attempt to obtain information for subjects who withdraw. 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 parent[s] or legal representative[s]/caregiver[s]), 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 eCRF must document the primary reason for withdrawal.
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance.
Subjects withdrawn from the study will proceed to the blinded Taper Period described in 
Section 7.2.4 and the assessments described in Table 5‒3 will be performed.
Subjects who are withdrawn from the study will not be replaced.
6.3.1
Potential drug-induced liver injury IMP discontinuation criteria
Subjects with potential drug-induced liver injury must be assessed to determine if IMP must be 
discontinued. In addition, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. 
The PDILI criteria below require immediate and permanent discontinuation of IMP: 
x Subjects with either of the following:
 ALT or AST ≥5xULN
 ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP:
x Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%).
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 37 of 144
x Subjects with ALT or AST ≥3xULN (and ≥2x Baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness).
Evaluation of PDILI must be initiated as described in Section 11.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately.
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation.
7
STUDY TREATMENTS
7.1
Description of investigational medicinal products
Investigational medicinal product will be provided as LCM oral solution (LCM 10mg/mL) and 
matching PBO. The LCM 10mg/mL oral solution and matching PBO oral solution are colorless 
to pale yellow in appearance. Both oral solutions will be packaged in amber polyethylene 
terephthalate (PET) bottles. 
Study medication will be measured and administered via a dosing syringe. If a subject is unable 
to swallow the oral solution, administration by feeding tube will be permitted. 
It should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the 
syrup), missed doses, or administration of an erroneous volume of syrup, study medication 
should not be readministered.
7.2
Treatment(s) to be administered
At Visit 3, subjects will be randomized in a double-blind manner to 1 of 2 parallel treatment 
arms: LCM or PBO in a 1:1 ratio. Randomization will occur after completion of the End-of-
Baseline video-EEG and after confirmation that the subject has met selection criteria. 
Randomization will be stratified by age category (≥1 month to <6 months of age, ≥6 months to 
<1 year of age, ≥1 year to <2 years of age, and ≥2 years to <4 years of age).
At the end of Visit 3, subjects should take the first dose of study medication while in the clinic. 
At each subsequent clinic visit, subjects should take study medication (and any concomitant 
AEDs) at the regular time(s). Study medication will be administered orally bid (at approximately 
12-hour intervals in the morning and in the evening).
SP0967 will target Maintenance Period doses of LCM 8mg/kg/day to 12mg/kg/day or matching 
PBO.
7.2.1
Titration Period
Subjects will be dispensed study medication and will begin treatment with LCM oral solution at 
a dose of LCM 4mg/kg/day or matching PBO. Table 7‒1 provides the recommended LCM (or 
matching PBO) dosing schedule during the Titration Period for subjects to reach the target doses 
for the Maintenance Period.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 38 of 144
Table 7‒1:
Recommended dosing schedule for LCM (or matching PBO) during 
the Titration Period
Target LCM (or matching PBO) doses for the Titration Period
Day 1 to Day 4
Day 5 to Day 8
Day 9 to Day 12
Day 13 to Day 16
Day 17 to Day 20
4mg/kg/day
6mg/kg/day
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10mg/kg/day
12mg/kg/day
LCM=lacosamide; PBO=placebo
Dosing flexibility during the Titration Period based on tolerability is allowed in SP0967. After 
completion of Day 4, investigators will assess whether a subject would tolerate a further dose 
increase or whether a subject should hold the dose for a longer duration. In addition to holds, 
subjects may have the study medication titrated to a higher dose or back titrated by LCM 
1mg/kg/day or 2mg/kg/day (or matching PBO) steps. If study medication is titrated to a higher 
dose, the subject should remain on the higher dose for ≥4 days unless a back-titration step based 
on tolerability is required. 
If study medication is back titrated, the back titrated dose must never be lower than LCM 
4mg/kg/day (or matching PBO) and be maintained for ≥3 days before a subsequent dose 
increase. After study medication is back titrated, if a subject returns to a higher dose previously 
administered, the dose must be maintained for ≥3 days (in order to reach steady state) before 
subsequent titration to a higher dose. After study medication is back titrated, if a subject 
subsequently receives a higher dose not previously administered, that dose should be maintained 
for ≥4 days unless tolerability concerns require a back titration. 
There is no limit to the number of titration steps or dose holds allowed and all are at the 
investigator’s discretion; however, subjects must achieve at least the minimum target dose of 
study medication (LCM 8mg/kg/day or matching PBO) for the final 3 days of the Titration 
Period. If it becomes apparent that the subject will not be able to reach the minimum target dose, 
then the subject should be withdrawn from the Titration Period and enter the Taper Period.
No adjustments in dose of study medication will be permitted after Day 20. Subjects who are not 
able to tolerate the study medication at an earlier time point during the Titration Period or who 
are not able to tolerate the reduced dose at the end of the Titration Period will be withdrawn from 
the study and enter the blinded Taper Period. Subjects who withdraw during the Transition 
Period will also enter the blinded Taper Period. 
7.2.2
Maintenance Period
Subjects who achieve at least the minimum target dose of study medication (LCM 8mg/kg/day 
or matching PBO) for the final 3 days of the Titration Period will enter the 7-day blinded 
Maintenance Period on the dose achieved at the end of the Titration Period and will continue to 
receive this dose for the duration of the Maintenance Period. No adjustments to study medication 
dose will be allowed during the Maintenance Period. 
Subjects who complete the Maintenance Period will be offered the opportunity to enroll in an 
open-label extension study (EP0034). Eligible subjects who choose to enroll in EP0034 will 
proceed to a blinded 12-day Transition Period. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 39 of 144
7.2.3
Transition Period
During the Transition Period, subjects randomized to PBO will be transitioned in a double-blind 
manner from PBO to LCM 8mg/kg/day over a 12-day period. Transition dosing will be 
administered according to Table 7‒2. Subjects randomized to LCM will remain on their 
Maintenance Period dose during the Transition Period.
Table 7‒2:
Transition Period LCM dosing schedule for subjects randomized to 
PBO
Maintenance Period 
LCM doses for the Transition Period
Day 28 to Day 31
Day 32 to Day 35
Day 36 to 39
PBO
4mg/kg/day
6mg/kg/day
8mg/kg/day
LCM=lacosamide; PBO=placebo
At Visit 1 of EP0034, all subjects will transition to a dose of LCM 10mg/kg/day. The SP0967 
final Transition Visit is the same as Visit 1 of EP0034.
7.2.4
Taper Period
Subjects who are not eligible for or who choose not to enter EP0034, or subjects who do not 
complete the Maintenance Period, will proceed to a blinded Taper Period of 8 to 16 days during 
which treatment with study medication will be withdrawn. The taper steps will be based on the 
dose of LCM (or matching PBO) achieved during the Maintenance Period according to 
Table 7-3. A slower taper is permitted if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the Medical Monitor, whenever possible. 
Subjects who are withdrawn during either the Titration Period or the Transition Period will also 
proceed to the Taper Period, and study medication will be tapered starting at the respective dose 
achieved during the Titration Period or the Transition Period. At the discretion of the 
investigator, AEDs may be added or adjusted and VNS adjustments may be made once the 
subject enters the Taper Period. 
Table 7-3:
Dosing of LCM (or matching PBO) during the Taper Period
LCM (or matching 
PBO) dose achieved
LCM (or matching PBO) doses for the Taper Period 
Day 28 to Day 31
Day 32 to Day 35
Day 36 to Day 39
Day 40 to Day 43
11 or 12mg/kg/day
9mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
9 or 10mg/kg/day
8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
7 or 8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
5 or 6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
NA
LCM=lacosamide; NA=not applicable; PBO=placebo
Note: The study day numbers provided are for subjects who complete the Maintenance Period and enter the Taper 
Period. The study day numbers provided do not apply to subjects who enter the Taper Period at other times.
Subjects who enter the Taper Period will return for the Taper Visit at the end of the Taper 
Period. 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 40 of 144
Taper of LCM may not be required for some subjects who are on the lowest dose of study 
medication or who need to discontinue study medication abruptly, depending on the treatment 
option selected by the investigator in consultation with the medical monitor.
7.3
Packaging
Lacosamide and matching PBO are manufactured, packaged, and labeled according to Good 
Manufacturing Practice (GMP) guidelines and applicable laws or regulations. The IMP is 
suitably packaged in such a way as to protect the IMP from deterioration during transport and 
storage.
Lacosamide 10mg/mL oral solution and matching PBO will be packaged in amber PET bottles, 
and will be measured and administered via a dosing syringe.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language.
7.5
Handling and storage requirements
The investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label.
Appropriate storage conditions must be ensured either by controlling the temperature or by 
completion of a temperature log in accordance with local requirements on a regular basis, 
showing minimum and maximum temperatures reached over the time interval.
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual.
The investigator (or designee) will instruct the subject‘s legal representative(s)/caregiver(s) (in 
accordance with local regulation) to store the 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, damaged (due to breakage or wastage), not used, partially 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 investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned.
The investigator 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.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 41 of 144
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers/partially used), unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB’s 
designee. 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 used, unused, IMP and empty IMP 
containers. Drug accountability must be done in the presence of the subject’s parent(s)/legal 
representative(s)/caregiver(s) in order to obtain 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 (defined as <75% or >125% compliant with 
the dosage schedule), 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 and prohibited concomitant treatments (medications and 
therapies)
Subjects must have been maintained on a stable dosage regimen of 1 to 3 marketed AEDs for 
≥2 weeks prior to Visit 1. 
Vagus nerve stimulation is allowed and will not be counted as concomitant AED use. The VNS 
device must have been implanted for ≥6 months prior to Visit 1, kept at a stable setting for 
≥2 weeks prior to Visit 1, and kept stable during the Baseline, Treatment, and Transition Periods. 
Use of the VNS device magnet is allowed.
For subjects who enter the Taper Period, AEDs may be added or adjusted and VNS adjustments 
may be made at the discretion of the investigator.
The following concomitant medications are prohibited during the study:
x Clozapine
x Monoamine oxidase-A inhibitors 
x Barbiturates (except as AEDs)
x Cannabidiols (not approved or indicated for epilepsy by local health authority)
Neuroleptics (except for clozapine) are allowed during the study but the investigator should 
make every effort to keep the dose stable.
Subjects who have been treated with felbamate and have experienced any serious toxicity issues 
are excluded from the study. Any subject who is currently treated with felbamate, and has 
received felbamate for a period of less than 12 months, is excluded from the study. Subjects 
treated with felbamate for ≥12 months prior to Visit 1 and who have not experienced serious 
toxicity issues are eligible.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 42 of 144
The following medications are not allowed unless used as described: 
x Amphetamines: stable use only. 
A stable daily dosage regimen of concomitant BZDs will be considered as a concomitant AED. 
Such use is permitted throughout the study and should be maintained for the video-EEG 
procedures. Use of BZDs as rescue medications (ie, not as part of a stable daily dosing regimen) 
is permitted. However, use of BZDs for any reason other than a stable daily dosage regimen as 
concomitant AED within 24 hours prior to or during the video-EEG is not permitted and may 
lead to the subject being withdrawn from the study (May Withdrawal Criterion 5; Section 6.3).
Therapy that becomes necessary (in the investigator’s opinion) during the course of the study 
must not be refused to a subject, even if described above as a therapy that is expressly not 
permitted. In cases where this occurs but withdrawal criteria have not been met, the advisability 
of the subject’s continuation in the study must be discussed between the Medical Monitor and 
the investigator. Other medications are permitted according to current clinical standards (eg, 
topical anesthetic).
7.8.2
Rescue medication
Use of BZDs as rescue medications (ie, not as part of a daily regimen) is permitted. However, 
use of BZDs for rescue within 24 hours prior to or during video-EEG recording is not permitted.
7.9
Blinding
Subjects, investigators, and all site personnel are blinded to study medication.
Lacosamide and PBO oral solutions are colorless to pale yellow solutions packaged in amber 
PET bottles. The blind is maintained as the accompanying packaging is identical in appearance 
so that neither the investigator/investigator’s designee nor the subject is able to tell whether the 
subject is receiving LCM or PBO.
An interactive voice/web response system (IXRS) will be used to assign a treatment to subjects 
who meet eligibility criteria at Visit 3, based on a predetermined randomization schedule. The 
IXRS is used to control all drug distribution and inventory for this study.
The IXRS will be responsible for subsequent issue of treatment kits, as appropriate to the visit 
schedule.
7.9.1
Procedures for maintaining and breaking the treatment blind
7.9.1.1
Maintenance of study treatment blind
All subject treatment details will be allocated and maintained by the IXRS.
7.9.1.2
Breaking the treatment blind in an emergency situation
In the event of an emergency, it will be possible to determine to treatment arm and dose the 
subject has been allocated by contacting the IXRS. All sites will be provided with details of how 
to contact the system for code breaking at the start of the study. The Medical Monitor or 
equivalent should be consulted prior to unblinding, whenever possible.
The Clinical Project Manager will be informed immediately via the IXRS when a code is broken, 
but will remain blinded to specific treatment information. Any unblinding of the IMP performed 
by the investigator must be recorded in the source documents and on the Study Termination 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 43 of 144
eCRF page. Subjects whose treatment is unblinded will be discontinued from the study and 
tapered off of LCM as noted in Table 7-3.
7.10
Randomization and numbering of subjects
An IXRS will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined randomization schedule provided by UCB or its designee. 
To enroll a subject (Visit 1), the investigator will contact the IXRS and provide brief details 
about the subject to be enrolled. Each subject will receive a 5-digit number assigned at Screening 
which serves as the subject identifier throughout the study. The subject number will be required 
in all communication between the investigator/investigator's designee and the IXRS regarding a 
particular subject. Subject numbers and kit numbers will be tracked via the IXRS. 
To randomize a subject (Visit 3), the investigator (or designee) will contact the IXRS and 
provide brief details about the subject to be randomized. The IXRS will allocate kit numbers to 
the subject based on the subject number during the course of the study.
Randomization will be stratified by age category (≥1 month to <6 months of age, ≥6 months to 
<1 year of age, ≥1 year to <2 years of age, and ≥2 years to <4 years of age).
8
STUDY PROCEDURES BY VISIT 
Detailed tabular schedules of study procedures are provided in Section 5.2. The subject should 
take concomitant AEDs at the usual time(s) on the morning of each clinic visit.
At all visits and telephone contacts, subjects will be instructed to call the investigator if any 
intolerable and/or serious AEs (SAEs) occur before the next visit or contact. After subjects begin 
study medication, if any AEs necessitate a subject’s withdrawal from the study, the subject 
should come in for a clinic visit as soon as possible after the occurrence of the AE. 
Planned clinic visits should be scheduled as indicated in Section 5.2 with a window of ±2 days 
relative to Visit 3 (Baseline Period), with the exception of the Safety Follow-Up Clinic Visit, 
which should be scheduled 14 days (±2 days) after the final dose of study medication, and the 
Safety Follow-Up Telephone Contact, which should be scheduled 30 days (-1/+3 days) after the 
final dose of study medication.
8.1
Baseline Period: Visit 1 (Day -7) to Visit 2 (Day -3 to Day -1)
At Visit 1 (Day -7), subjects who meet the selection criteria will begin a 7-day Baseline Period 
(Day -7 to Day -1). Visit 1 may occur over more than 1 day; however, all results of Visit 1 
assessments should be available before Visit 3. In the event that additional time is needed to 
access inpatient facilities to perform the video-EEG, a maximum of 7 days may be added to the 
period between Visit 1 and 2. During the Baseline Period, study visits are scheduled on Days -7,
-3, -2, and -1.
8.1.1
Baseline Period: Visit 1 (Day -7) 
At Visit 1, subjects will be evaluated for their suitability for enrollment. It is acceptable for this 
visit to be conducted on more than 1 day; however, all results of Visit 1 assessments should be 
available prior to randomization. Prior to the conduct of any study-related procedures, a 
complete explanation (both verbal and written) of the nature and purpose of the study will be 
given to the subject’s parent(s)/legal representative(s) by the investigator (or designee). The 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 44 of 144
parent(s)/legal representative(s) of the subject 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 pretreatment assessments (for further details of the assessments 
and the required procedures and methods, refer to Section 9, Section 10, and Section 11 of this 
protocol):
x Informed consent
x Demographics (date of birth [where permitted], age group category, age in months and years, 
race, ethnicity, and gender)
x Inclusion/exclusion criteria
x Medical history
x Seizure history/count
x Concomitant medications (including any current medication intake as well as any 
medications taken ≤30 days prior to Visit 1)
x Concomitant AEDs (including any current medication intake as well as any previous AED 
taken prior to Visit 1)
x VNS assessment (if applicable)
x Physical examination (complete)
x Vital signs (including BP and pulse rate, including orthostatic assessments where feasible 
according to investigator judgment)
x Body weight
x Height
x Head circumference
x Neurological examination (complete)
x 12-lead ECG (2 interpretable recordings [approximately 20 to 30 minutes apart] to be 
performed prior to any blood draws and vital signs assessment and, if possible, with the 
subject in a supine position for 5 minutes preceding the ECG recording)
x Blood sample for clinical chemistry/hematology
x Contact IXRS
x AE reporting
8.1.2
Baseline Period: Visit 2 (Day -3 to Day -1) 
From Visit 2 (Day -3 to Day -1) to Visit 3 (Day 1), an End-of-Baseline video-EEG (up to 72 
hours of continuous recording with every attempt to obtain at least 48 hours of interpretable 
recording) will be performed. The Day -3 assessments should be conducted prior to the start of 
video-EEG monitoring. The video-EEG will be conducted in an inpatient setting. Upon
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 45 of 144
completion of the End-of-Baseline video-EEG (Visits 2 and 3), the investigator will assess the 
electrographic seizure count and confirm the selection criteria have been met. If the subject 
meets all selection criteria, including the requisite number of seizures based on the End-of-
Baseline video-EEG data, the subject may be randomized at Visit 3. Assessment of the video-
EEG seizure count will also be performed locally by the investigator, subinvestigator, or 
qualified designated reader for the purpose of study analyses; however, completion of this review 
is not required prior to randomization.
During Visit 2, the following assessments will be performed:
x Inclusion/exclusion criteria (Day -3 only)
x Concomitant medications 
x Concomitant AEDs 
x VNS assessment (Day -3 only and only if applicable)
x Physical examination (brief) (Day -3 only)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment; Day -3 only)
x Body weight (Day -3 only)
x Neurological examination (brief) (Day -3 only)
x Video-EEG 
x Rescue medication assessment
x AE reporting 
x Review withdrawal criteria 
8.2
Titration Period: Visit 3 (Day 1) to Telephone Contact 3 (Day 20)
Beginning with Visit 3 at Day 1 and continuing up to Telephone Contact 3 at Day 20, telephone 
contacts and clinic visits will be conducted during the Titration Period.
Subjects will be randomized into a treatment arm and study medication will be dispensed. The 
subject will take the first dose of study medication in the clinic. The subject will be instructed to 
call the investigator if any intolerable and/or SAEs occur. If any change in the study medication 
is required, the subject should come in for a clinic visit as soon as possible.
During the Titration Period, visits are scheduled on Days 1, 9, and 17, and telephone contacts are 
scheduled on Days 5, 13, and 20.
8.2.1
Titration Period: Visit 3 (Day 1)
Randomization and initial dispensing of study medication will occur at Visit 3 and after the 
completion of the video-EEG and confirmation that the subject has met selection criteria.
During Visit 3, the following assessments will be performed:
x Inclusion/exclusion criteria
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 46 of 144
x Concomitant medications
x Concomitant AEDs
x 12-lead ECG will be at the discretion of the investigator. The ECG (2 interpretable 
recordings [approximately 20 to 30 minutes apart] to be performed, if possible, with the 
subject in a supine position for 5 minutes preceding ECG recording) 
x Video-EEG (End-of-Baseline video-EEG)
x Rescue medication assessment
x Contact IXRS
x Randomization
x Dispense study medication and administer first dose of study medication before the 
conclusion of visit
x AE reporting
x Review withdrawal criteria
x Healthcare resource use
x Investigators must make every attempt to administer the Bayley-III scales (for subjects who 
are <18 months of age who originate in English-speaking countries) 
x BRIEF-P score 
x PedsQL score 
x Achenbach CBCL (the CBCL/1½-5 will be completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 months of age at Visit 3)
8.2.2
Titration Period: Telephone Contact 1 (Day 5), Telephone Contact 2 
(Day 13), and Telephone Contact 3 (Day 20)
During the Titration Period telephone contacts (Telephone Contact 1, Telephone Contact 2, and 
Telephone Contact 3), the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x AE reporting
x Review withdrawal criteria
x Dosing instructions
At Telephone Contact 3, in addition to the procedures noted, the investigator or designee will 
confirm that the subject has tolerated study medication. After Day 20, the dose must remain 
stable.
8.2.3
Titration Period: Visit 4 (Day 9)
At Visit 4, the following assessments will be performed:
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 47 of 144
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
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x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Review withdrawal criteria
8.2.4
Titration Period: Visit 5 (Day 17)
During Visit 5, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Neurological examination (brief)
x 12-lead ECG (2 interpretable recordings [approximately 20 to 30 minutes apart] to be 
performed prior to any blood draws and vital signs assessment and, if possible, with the 
subject in a supine position for 5 minutes preceding ECG recording)
x Blood sample for clinical chemistry/hematology
x Blood sample for determination of LCM plasma concentration 
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Review withdrawal criteria
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 48 of 144
8.3
Maintenance Period: Visit 6/Early Termination (Day 24 to 
Day 27)
Subjects completing the Titration Period will enter the Maintenance Period and continue on the 
final dose of LCM achieved during the Titration Period. Dose reduction or escalation during the 
Maintenance Period is not permitted. Subjects who are withdrawn will enter the Taper Period 
(see Section 7.2.4). Subjects who complete the Maintenance Period may be eligible to participate 
in the open-label extension study (EP0034).
During the Maintenance Period, study visits are scheduled on Days 24 to 27. The subject should 
take concomitant AEDs and study medication at the usual time(s) on the morning of each clinic 
visit.
8.3.1
Maintenance Period: Visit 6/Early Termination (Day 24, Day 25, and 
Day 26)
The Day 24 assessments should be conducted prior to the start of the End-of Maintenance Period 
video-EEG monitoring (up to 72 hours of continuous recording with every attempt to obtain at 
least 48 hours of interpretable recording). Assessment of video-EEG seizure count will be 
performed locally by the investigator, subinvestigator, or qualified designated reader for the 
purpose of the study analyses. The following assessments will be performed on Day 24 for all 
subjects:
x Concomitant medications 
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Neurological examination (brief)
x Video-EEG 
x Rescue medication assessment
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Review withdrawal criteria
The following assessments will be performed on Day 25 and Day 26 during the video-EEG:
x Concomitant medications 
x Concomitant AEDs
x Rescue medication assessment
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 49 of 144
x AE reporting
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8.3.2
Maintenance Period: Visit 6/Early Termination (Day 27)
On the final day of the Maintenance Period, the following assessments will be performed after 
the completion of the End of Maintenance Period video-EEG:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (complete)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Height
x Head circumference
x Neurological examination (complete)
x 12-lead ECG (2 interpretable recordings [approximately 20 to 30 minutes apart] to be 
performed prior to any blood draws and vital signs assessment and, if possible, with the 
subject in a supine position for 5 minutes preceding ECG recording)
x Blood sample for clinical chemistry/hematology
x Blood sample for determination of LCM plasma concentration 
x Clinical Global Impression of Change
x Caregiver’s Global Impressions of Change
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Rescue medication assessment
x Review withdrawal criteria
x Healthcare resource use
x PedsQL (same version used at Visit 3)
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 50 of 144
8.4
Transition Period: Transition Visit 1 (Day 32) to Transition 
Visit 2 (Day 40)
Eligible subjects who choose to enter EP0034 will enter a 12-day Transition Period upon 
completion of the Maintenance Period.
During the Transition Period, subjects assigned to PBO will be transitioned in a double-blind 
manner from PBO to LCM 8mg/kg/day over a 12-day period according to the schedule shown in 
Table 7‒2. Subjects assigned to LCM 8mg/kg/day to 12mg/kg/day will remain at the dose 
achieved during the Maintenance Period. At the entry visit of EP0034, all subjects will transition 
to a dose of LCM 10mg/kg/day.
During the Transition Period, study visits will be scheduled on Days 32 and 40, and a telephone 
contact will be conducted on Day 36.
8.4.1
Transition Period: Transition Visit 1 (Day 32) 
During Transition Visit 1, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Neurological examination (brief)
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Review withdrawal criteria
8.4.2
Transition Period: Transition Telephone Contact 1 (Day 36)
During Transition Telephone Contact 1, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x AE reporting
x Review withdrawal criteria
x Dosing instructions
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 51 of 144
8.4.3
Transition Period: Transition Visit 2 (Day 40)
Transition Visit 2 will also serve as Visit 1 for EP0034.
During Transition Visit 2, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (complete)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Neurological examination (complete)
x 12-lead ECG (2 interpretable recordings [approximately 20 to 30 minutes apart] to be 
performed prior to any blood draws and vital signs assessment and, if possible, with the 
subject in a supine position for 5 minutes preceding ECG recording)
x Blood sample for clinical chemistry/hematology
x Contact IXRS
x Return study medication
x AE reporting
x Review withdrawal criteria
8.5
Taper Period: Telephone Contact 4 (Day 32) and Taper Visit 
(Day 36, Day 40, or Day 44)
A blinded Taper Period (8 to 16 days, depending on the dose level achieved) will be required for 
subjects who discontinue study medication prematurely and for subjects who complete the 
Maintenance Period but will not enroll in EP0034. Study medication will be tapered as described 
in Table 7-3.
During the Taper Period, a telephone contact will be conducted on Day 32 and a Taper Visit will
be scheduled at the end of the Taper Period, on Day 36, 40, or 44. Note that the study day 
numbers provided are for subjects who complete the Maintenance Period and enter the Taper 
Period; the study day numbers provided do not apply to subjects who enter the Taper Period at 
other times.
8.5.1
Taper Period: Telephone Contact 4 (Day 32)
During Telephone Contact 4, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x AE reporting
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 52 of 144
x Review withdrawal criteria
8.5.2
Taper Period: Taper Visit (Day 36, Day 40, or Day 44)
A Taper Visit will be scheduled at the end of the Taper Period (Day 36, 40, or 44), depending on 
dose level achieved.
During the Taper Visit, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Neurological examination (brief)
x 12-lead ECG will be required for subjects with a clinically significant abnormal reading at 
the previous clinic visit. For non-clinically significant abnormalities, repeat of this 
assessment is at the discretion of the investigator. The ECGs (2 interpretable recordings 
[approximately 20 to 30 minutes apart] is to be performed prior to any blood draws and vital 
signs assessment and, if possible, with the subject in a supine position for 5 minutes 
preceding ECG recording)
x Blood sample for clinical chemistry/hematology collection will be required for subjects with 
a clinically significant abnormal value at the previous clinic visit. For non-clinically 
significant abnormalities, repeat of these assessments are at the discretion of the investigator.
x Contact IXRS
x Dosing instructions
x Return study medication
x AE reporting
x Review withdrawal criteria
8.6
Safety Follow-Up Period
There will be a 30-day Safety Follow-Up Period for all subjects who will not be entering 
EP0034.
8.6.1
Safety Follow-Up Period: Safety Follow-Up Clinic Visit (Day 50, 
Day 54, or Day 58)
The Safety Follow-Up Clinic Visit will occur 14 days (±2 days) after the final dose of study 
medication and will include the following assessments:
x Concomitant medications
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 53 of 144
x Concomitant AEDs
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investigator judgment)
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assessment is at the discretion of the investigator.  
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a clinically significant abnormal value at the previous clinic visit. For non-clinically 
significant abnormalities, repeat of these assessments are at the discretion of the investigator.
x AE reporting
8.6.2
Safety Follow-Up Period: Safety Follow-Up Telephone Contact 
(Day 66, Day 70, Day 74, or Day 93)
The Safety Follow-Up Telephone Contact will occur 30 days (-1/+3 days) after the final dose of 
study medication and will include the following assessments:
x Concomitant medications
x Concomitant AEDs
x AE reporting
8.7
Unscheduled Visit
Unscheduled visits can be conducted at the discretion of the investigator (eg, due to an AE). 
During the Unscheduled Visit, the following assessments will be performed:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x AE reporting
x Review withdrawal criteria
In addition to the required assessments listed above, additional assessments may be performed at 
the investigator’s discretion.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 54 of 144
9
ASSESSMENT OF EFFICACY
9.1
Primary and secondary efficacy variables
The primary and secondary efficacy variables are based on the ADF of partial-onset seizures as 
measured on video-EEG (up to 72 hours of continuous recording with every attempt to obtain at 
least 48 hours of interpretable recording). 
Partial-onset seizure count will be based on electrographic seizures with or without clinical 
correlate depending upon age as specified below. 
Partial-onset seizure frequency for infants aged ≥1 month to ≤6 months will be based on 
electrographic seizures. Partial-onset seizure frequency for children aged >6 months to <4 years 
will be based on electrographic seizures with an accompanying clinical correlate.
Electrographic seizures are defined as recognizable ictal patterns on an EEG involving 
≥2 contiguous electrodes. The seizures are initiated as a unilateral or strongly asymmetric 
abnormal epileptiform discharge lasting a total of >10 seconds. 
The video-EEG recordings will be evaluated for seizure counts locally by the investigator, 
subinvestigator, or qualified designated reader. 
Calculation of the Baseline Period ADF of electrographic partial-onset seizures and the 
Maintenance Period ADF of electrographic partial-onset seizures will be based on results from a 
video-EEG during each period. Subjects are expected to have at least 48 hours of interpretable 
video-EEG during each period. For subjects who drop out during the End-of-Maintenance Period 
video-EEG, the number of hours from the start of the End-of-Maintenance Period video-EEG to 
the time of withdrawal (in hours) will be considered for analysis. Subjects who discontinue on or 
before Day 20 will not require a video-EEG.
9.2
Other efficacy assessments
9.2.1
Global Impression of Change
The Clinical and Caregiver’s Global Impression of Change will be administered according to the 
tabular schedules of study procedures (Section 5.2).
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the 
investigator assesses the subject’s change from Baseline in clinical status, including an 
evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional 
status.
The Caregiver’s Global Impression of Change is a 7-point categorical rating scale in which the 
caregiver(s) assesses the subject’s change from Baseline in clinical status, including an 
evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional 
status.
9.2.2
PedsQL
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 2001). 
The PedsQL will be administered only in countries where a translated version is available. The 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 55 of 144
version of the PedsQL used at Visit 3 (Baseline) should be maintained for the duration of the 
study in accordance with the tabular schedules of study procedures (Section 5.2).
The PedsQL Measurement Model consists of developmentally appropriate forms for pediatric 
subjects ≥1 month to ≤12 months, ≥13 months to <24 months, ≥2 years to ≤4 years, ≥5 years to 
≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 years of age. Parent proxy report of child 
health-related quality of life (HRQoL) is measured for pediatric subjects ≤4 years of age.
The multidimensional PedsQL generic core scales encompass the essential core domains for 
pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning. The PedsQL assessment is retrospective to the prior 
4 weeks, and individual items are scored using a 5-point Likert scale (never, almost never, 
sometimes, often, or almost always). A total health summary score ranging between 0 and 100 is 
calculated from the sum of the raw scores, with higher scores indicating higher HRQoL.
9.2.3
Healthcare resource use
For healthcare resource use, the following will be evaluated: concomitant medications and 
AEDs, medical procedures, and healthcare provider consultations including hospitalizations not 
foreseen by the protocol.
10
ASSESSMENT OF PHARMACOKINETIC AND 
PHARMACODYNAMIC VARIABLES
Blood samples for the determination of LCM plasma concentrations will be collected according 
to the tabular schedules of study procedures (see Section 5.2). In each case, the time the subject 
took the most recent dose of study medication and the time of blood sampling must be recorded. 
Actual sampling times will be recorded in the eCRF to the minute.
Details of plasma sample collection and processing, sample labeling, and shipment will be 
provided in the laboratory manual.
11
ASSESSMENT OF SAFETY
11.1
Adverse events
11.1.1
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 (ie, after 
the signing of the Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no investigational product 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 investigational product is being studied 
should be recorded as AEs only if their nature changes considerably or their frequency or 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 56 of 144
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 Period.
11.1.1.1
Signs and symptoms of depression
Subjects should be monitored for any changes in mood, ideas, or behavior for warning signs of 
depression. The investigator should be aware of common warning signs that might be a signal for 
risk of depression. For common signs and symptoms of depression in children, reference should 
be made to the current version of the Diagnostic and Statistical Manual of Mental Disorders. 
Each subject’s parent(s)/legal representative(s)/caregiver(s) (in accordance with local regulation) 
should also be advised accordingly and effort should be made at clinic visits to specifically 
assess potential depression.
11.1.2
Procedures for reporting and recording adverse events
The subject’s parent(s) and/or legal representative(s)/caregiver(s) 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 the subject’s health (since your last visit)?”
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study.
11.1.3
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 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 
medication) are described in the eCRF Completion Guidelines.
11.1.4
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 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 
after the subject has discontinued his/her IMP.
11.1.5
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:
x 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”
x 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
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 57 of 144
11.1.6
Suspected transmission of an infectious agent via a medicinal 
product
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
11.1.7
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are 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).
11.1.8
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 Patient 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.
11.2
Serious adverse events
11.2.1
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:
x Death
x Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)
x Significant or persistent disability/incapacity
x Congenital anomaly/birth defect (including that occurring in a fetus)
x 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
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 58 of 144
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 11.3], 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.)
x 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 
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. 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.)
11.2.2
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. The Investigator SAE 
Report form must be completed in English. 
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 
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05 Apr 2018
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Page 59 of 144
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.
11.2.3
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. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events are provided in Section 11.6.1.4.
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety database without limitation of time.
11.3
Adverse events of special interest
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound.
The following are LCM’s AEs of special interest:
x The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (second-degree Type I and II and third-degree), and marked bradycardia (<45bpm)
x Syncope or loss of consciousness (other than seizure related)
x 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 FDA
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
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 60 of 144
x Potential Hy's Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin 
in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without 
waiting for any additional etiologic investigations to have been concluded). Follow-up
information should then be reported if an alternative etiology is identified during 
investigation and monitoring of the subject.
11.4
Immediate reporting of adverse events
The following AEs must be reported immediately:
x SAE: AE that the investigator classifies as serious by the above definitions regardless of 
causality
x Suspected transmission of an infectious agent via a medicinal product
x AE of special interest (see Section 11.3)
11.5
Anticipated serious adverse events
The following list of Anticipated SAEs (Table 11‒1) is anticipated to occur in the population 
studied in this protocol at some frequency that is independent of drug exposure. 
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 11.2.2.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 61 of 144
Table 11‒1: Anticipated SAEs for the pediatric epilepsy 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
Convulsiona 
Incontinence 
Status epilepticus 
Psychiatric disorders
Psychotic behaviour 
Abnormal behaviour 
Anxiety 
Sleep disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; 
SOC=system organ class 
a Convulsion if consistent with the seizure type known for the subject.
11.6
Laboratory measurements
Blood specimens for routine assay of hematology and clinical chemistry testing will be collected 
according to the tabular schedule of study procedures (Section 5.2). A central laboratory will 
perform the routine analysis of blood specimens. The procedures for handling and shipping these 
specimens will be provided to the sites. In exceptional circumstances, local laboratory analysis 
may be performed. The medical monitor should be contacted beforehand to discuss these 
circumstances.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 62 of 144
The laboratory tests to be performed are presented in Table 11‒2 as follows:
Table 11‒2: Laboratory measurements
Hematology
Clinical chemistry
Hematocrit
Hemoglobin
Platelet count
RBC count
WBC count
Differential count
Calcium
Phosphorus
Serum electrolytes (sodium, potassium, chloride, 
bicarbonate)
Creatinine
BUN
AST
ALT
Total bilirubin
ALP
GGT
Glucose
Albumin
Total serum protein
Uric acid
Total cholesterol
Triglycerides
ALP= alkaline phosphatase;  ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma glutamyltransferase; RBC=red blood cell; WBC=white blood cell
Creatinine clearance will be estimated using the updated Schwartz bedside formula (Schwartz 
and Work, 2009).
11.6.1
Liver function tests and evaluation of PDILI
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1 with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 11.3), and, if applicable, also reported as an 
SAE (see Section 11.2).
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.6.1.4).
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05 Apr 2018
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Lacosamide
SP0967
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Page 63 of 144
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor.
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result.
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 2 
laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages.
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative.
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings.
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur.
The table below summarizes the approach to investigate PDILI. 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 64 of 144
Table 11‒3: Required investigations and follow up of PDILI 
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptoms
a of 
hepatitis or 
hypersensitivity
Consultation 
requirements
Actions
Testing
Evaluation
≥3xULN
≥2xULN
b
NA
Hepatology consult.
c
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP.
Immediate, 
permanent IMP 
discontinuation.
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.6.1.3);
recommended to 
occur at the site 
with HCP.
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
values.
d
≥5xULN
NA
NA
≥3xULN
NA
Yes
Immediate, 
temporary or 
permanent, IMP 
discontinuation.
≥3xULN 
(and ≥2x 
Baseline) 
and
<5xULN
<2xULN
No
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met.
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 11.6.1.2).
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 65 of 144
Table 11‒3: Required investigations and follow up of PDILI 
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptoms
a of 
hepatitis or 
hypersensitivity
Consultation 
requirements
Actions
Testing
Evaluation
≥5xULN 
(and ≥2x 
Baseline) 
<2xULN
No
Discussion with
Medical Monitor 
required.
Immediate, 
permanent IMP 
discontinuation.
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
Section 11.6.1.3)
Monitoring of liver chemistry 
values at least twice per week 
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or return to within Baseline 
values.d
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal 
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause).
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor.
.c Details provided in Section 11.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist.
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 66 of 144
11.6.1.1
Consultation with Medical Monitor and local hepatologist
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 11.6.1.3) and SAE report (if applicable).
11.6.1.2
Immediate action: determination of IMP discontinuation
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒3 for details).
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative.
11.6.1.3
Testing: identification/exclusion of alternative etiology
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒4 (laboratory measurements) and Table 11‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable.
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
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Page 67 of 144
The following measurements are to be assessed:
Table 11‒4: PDILI laboratory measurements
Virology-
related
Hepatitis A IgM antibody
HBsAg
Hepatitis E IgM antibody
HBcAb-IgM
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing)
Immunology
Anti-nuclear antibody (qualitative and quantitative)
Anti-smooth muscle antibody (qualitative and quantitative)
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative)
Hematology
Hematocrit
Hemoglobin
Platelet count
RBC count
WBC count
Differential count
Urinalysis
Toxicology screen
Chemistry
Amylase
Bilirubin (If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % 
direct bilirubin)
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation
AST
ALT
ALP
GGT
Albumin
Additional
Prothrombin time/INR
a
PK sample
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 68 of 144
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma-glutamyl transferase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RBC=red blood cell; 
RNA=ribonucleic acid; ULN=upper limit of normal; WBC=white blood cell
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause).
The following additional information is to be collected:
Table 11‒5: PDILI information to be collected
New or updated information
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included.
Pertinent medical history, including the following:
x 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)
x 
Adverse reactions to drugs
x 
Allergies
x 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
x 
Recent travel 
x 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.)
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash)
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function
Results of liver imaging or liver biopsy, if done
Results of any specialist or hepatology consult, if done
Any postmortem/pathology reports
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury
11.6.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 11‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to Baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 69 of 144
11.7
Other safety measurements
11.7.1
Physical examination
Physical examinations will be performed according to the tabular schedule of study procedures 
(Section 5.2) by a medically qualified clinician licensed to perform the examination. Subsequent 
to Visit 1, clinically significant physical examination findings should be reported as AEs.
11.7.1.1
Complete physical examination
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems.
11.7.1.2
Brief physical examination
The brief physical examination will include review of the following body systems: 
x Cardiovascular
x Pulmonary
x Abdominal (hepato-gastrointestinal)
x Dermatologic
11.7.2
Neurological examination
Neurological examinations will be performed according to the tabular schedule of study 
procedures (Section 5.2) by a medically qualified clinician with documented training in the 
conduct of neurological examinations. If possible, the same clinician should conduct all 
neurological examinations for the same subject during the study. The investigator or 
subinvestigator is responsible for confirming the diagnosis of partial-onset seizures. Subsequent 
to Visit 1, clinically significant neurological examination findings should be reported as AEs.
11.7.2.1
Complete neurological examination
The complete neurological examination will include selected assessment of general neurological 
status (level of consciousness, mental status, speech), cranial nerves, reflexes, motor system 
(general motor status, muscle strength, muscle tone), coordination/cerebellar function, and 
sensation.
11.7.2.2
Brief neurological examination
The brief neurological examination will include selected assessment of general neurological 
status, reflexes, muscle strength, and coordination/cerebellar function.
11.7.3
Vital signs, body weight, and height
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits after at 
least 3 minutes at rest in a supine position, according to the tabular schedule of study procedures 
(Section 5.2). Assessment of orthostatic changes will be as follows: after the 3 minute 
measurement in a supine position, the subject is asked to stand up, and BP and pulse rate are 
taken 1 minute and 3 minutes after standing up, as feasible.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 70 of 144
Body weight will be determined without shoes and wearing light clothing, and height will be 
measured without shoes. Body weight and height will be assessed according to the tabular 
schedule of study procedures (Section 5.2).
11.7.4
12-lead ECG
Standard 12-lead ECGs will be performed according to the tabular schedule of study assessments 
(Section 5.2). Care should be taken to assure proper lead placement and quality ECG recordings. 
Two interpretable recordings will be performed prior to any blood draws and vital signs 
assessment and, if possible, with the subject in a supine position for 5 minutes preceding the 
ECG recording and the subject should be motionless during the recording. The second recording 
will be conducted approximately 20 to 30 minutes after the first recording. 
11.7.5
Overall ECG interpretation
Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified 
designated reader and at a central ECG laboratory. If the reading identifies second or third degree 
AV block, a QTc ≥500ms, or another abnormal ECG finding that is assessed by the investigator 
to be clinically significant, then the ECG should be repeated on the same day. If the clinically 
significant abnormality is confirmed by the repeat ECG, then the subject must be withdrawn 
from the study (see Section 6.3). The investigator may consult with the cardiologist at the central 
ECG laboratory 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.
11.7.6
Achenbach CBCL
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. Behavioral problems will be scored by the 
parent(s)/legal representative(s)/caregiver(s). The CBCL/1½-5 checklist for children 18 months 
to 5 years and 11 months of age will be used in this study. The Achenbach CBCL/1½-5 will be 
completed by the parent(s)/legal representative(s)/caregiver(s) of subjects ≥18 months of age at 
Visit 3. The Achenbach CBCL will be administered only in countries where a translated version 
is available.
The scale will be completed in accordance with the tabular schedules of study procedures 
(Section 5.2) and should be completed by the same parent(s)/legal representative(s)/caregiver(s). 
The completion of the Achenbach CBCL will require approximately 45 minutes.
In the CBCL/1½-5 checklist, the occurrence of certain problems and behaviors at the time of 
administering the questionnaire or within the past 2 months will be scored on the following 
scale:
x 0=not true (as far as known)
x 1=somewhat or sometimes true
x 2=very true or often true
Eight syndrome scores will be calculated from these questions, which will in turn be summarized 
by 2 composite scores. Additionally, for each score on the question, syndrome, and total level, 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 71 of 144
categorizations based on a normative sample will be used to evaluate normal, borderline, or 
clinically relevant behavior.
Baseline assessment of the Achenbach CBCL will be performed at Visit 3; however, due to the 
short study duration of SP0967, the next assessment will be collected in subjects entering into the 
EP0034 study. Thus, the analysis of these data will be conducted in EP0034.
11.7.7
BRIEF-P
The BRIEF-P is a validated tool that will be used for the evaluation of subjects ≥2 years of age 
and will be administered according to the tabular schedules of study procedures (Section 5.2).
The BRIEF-P will be administered only in countries where a translated version is available.
The BRIEF-P includes rating forms used by parents to assess subjects’ executive functioning 
within the context of the subject’s everyday environment. It requires that the parent must have 
had recent and extensive contact with the child over the past 6 months. Executive functions 
broadly encompass a set of cognitive skills that are responsible for the planning, initiation, 
sequencing, and monitoring of complex goal directed behavior. 
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. The 
clinical scales form 3 broad overlapping indexes: Inhibitory Self-Control (Inhibit and Emotional 
Control), Flexibility (Shift and Emotional Control), and Emergent Metacognition (Working 
Memory and Plan/Organize) and 1 composite score (Global Executive Composite).
The BRIEF-P includes validity scales to measure negativity and inconsistency of responses.
Baseline assessment of the BRIEF-P will be performed at Visit 3; however, due to the short 
study duration of SP0967, the next assessment will be collected in subjects entering into the 
EP0034 study. Thus, the analysis of these data will be conducted in EP0034.
11.7.8
Bayley Scales of Infant and Toddler Development, Third Edition
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the major 
facets of a young child’s development (Bayley, 2006). The Bayley-III scales are a standardized, 
individually administered, adaptive assessment that measures the developmental functioning of 
infants and young pediatric subjects from 1 month to 42 months of age (Bayley, 2006). The 
Bayley-III scales measure cognitive, language, motor, social-emotional, and adaptive 
development and are a revision of the predecessor, the Bayley Scales of Infant Development, 
Second Edition (Bayley, 1993). The Bayley-III scales are a technically sound instrument, with 
strong internal consistency, as well as test-retest stability. The Bayley-III scales are validated 
only in English. 
The scales are validated as a tool for assessment of neurological development in young pediatric 
subjects and are therefore considered appropriate for SP0967.
The Bayley-III scales are an individually administered, adaptive assessment that presents 
pediatric subjects with situations and tasks designed to produce an observable set of behavioral 
responses. They consist of a cognitive scale, a language composite scale with receptive and 
expressive language subscales, and a motor composite scale with fine and gross motor subscales 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 72 of 144
to be completed by the investigator or designee. It also has a social emotional scale, comprising 
social-emotional competence, and sensory processing, and an adaptive behavior scale, which 
assesses the attainment of skills necessary for the development of independence, to be completed 
by the child’s parent(s)/legal representative(s)/caregiver(s). 
The completion of the Bayley-III scales will require approximately 50 minutes for pediatric 
subjects who are 12 months old or younger and 90 minutes for pediatric subjects aged 12 months 
to 18 months. 
Investigators must make every attempt to administer the scale according to the tabular schedules 
of study procedures (Section 5.2). If needed, the investigators may utilize trained pediatric 
psychologists or other appropriately skilled individuals to administer the scale. 
Due to the short study duration of SP0967, the next assessment will be collected in subjects 
entering into the EP0034 study. Thus, the analysis of these data will be conducted in EP0034.
12
STUDY MANAGEMENT AND ADMINISTRATION
12.1
Adherence to protocol
The investigator should not deviate from the protocol. However, the investigator should take any
measure necessary in deviation from or not defined by the protocol in order to protect clinical
study subjects from any immediate hazard to their health and safety. In this case, this action
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or
sponsor. After implementation of such measure, the investigator must notify the Clinical Project 
Manager (CPM) of the sponsor within 24 hours and follow any local regulatory requirements.
12.2
Monitoring
UCB (or designee) will monitor the study to meet the sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, 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 authority(ies) regulations, and investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records.
12.2.1
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 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 73 of 144
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, 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 Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee).
12.2.2
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 12.2.1.
12.3
Data handling
12.3.1
Case Report form completion
This study is performed using remote data capture (RDC). 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 electronic 
eCRF.
Detailed instructions will be provided in the eCRF Completion Guidelines.
12.3.2
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. Case Report form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person.
In the event that the study is performed using RDC, the data are entered into the eCRFs once and 
are subsequently verified.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 74 of 144
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.
12.3.3
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.
12.4
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.
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 medication and other material in accordance with UCB procedures for the study.
12.5
Archiving and data retention
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with UCB (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95, 2002 [Section 4.9.5]). The investigator will contact UCB for authorization 
prior to the destruction of any study records or in the event of accidental loss or destruction of 
any study records. The investigator will also notify UCB should he/she relocate or move the 
study-related files to a location other than that specified in the sponsor’s trial master file.
12.6
Audit and inspection
The investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 75 of 144
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 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).
12.7
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.
13
STATISTICS
A description of statistical methods is presented below and will be described in more detail in the 
Statistical Analysis Plan (SAP).
13.1
Definition of analysis sets
The Safety Set (SS) will include all randomized subjects who took at least 1 dose of study 
medication. This is the primary analysis set for the safety variables.
The primary analysis set for the efficacy data will be the Full Analysis Set (FAS), which will 
include all subjects in the SS.
The secondary analysis set for the efficacy data will be the Per-Protocol Set (PPS), which 
includes all subjects in the FAS who did not have important protocol deviations related to 
efficacy.
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects having provided at 
least 1 measurable postdose plasma sample (with recorded sampling time) on at least 1 visit with 
documented study medication intake times.
13.1.1
Analysis of the primary efficacy variable
Analyses of the primary efficacy variables are based on the ADF of electrographic partial-onset 
seizures. 
Partial-onset seizure count will be based on electrographic seizures. Electrographic seizures are 
defined as recognizable ictal patterns on an EEG involving ≥2 contiguous electrodes. The 
seizures are initiated as a unilateral or strongly asymmetric abnormal epileptiform discharge 
lasting a total of >10 seconds. The video-EEG recordings will be evaluated for seizure counts 
locally by the investigator, subinvestigator, or qualified designated reader. Subjects who
discontinue on or before Day 20 will not require a video-EEG.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 76 of 144
Partial-onset seizure frequency for infants aged ≥1 month to ≤6 months will be based on 
electrographic seizures. Partial-onset seizure frequency for children aged >6 months to <4 years 
will be based on electrographic seizures with an accompanying clinical correlate.
Calculation of the Baseline Period ADF of electrographic partial-onset seizures and the 
Maintenance Period ADF of electrographic partial-onset seizures will be based on results from a
video-EEG (up to 72 hours of continuous recording with every attempt to obtain at least 48 hours 
of interpretable recording) during each period. Subjects are expected to have at least 48 hours of 
interpretable video-EEG during each period. For subjects who drop out during the 
End-of-Maintenance Period video-EEG, the number of hours from the start of the 
End-of-Maintenance Period video-EEG to the time of withdrawal (in hours) will be considered 
for analysis. 
The ADF of electrographic partial-onset seizures will be calculated as (number of partial-onset 
seizures recorded on the video-EEG divided by the number of interpretable hours recorded) 
multiplied by 24.
13.1.1.1
Analysis of the primary efficacy variable for the US
Contingent upon ≤10% of subjects discontinuing early from the study, the primary efficacy 
parameter for the US is the change in ADF of electrographic partial-onset seizures during the 
Maintenance Period compared to the end of the Baseline Period. Seizure ADF will be analyzed 
using analysis of covariance with terms for treatment, age category (4 age stratification 
categories, pooled as appropriate), and center (properly pooled), on log-transformed seizure ADF 
using the transformation of ln (X+1), where X is the seizure ADF. Log-transformed Baseline 
seizure ADF will be used as a covariate. The seizure ADF between LCM and PBO will be 
compared using least squares means (LSMs). The percent reduction over PBO will be estimated 
as 100 x (1 – exp [LSM Treatment {TRT} - LSMPBO]). The analysis of this efficacy variable 
will consist of all subjects in the FAS who have at least 48 hours of interpretable recordings 
during both the End-of-Baseline Period video-EEG and the End-of-Maintenance Period video-
EEG.
The following additional sensitivity analyses on this primary efficacy variable will be conducted 
in order to assess the effect of early discontinuations, protocol deviations, and operational bias on 
this primary endpoint:
x Repeat the primary analysis using the PPS.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using the Baseline 
observation-carried-forward approach. This will be applied for all subjects who discontinued 
early from the study.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced by the overall mean ADF 
of partial-onset seizures from the End-of-Maintenance Period video-EEG from the subject’s 
respective treatment arm. This will be applied for all subjects who discontinued early from 
the study.
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Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 77 of 144
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using multiple imputation 
by treatment arm and age group (≥1 month to <6 months of age, ≥6 months to <1 year of age, 
≥1 year to <2 years of age, and ≥2 years to <4 years of age) using monotone regression. This 
will be applied for all subjects who discontinued early from the study.
x Repeat the primary analysis using the FAS for all subjects who have at least 24 hours of 
interpretable recordings during both the End-of-Baseline Period video-EEG and the 
End-of-Maintenance Period video-EEG.
Contingent upon >10% of subjects discontinuing early from the study, the primary efficacy 
parameter for the US is identical to the primary efficacy parameter for the EU, described below. 
The endpoint not designated as primary will still be summarized as a secondary efficacy 
parameter.
13.1.1.2
Analysis of the primary efficacy variable for the EU
The primary efficacy parameter for the EU is the proportion of responders during the 
Maintenance Period. Subjects with a 50% or more reduction in seizure ADF will be categorized 
as responders; this classification requires at least 48 hours of interpretable recordings during both 
the End-of-Baseline Period video-EEG and the End-of-Maintenance Period video-EEG. The 
proportion of responders between LCM and PBO will be analyzed using logistic regression with 
age category (4 age stratification categories, pooled as appropriate) and center (properly pooled) 
as factors. Subjects who withdraw or drop out before the first 48 hours of the End-of-
Maintenance Period video-EEG with reasons related to lack of efficacy will be considered non 
responders; all other subjects will be missing for this analysis. The number and percentage of 
subjects with a 50% or more reduction in seizure ADF will be presented by treatment group. 
The following additional sensitivity analyses on this primary efficacy variable will be conducted 
in order to assess the effect of early discontinuations, protocol deviations, and operational bias on 
this primary endpoint:
x Repeat the primary analysis using the PPS.
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prior to performance of the End-of-Maintenance Period video-EEG with reasons related to 
lack of efficacy will be considered non responders, and subjects who discontinued from the 
study early for any other reason will be considered responders.
x Repeat the primary analysis using the FAS, except all subjects who discontinued from the 
study early will be considered non responders.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using multiple imputation 
by treatment arm and age group (≥1 month to <6 months of age, ≥6 months to <1 year of age, 
≥1 year to <2 years of age, and ≥2 years to <4 years of age) using monotone regression. This 
will be applied for all subjects who discontinued from the study early, and the imputed End-
of-Maintenance Period ADF of partial-onset seizures will be used to determine whether a 
subject is a responder.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 78 of 144
x Repeat the primary analysis using the FAS for all subjects who have at least 24 hours of 
interpretable recordings during both the end of Baseline Period video-EEG and the end of 
Maintenance Period video-EEG.
13.1.2
Analysis of secondary efficacy variables
The percent change in ADF of electrographic partial-onset seizures is calculated as the seizure 
ADF during the End-of-Maintenance Period video-EEG minus the seizure ADF during the 
End-of-Baseline Period video-EEG divided by the seizure ADF at Baseline and then multiplied 
by 100. Descriptive statistics for ADF of electrographic partial-onset seizures and its absolute 
and percentage change from Baseline will be summarized by treatment group.
For subjects who complete the Maintenance Period, the number and percentage of subjects who 
achieved “seizure-free” status from all seizure types, and from partial-onset seizure types only 
during the Maintenance Period will be tabulated and presented by treatment group.
The number and percentage of subjects experiencing a ≥25% to <50%, 50 to 75%, or >75% 
reduction in ADF of partial-onset seizures will also be presented by treatment group, as will the 
number and percentage experiencing no change, and the number and percentage experiencing an 
increase ≥25%.
13.1.3
Other efficacy analyses
The number and percentage of subjects with each Clinical Global Impression of Change, 
Caregiver’s Global Impression of Change, and the PedsQL health summary score will be 
summarized by treatment group.
Descriptive statistics will be presented by treatment group for the number of medical resources 
used during the study, healthcare provider consultations not related to study, procedures, hospital 
stays, and length of hospital stays.
13.2
Planned safety and other analyses
Descriptive statistics will be used to provide an overview of the safety and PK results.
13.2.1
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) and tabulated by system organ class (SOC) and preferred term (PT). 
Treatment-emergent AEs will be defined as those events that start on or after the date of first 
study medication administration and within 30 days following the date of final study medication 
administration, or whose severity worsens within this time frame. The incidence of TEAEs will 
be presented by SOC and PT. Serious AEs and TEAEs leading to withdrawal will also be 
tabulated and listed.
Other variables assessing safety are ECG, measurements of laboratory parameters (hematology 
and clinical chemistry) and vital signs (body weight, height and BMI), and physical and 
neurological examination findings.
Measurement and change from Baseline in vital signs (BP and pulse rate), body weight, 
laboratory parameters (hematology and clinical chemistry), and 12-lead ECG measurements will 
be summarized using descriptive statistics. When analyzing categorical data, the number and 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 79 of 144
percentage of subjects in each category will be presented by treatment group. In addition, shift 
tables may be used to evaluate the number and percentage of subjects having a different 
postbaseline status when compared to their baseline status.
Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted.
Baseline assessment of the Bayley-III scales, Achenbach CBCL, and BRIEF-P will be 
performed; however, due to the short study duration of SP0967, the next assessment will be 
collected in subjects entering into the EP0034 study and analysis of these data will be conducted 
in EP0034.
13.2.2
Pharmacokinetics and pharmacodynamics
13.2.2.1
Descriptive statistics of LCM and AED plasma concentrations
The results of LCM plasma concentrations will be summarized using descriptive statistics: 
arithmetic mean, standard deviation, median, range, geometric mean, and geometric coefficient 
of variation.
13.2.2.2
Population pharmacokinetics
A population exposure-response model (PK/pharmacodynamics) between LCM plasma 
concentration and seizure counts will be developed using NONMEM. The methods will be 
described in the DAP (Data Analysis Plan) and the results will be reported in a modeling report. 
13.3
Handling of protocol deviations
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on either primary efficacy outcome or key safety outcomes for an individual 
subject. The criteria for identifying important protocol deviations and the classification of 
important protocol deviations will be defined within the project Data Cleaning Plan. To the 
extent feasible the rules for identifying protocol deviations will be defined without review of the 
data and without consideration of the frequency of occurrence of such deviations. Whenever 
possible, criteria for identifying important protocol deviations will be implemented 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all subjects.
Important protocol deviations will be reviewed as part of the blinded data cleaning meetings 
prior to database lock to confirm exclusion from analysis sets.
13.4
Handling of dropouts or missing data
Subjects who prematurely discontinue the study will be evaluated based on the data collected at 
each visit attended.
As described in Section 13.1.1, subjects are expected to have at least 48 hours of interpretable 
video-EEG during each period. For subjects who drop out during the End-of-Maintenance Period 
video-EEG, the number of hours from the start of the End-of-Maintenance Period video-EEG to 
the time of withdrawal (in hours) will be considered for analysis. Subjects who discontinue prior 
to the End-of-Maintenance Period video-EEG will not be included in the analyses (ie, data will 
not be carried forward from the End-of-Baseline Period video-EEG).
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 80 of 144
The impact of missing data on the assessment of primary efficacy will be evaluated with 
sensitivity analyses with further details to be included in the SAP. 
No imputation of missing values associated with an individual date or visit is planned for the 
primary safety analysis, with the exception of partial date information for AEs and concomitant 
medications in order to determine whether they are treatment emergent. 
13.5
Planned interim analysis and data monitoring
No formal interim analysis for determination of efficacy is planned for this study. To ensure 
subject safety, interim reviews of safety data will be performed using an Independent Data 
Monitoring Committee (IDMC). Serious adverse events and other significant events are 
monitored and will be triaged by the Medical Monitor and UCB Patient Safety in real time. After 
this triage, events will be passed on to the IDMC as appropriate. In addition, 3 interim reviews of 
safety data by the IDMC are planned when 25%, 50%, and 75% of subjects have been 
randomized and at study completion. The objective, procedures, and timing of IDMC safety 
assessments to evaluate risk and benefit for subjects in SP0967 will be described in an IDMC 
Charter.
A blinded sample size re-estimation will be performed when 50% of subjects have been 
randomized, completed the study, and have data available for analysis to check the validity of 
these assumptions using interim data from the study. The sample size re-estimation with equal 
allocation in each arm will be performed using the related residual variance combined with
Guenther adjustment (Friede and Kieser, 2011). An assessment of the observed dropout rate will 
also be made as part of this analysis, and the potential dropout rate of 14% used for calculation 
of the initial sample size (see Section 13.6) will be modified based on the observed rate. 
Additionally, an assessment of the observed difference of End-of-Baseline Period video-EEG 
interpretation rate will be made; the anticipated rate of 5% will be modified based on the 
observed rate (see Section 13.6).
The final sample size will be modified according to the sample size re-estimate and also the 
anticipated dropout rate and anticipated rate of difference of interpretation of the End-of-
Baseline Period video-EEG; however, an upper bound will be applied to reach a maximum 
sample size based on practical and logistical considerations. The initial sample size re-estimate 
using Guenther adjustment will not be adjusted above 109 subjects per treatment arm, the 
original estimated overall study drop-out rate will not be adjusted above 24%, and the difference 
of End-of-Baseline Period video-EEG interpretation rate will not be adjusted above 10%.
13.6
Determination of sample size
Assuming an effect size of 0.402, in which the effect size was calculated using a PBO-subtracted 
difference of -0.249 and a common standard deviation of 0.62 on the log-transformed data, the 
difference of -0.249 on the log-transformed data is equivalent to approximately 22% reduction 
over PBO after exponentiation. With this effect size, power of 80%, and a 2-sided test at the 
5% level of significance, a sample of 99 subjects in each treatment arm will be needed.
Assuming a responder rate of 20% and 40% for the PBO and LCM groups, respectively, a 
2-sided continuity corrected Chi-square test at a significance level of 5% will provide 
approximately 83% power with 99 subjects in the PBO group and 99 subjects in the LCM group.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 81 of 144
Subjects are randomized into the study based on the initial interpretation of the video-EEG to 
meet study entry requirements. However, the subsequent detailed assessment of seizure types 
and counts needed for the efficacy analyses could lead to a discrepancy in seizure counts (ie, a 
subject initially thought to be eligible is later found to have fewer than the required number of 
partial-onset seizures during the End-of-Baseline Period video-EEG). To account for an 
anticipated difference of interpretation of the End-of-Baseline Period video-EEG of 5% as well 
as the potential subject dropout rate of approximately 14%, the planned number of subjects to 
enroll is 122 subjects per treatment arm.
A blinded sample size re-estimation will be performed when 50% of subjects have been 
randomized, completed the study, and have data available for analysis to check the validity of 
these assumptions as described in Section 13.5.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Informed consent
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’s legal representative(s) in both oral and written form 
by the investigator (or designee). Subject’s legal representative(s) will have the opportunity to 
discuss the study and its alternatives with the investigator.
Prior to participation in the study, the Informed Consent form should be signed and personally 
dated by the subject’s legal representative(s), and by the person who conducted the informed 
consent discussion (investigator or designee). The subject’s legal representative(s) must receive a 
copy of the signed and dated Informed Consent form. As part of the consent process, each 
subject’s legal representative(s) must consent to direct access to the subject’s 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.
All studies conducted at centers in the US must include the use of a Health Insurance Portability 
and Accountability Act Authorization form.
The subject’s legal representative(s) may withdraw his/her consent to participate in the study at 
any time. A subject is considered as enrolled in the study when his/her legal representative(s) 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 written consent from 
his/her legal representative(s) in order to participate in the study.
14.2
Subject identification cards
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative(s) 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 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 82 of 144
contact information. The investigator will instruct the subject’s parent(s)/legal 
representative(s)/caregiver(s) to keep the card with him/her at all times.
14.3
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 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.
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.
14.4
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.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 83 of 144
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).
14.5
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.
15
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable.
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 84 of 144
16
REFERENCES
Aicardi J. Syndromic classification in the management of childhood epilepsy. J Child Neurol. 
1994;9(Suppl 2):14-18.
Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as 
add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, 
placebo-controlled study: Gabapentin Pediatric Study Group. Epilepsia. 1999;40:1147-54.
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006.
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993.
Bourgeois BF, Goodkin HP. Efficacy of antiepileptic drugs in adults vs children: does one size 
fit all? Neurology. 2012;79;1420-1.
CHMP/EWP/566/98 Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders (EMA) Rev 2, 20 Jan 2010.
Clinical Global Impression of Change, the Caregiver Global Impression of Change, quality of 
life assessments (Pediatric Quality of Life Inventory [PedsQL™]).
http://www.pedsql.org/PedsQL-CostStructure.pdf and http://plaza.umin.ac.jp/qol-research/. 
Accessed on 10 July 2014. 
Cognitive function assessments (Behavior Rating Inventory of Executive Function®
[BRIEF®]/BRIEF® Preschool Version [BRIEF® P].
http://www4.parinc.com/ Products/PermsLicensing.aspx?id=6 and 
http://www4.parinc.com/products/PermsLicensing.aspx?id=8. Accessed 10 July 2014. 
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.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 1999;Feb:9-11.
Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A placebo-controlled 
trial of lamotrigine add-on therapy for partial seizures in children: Lamictal Pediatric Partial 
Seizure Study Group. Neurology. 1999;53:1724-31.
Elterman RD, Glauser TA, Wylie E, Reife R, Wu SC, Pledger G. A double-blind, randomized 
trial of topiramate as adjunctive therapy for partial-onset seizures in children: Topiramate YP 
Study Group. Neurology. 1999;52:1338-44.
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009. 
Friede T, Kieser M. Blinded sample size recalculation for clinical trials with normal data and 
baseline adjusted analysis. Pharm Stat. 2011;10:8-13.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 85 of 144
Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. on behalf of 
the N159b Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam in 
pediatric partial seizures. Neurology. 2006;66:1654-60.
Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. Adjunctive 
therapy with oxcarbazepine in children with partial seizures: the Oxcarbazepine Pediatric Study 
Group. Neurology. 2000;54:2237-44.
Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in children. Expert Rev Neurother. 
2007;7:179-193.
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4.
Institute of Medicine. Epilepsy across the spectrum: promoting health and understanding. 
Washington, DC: The National Academies Press; 2012.
Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of 
antiepileptic drugs in adults predicts efficacy in children: A systematic review. Neurology. 
2012;79;1482-9.
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5:693-722.
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset 
seizures. Neuropsychiatr Dis Treat. 2013;9:629-37.
Sander JW. New drugs for epilepsy. Curr Opin Neurol. 1998;11:141-8.
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 5th 
ed. La Mesa: Jerome M Sattler; 2006.
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009;4:1832-43.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
version 4.0 generic core scales in healthy and patient populations. Med Care. 2001; 39:800-12
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 86 of 144
17
APPENDICES
17.1
AMENDMENT 1
Rationale for the amendment
The primary purposes of this amendment are to implement the contingent primary efficacy 
variable for the US, include sensitivity analyses for the primary endpoint, to clarify the 
enrollment of subjects <2 years of age, and to provide additional detail regarding the sample size 
re-estimation at the request of FDA.
Modifications and changes 
Global changes
The following changes were made throughout the protocol:
x Contact details for the Clinical Project Manager have been updated
x The Sponsor Declaration has been updated for electronic signature
x The language of the percentage of subjects <2years of age to be included in the study has 
been clarified 
x The contingent primary efficacy variable for the US has been defined
x The anticipated SAE table has been updated to include a footnote for convulsion
x Text for adherence to the protocol has been updated
x Text for healthcare resource use has been updated
x Rescue medication assessment has been added
x Analysis of the primary efficacy variable for the US and EU has been updated 
x The sensitivity analysis has been described
x Sample size re-estimation text has been further detailed
Specific changes
Change #1
SPONSOR DECLARATION
The Clinical Project Manager has changed.
Clinical Project Manager
_____________________________
Date/Signature
REDACTED
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 87 of 144
Clinical Trial Biostatistician
, MA
_____________________________
Date/Signature
Study Physician
, MD
_____________________________
Date/Signature
Clinical Program Director
, BS
_____________________________
Date/Signature
Has been revised and moved to Section 19: 
19
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.
Change #2
STUDY CONTACT INFORMATION
The Clinical Project Manager contact details have been updated.
Name:
Address:
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES
Phone:
Fax:
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 88 of 144
Has been changed to: 
Name:
Address:
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim 
GERMANY
Phone:
Fax:
Change #3
Section 1 SUMMARY
Reference to the Food and Drug Administration has been clarified that it is for the US and the 
contingent primary efficacy variable has been defined, 5th paragraph.
Based on Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
requirements, 2 (co-) primary efficacy variables have been defined for this study based on 
electrographic partial-onset seizures with or without clinical correlate depending upon subject 
age. The primary efficacy variable will be the change in average daily frequency (ADF) of 
electrographic partial-onset seizures (US) or proportion of subjects experiencing ≥50% reduction 
in their ADF of electrographic partial-onset seizures (EU) as measured on the 72-hour
end-of-Maintenance Period video-electroencephalogram (EEG) compared to the 72-hour
end-of-Baseline Period video-EEG. Partial-onset seizures will be counted by a central reader 
evaluating the characteristic ictal patterns of electrographic seizures. 
Has been changed to: 
Based on US Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
requirements, 2 (co-) primary efficacy variables have been defined for this study based on 
electrographic partial-onset seizures with or without clinical correlate depending upon subject 
age. The primary efficacy variable will be the change in average daily frequency (ADF) of 
electrographic partial-onset seizures (US) or proportion of subjects experiencing ≥50% reduction 
in their ADF of electrographic partial-onset seizures (EU) as measured on the 72-hour
End-of-Maintenance Period video-electroencephalogram (EEG) compared to the 72-hour
End-of-Baseline Period video-EEG. Partial-onset seizures will be counted by a central reader 
evaluating the characteristic ictal patterns of electrographic seizures. At the request of FDA, a 
contingent primary efficacy variable has also been defined based on the percentage of subjects
who discontinue early from the study prior to completing the End-of-Maintenance Period 
video-EEG. Contingent upon >10% of subjects discontinuing early from the study, the primary 
efficacy parameter for the US will become identical to the primary efficacy parameter for the 
EU. The endpoint not designated as primary will still be summarized as a secondary efficacy 
parameter. 
Change #4
Section 4.1.1 Primary efficacy variable
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 89 of 144
The contingent primary efficacy variable has been defined. 
For the US: 
The primary efficacy variable will be the change in ADF of electrographic partial-onset seizures 
as measured on the 72-hour end-of-Maintenance Period video-EEG compared to the 72-hour
end-of-Baseline Period video-EEG. 
Has been changed to:
For the US, the primary efficacy variable will be contingent on the percentage of subjects that 
discontinue from the study after the first dose of study medication but prior to performance of the 
72-hour End-of-Maintenance Period video-EEG (ie, early discontinuation).
The following variable will be considered primary for the US given that ≤10% of subjects 
discontinue early from the study:
x The change in ADF of electrographic partial-onset seizures as measured on the 72-hour
End-of-Maintenance Period video-EEG compared to the 72-hour End-of-Baseline Period 
video-EEG. 
If >10% of subjects discontinue early from the study, the following contingency endpoint will be 
considered primary for the US (same as the primary efficacy variable for the EU):
The proportion of responders where a responder is a subject experiencing a 50% or greater 
reduction in their ADF of electrographic partial-onset seizures recorded on the 72-hour
End-of-Maintenance Period video-EEG compared to the 72-hour end of Baseline Period 
video-EEG.
Change #5
Section 5.1.2 Planned number of subjects and sites
The language of the percentage of subjects <2 years of age to be included in the study has been 
clarified, 1st and 2nd paragraphs.
A total of approximately 244 subjects (122 subjects per treatment arm) are planned to be 
randomized.
Subjects will be enrolled in the following age categories as detailed below:
x ≥1 month to <6 months of age (≥25 subjects)
x ≥6 months to <1 year of age (≥25 subjects)
x ≥1 year to <2 years of age (≥25 subjects)
x ≥2 years to <4 years of age (≥20 subjects)
Approximately 175 sites are planned in order to recruit the required subjects; additional sites will 
be added if deemed necessary. A target of approximately 50% of the randomized subjects should 
consist of subjects <2 years of age. Of these subjects (122), a target of 20% will be enrolled in 
each of the 3 age categories <2 years of age.
Has been changed to:
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 90 of 144
A total of approximately 244 subjects (122 subjects per treatment arm) are planned to be 
randomized. Approximately 50% of the 244 randomized subjects should be <2 years of age. Of 
these (n=122), a minimum target of 20% (n=25) of subjects will be enrolled in each of the 3 age 
categories: ≥1 month to <6 months, ≥6 months to <1 year, and ≥1 year to <2 years.
Subjects will be enrolled in the following age categories as detailed below:
x ≥1 month to <6 months of age (≥25 subjects)
x ≥6 months to <1 year of age (≥25 subjects)
x ≥1 year to <2 years of age (≥25 subjects)
x ≥2 years to <4 years of age (≥20 subjects)
Approximately 175 sites are planned in order to recruit the required subjects; additional sites will 
be added if deemed necessary. 
Change #6
Section 5.2 Schedule of study assessments
Schedule of study assessments Table 5-1 has been updated to include rescue medication 
assessment.
REDACTED COPY 
This document cannot be used to support any marketing authorization application 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 91 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
Informed consent
X
Demographics
c
X
Inclusion/exclusion criteria
X
X
X
Medical history
X
Seizure history/count
X
Concomitant medications
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant AEDs
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
VNS assessmentf
X
X
X
X
X
X
Physical examination (complete)
X
X
Physical examination (brief)
X
X
X
X
Vital signs (including BP and 
pulse rate)g
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Height
X
X
Head circumference
X
X
Neurological examination 
(complete)
X
X
Neurological examination (brief)
X
X
X
X
ECG (12-lead)h
X
X
X
X
Video-EEGi
X
X
X
X
X
X
X
X
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 92 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
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5
9
13
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25
26
27
Clinical chemistry/hematology
X
X
X
Concomitant AED plasma 
concentration
X
X
X
LCM plasma concentration
X
X
X
Clinical GIC 
X
Caregiver’s GIC
X
Contact IXRS
X
X
X
X
X
X
Randomization
Xj
Dispense study medication
Xj
X
X
X
X
Return study medication
X
X
X
X
Dosing instructionsk
X
X
X
AE reporting
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
Healthcare resource use
X
X
X
X
Bayley-III scalesl
X
BRIEF-Pm
X
X
PedsQLn
X
X
Achenbach CBCLo
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; 
CBCL=Childhood Behavior Checklist; ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination; GIC=Global Impression of 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 93 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
Change; IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; T=Telephone Contact; 
UV=Unscheduled Visit; V=Visit; VNS=vagus nerve stimulation.
a If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments may be performed at the investigator’s 
discretion.
b The Day -3 and Day 24 assessments should be conducted prior to the start of video-EEG monitoring. A maximum of 7 days may be added to the 
period between Visit 1 and 2 in the event that additional time is needed to access inpatient facilities to perform the video-EEG, 
c Demographics: date of birth, age group category, age in months and years, race, ethnicity, and gender. In countries where recording of complete 
date of birth is not permitted, only permitted data will be collected.
d The concomitant medications recording will include any current medication intake as well as any medications taken ≤30 days prior to Visit 1.
e The concomitant AED recording will include any current medication intake as well as any previous AED taken prior to Visit 1.
f The VNS setting will be assessed as applicable.
g Orthostatic assessments of BP and pulse rate will be assessed where it is feasible according to investigator judgment.
h A 12-lead ECG (2 interpretable recordings) will be performed prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recording. The second recording will be conducted 20 to 30 minutes after the first 
recording. Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified designated reader and at a central ECG 
laboratory. The investigator may consult with the cardiologist at the central ECG laboratory to confirm the presence of a clinically significant ECG 
abnormality; however, 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.
i The video-EEG (72 hours of continuous recording) will be conducted in an inpatient setting. Upon completion of the Baseline video-EEG (Visits 2 
and 3), the investigator will assess the electrographic seizure count and confirm the selection criteria have been met. If the subject meets all 
selection criteria, including the requisite number of seizures based on the video-EEG data, the subject may be randomized at Visit 3. All 
video-EEG data recordings will be transmitted to a central reader for the purposes of data analysis. The End-of-Maintenance Period video-EEG 
will be done at Visit 6. Subjects who discontinue on or before Day 20 will not require a video-EEG.
j Randomization and initial dispensing of study medication will occur at Visit 3 and after the completion of the video-EEG and confirmation that the 
subject has met selection criteria. 
k Dosing instructions will be provided to the caregiver(s) during the telephone contacts. At a minimum, AEs and tolerability should be discussed 
with the caregiver(s) in order to determine the next dose for the subject. See Section 7.2.1 for additional details on dosing options. 
l The Bayley Scales of Infant and Toddler Development, Third Edition, will be completed by subjects who are <18 months of age who originate in 
English-speaking countries. 
m The BRIEF-P will be used only for subjects who are ≥2 years of age at Visits 3 and 6. BRIEF-P will be used only in countries where a translated 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 94 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
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version is available.
n The version of the PedsQL used at Visit 3 should be consistent with the subject’s age at Visit 3 and should be maintained for each subject for the 
duration of the study. The PedsQL will be used only in countries where a translated version is available. 
o The Achenbach CBCL/1½-5 will be completed by the parent(s)/legal representative(s)/caregiver(s) of subjects ≥18 months of age at Visits 3 and 6. 
The Achenbach CBCL will be administered only in countries where a translated version is available.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 95 of 144
Has been changed to:
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
Informed consent
X
Demographics
c
X
Inclusion/exclusion criteria
X
X
X
Medical history
X
Seizure history/count
X
Concomitant medications
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant AEDs
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
VNS assessmentf
X
X
X
X
X
X
Physical examination (complete)
X
X
Physical examination (brief)
X
X
X
X
Vital signs (including BP and 
pulse rate)g
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Height
X
X
Head circumference
X
X
Neurological examination 
(complete)
X
X
Neurological examination (brief)
X
X
X
X
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 96 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
T3
V6/ET
UV
a
Study Day
-7
-3
b
-2
-1
1
5
9
13
17
20
24b
25
26
27
ECG (12-lead)h
X
X
X
X
Video-EEGi
X
X
X
X
X
X
X
X
Rescue medicationj
X
X
X
X
X
X
X
X
Clinical chemistry/hematology
X
X
X
Concomitant AED plasma 
concentration
X
X
X
LCM plasma concentration
X
X
X
Clinical GIC 
X
Caregiver’s GIC
X
Contact IXRS
X
X
X
X
X
X
Randomization
Xk
Dispense study medication
Xk
X
X
X
X
Return study medication
X
X
X
X
Dosing instructionsl
X
X
X
AE reporting
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
Healthcare resource use
X
X
X
X
Bayley-III scalesm
X
BRIEF-Pn
X
X
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 97 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
V2
V3
T1
V4
T2
V5
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20
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25
26
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Achenbach CBCLp
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AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; 
CBCL=Childhood Behavior Checklist; ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination; GIC=Global Impression of 
Change; IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; T=Telephone Contact; 
UV=Unscheduled Visit; V=Visit; VNS=vagus nerve stimulation.
a If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments may be performed at the investigator’s 
discretion.
b The Day -3 and Day 24 assessments should be conducted prior to the start of video-EEG monitoring. A maximum of 7 days may be added to the 
period between Visit 1 and 2 in the event that additional time is needed to access inpatient facilities to perform the video-EEG. 
c Demographics: date of birth, age group category, age in months and years, race, ethnicity, and gender. In countries where recording of complete 
date of birth is not permitted, only permitted data will be collected.
d The concomitant medications recording will include any current medication intake as well as any medications taken ≤30 days prior to Visit 1.
e The concomitant AED recording will include any current medication intake as well as any previous AED taken prior to Visit 1.
f The VNS setting will be assessed as applicable.
g Orthostatic assessments of BP and pulse rate will be assessed where it is feasible according to investigator judgment.
h A 12-lead ECG (2 interpretable recordings) will be performed prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recording. The second recording will be conducted 20 to 30 minutes after the first 
recording. Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified designated reader and at a central ECG 
laboratory. The investigator may consult with the cardiologist at the central ECG laboratory to confirm the presence of a clinically significant ECG 
abnormality; however, 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.
i The video-EEG (72 hours of continuous recording) will be conducted in an inpatient setting. Upon completion of the Baseline video-EEG (Visits 2
and 3), the investigator will assess the electrographic seizure count and confirm the selection criteria have been met. If the subject meets all 
selection criteria, including the requisite number of seizures based on the video-EEG data, the subject may be randomized at Visit 3. All 
video-EEG data recordings will be transmitted to a central reader for the purposes of data analysis. The end-of-Maintenance Period video-EEG 
will be done at Visit 6. Subjects who discontinue on or before Day 20 will not require a video-EEG.
j Additional assessment for changes in VNS or rescue medication taken within 24 hours prior to and until the end of the video-EEG monitoring.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 98 of 144
Table 5-1:
Schedule of study assessments (Baseline and Treatment Periods)
Assessment
Baseline Period
(7 days)
Treatment Period (27 days)
Titration Period
(20 days)
Maintenance Period
(7 days)
Visit
V1
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k Randomization and initial dispensing of study medication will occur at Visit 3 and after the completion of the video-EEG and confirmation that the 
subject has met selection criteria. 
l Dosing instructions will be provided to the caregiver(s) during the telephone contacts. At a minimum, AEs and tolerability should be discussed 
with the caregiver(s) in order to determine the next dose for the subject. See Section 7.2.1 for additional details on dosing options. 
m The Bayley Scales of Infant and Toddler Development, Third Edition, will be completed by subjects who are <18 months of age who originate in 
English-speaking countries. 
nThe BRIEF-P will be used only for subjects who are ≥2 years of age at Visits 3 and 6. BRIEF-P will be used only in countries where a translated 
version is available.
o The version of the PedsQL used at Visit 3 should be consistent with the subject’s age at Visit 3 and should be maintained for each subject for the 
duration of the study. The PedsQL will be used only in countries where a translated version is available. 
p The Achenbach CBCL/1½-5 will be completed by the parent(s)/legal representative(s)/caregiver(s) of subjects ≥18 months of age at Visits 3 and 6. 
The Achenbach CBCL will be administered only in countries where a translated version is available.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 99 of 144
Change #7
Section 5.4 Rationale for study design and selection of dose 
Text defining the contingent primary efficacy variable has been added, 4th paragraph.
Based on US FDA and EMA requirements, 2 (co-) primary efficacy variables have been defined 
for this study based on electrographic partial-onset seizures with or without clinical correlate 
depending upon subject age. The primary efficacy variable will be the change in ADF of 
electrographic partial-onset seizures (US) or proportion of subjects experiencing ≥50% reduction 
in their ADF of electrographic partial-onset seizures (EU) as measured on the 72-hour End-of-
Maintenance Period video-EEG compared to the 72-hour End-of-Baseline Period video-EEG. At 
the request of FDA, a contingent primary efficacy variable has also been defined based on the 
percentage of subjects who discontinue early from the study prior to completing the 
End-of-Maintenance Period video-EEG. Contingent upon >10% of subjects discontinuing early 
from the study, the primary efficacy parameter for the US will become identical to the primary 
efficacy parameter for the EU.
The endpoint not designated as primary will still be summarized as a secondary efficacy 
parameter
Change #8
Section 8.1.2 Baseline Period: Visit 2 (Day -3 to Day -1)
Rescue medication has been added to the list of assessments.
x Inclusion/exclusion criteria (Day -3 only)
x Concomitant medications 
x Concomitant AEDs 
x VNS assessment (Day -3 only and only if applicable)
x Physical examination (brief) (Day -3 only)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment; Day -3 only)
x Body weight (Day -3 only)
x Neurological examination (brief) (Day -3 only)
x Video-EEG (72 hours of continuous recording)
x AE reporting 
x Review withdrawal criteria
Has been changed to:
x Inclusion/exclusion criteria (Day -3 only)
x Concomitant medications 
x Concomitant AEDs 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 100 of 144
x VNS assessment (Day -3 only and only if applicable)
x Physical examination (brief) (Day -3 only)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment; Day -3 only)
x Body weight (Day -3 only)
x Neurological examination (brief) (Day -3 only)
x Video-EEG (72 hours of continuous recording)
x Rescue medication assessment
x AE reporting 
x Review withdrawal criteria 
Change #9
Section 8.2.1 Titration Period: Visit 3 (Day 1)
Rescue medication has been added to the list of assessments.
Randomization and initial dispensing of study medication will occur at Visit 3 and after the 
completion of the video-EEG and confirmation that the subject has met selection criteria.
During Visit 3, the following assessments will be performed:
x Inclusion/exclusion criteria
x Concomitant medications
x Concomitant AEDs
x 12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed, if possible, 
with the subject in a supine position for 5 minutes preceding ECG recording)
x Video-EEG (end-of-Baseline video-EEG)
x Contact IXRS
x Randomization
x Dispense study medication and administer first dose of study medication before the 
conclusion of visit
x AE reporting
x Review withdrawal criteria
x Healthcare resource use
x Bayley-III scales (for subjects who are <18 months of age who originate in English-speaking 
countries)
x BRIEF-P score 
x PedsQL score 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 101 of 144
x Achenbach CBCL (the CBCL/1½-5 will be completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 months of age at Visit 3)
Has been changed to:
Randomization and initial dispensing of study medication will occur at Visit 3 and after the 
completion of the video-EEG and confirmation that the subject has met selection criteria.
During Visit 3, the following assessments will be performed:
x Inclusion/exclusion criteria
x Concomitant medications
x Concomitant AEDs
x 12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed, if possible, 
with the subject in a supine position for 5 minutes preceding ECG recording)
x Video-EEG (End-of-Baseline video-EEG)
x Rescue medication assessment
x Contact IXRS
x Randomization
x Dispense study medication and administer first dose of study medication before the 
conclusion of visit
x AE reporting
x Review withdrawal criteria
x Healthcare resource use
x Bayley-III scales (for subjects who are <18 months of age who originate in English-speaking 
countries)
x BRIEF-P score 
x PedsQL score 
Achenbach CBCL (the CBCL/1½-5 will be completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 months of age at Visit 3)
Change #10
Section 8.3.1 Maintenance Period: Visit 6/Early Termination (Day 24, Day 25 and 
Day 26)
Rescue medication has been added to the list of assessments.
The Day 24 assessments should be conducted prior to the start of video-EEG monitoring. The 
following assessments will be performed on Day 24 for all subjects:
x Concomitant medications 
x Concomitant AEDs
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 102 of 144
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Neurological examination (brief)
x Video-EEG (72 hours of continuous recording)
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Review withdrawal criteria
The following assessments will be performed on Day 25 and Day 26 during the 72-hour
video-EEG:
x Concomitant medications 
x Concomitant AEDs
x AE reporting
x Review withdrawal criteria
Has been changed to:
The Day 24 assessments should be conducted prior to the start of video-EEG monitoring. The 
following assessments will be performed on Day 24 for all subjects:
x Concomitant medications 
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (brief)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Neurological examination (brief)
x Video-EEG (72 hours of continuous recording)
x Rescue medication assessment
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 103 of 144
x Review withdrawal criteria
The following assessments will be performed on Day 25 and Day 26 during the 72-hour video-
EEG:
x Concomitant medications 
x Concomitant AEDs
x Rescue medication assessment
x AE reporting
x Review withdrawal criteria
Change #11
Section 8.3.2 Maintenance Period: Visit 6/Early Termination (Day 27)
Rescue medication has been added to the list of assessments.
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (complete)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Height
x Head circumference
x Neurological examination (complete)
x 12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in a supine 
position for 5 minutes preceding ECG recording)
x Blood sample for clinical chemistry/hematology
x Blood sample for determination of concomitant AED plasma concentration 
x Blood sample for determination of LCM plasma concentration 
x Clinical Global Impression of Change
x Caregiver’s Global Impressions of Change
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 104 of 144
x Review withdrawal criteria
x Healthcare resource use
x BRIEF-P
x PedsQL (same version used at Visit 3)
x Achenbach CBCL (the CBCL/1½-5 will be completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 months of age at Visit 6/ET) 
Has been changed to:
x Concomitant medications
x Concomitant AEDs
x VNS assessment (if applicable)
x Physical examination (complete)
x Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment)
x Body weight
x Height
x Head circumference
x Neurological examination (complete)
x 12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in a supine 
position for 5 minutes preceding ECG recording)
x Blood sample for clinical chemistry/hematology
x Blood sample for determination of concomitant AED plasma concentration 
x Blood sample for determination of LCM plasma concentration 
x Clinical Global Impression of Change
x Caregiver’s Global Impressions of Change
x Contact IXRS
x Dispense study medication
x Return study medication
x AE reporting
x Rescue medication assessment
x Review withdrawal criteria
x Healthcare resource use
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 105 of 144
x BRIEF-P
x PedsQL (same version used at Visit 3)
x Achenbach CBCL (the CBCL/1½-5 will be completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 months of age at Visit 6/ET) 
Change #12
Section 9.2.3 Healthcare resource use
Healthcare resource use section has been updated, 1st paragraph.
For healthcare resource use, the following will be evaluated: concomitant medications and 
AEDs, medical procedures, healthcare provider consultations not related to study, and 
hospitalizations not related to study.
Has been changed to:
For healthcare resource use, the following will be evaluated: concomitant medications and 
AEDs, medical procedures, and healthcare provider consultations including hospitalizations not 
foreseen by the protocol.
Change #13
Section 11.1.4
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 
after the subject has discontinued his/her IMP.
Has been changed to:
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 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 
after the subject has discontinued his/her IMP.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 106 of 144
Change #14
Section 11.5 Anticipated serious adverse events
The anticipated SAE table has been updated to include a footnote for convulsion.
Table 11-1:
Anticipated SAEs for the pediatric epilepsy 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 behaviour 
Abnormal behaviour 
Anxiety 
Sleep disorder 
Reproductive system and breast disorders
Menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; 
SOC=system organ class 
Has been changed to:
Table 11-1: Anticipated SAEs for the pediatric epilepsy 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
Convulsiona 
Incontinence 
Status epilepticus 
Pregnancy, puerperium and perinatal disorders
Abortion spontaneous 
Psychiatric disorders
Psychotic behaviour 
Abnormal behaviour 
Anxiety 
Sleep disorder 
Reproductive system and breast disorders
Menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; 
SOC=system organ class 
a  Convulsion if consistent with the seizure type known for the subject.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 107 of 144
Change #15
Section 12.1 Adherence to protocol
Text for adherence to the protocol has been updated.
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.
Has been changed to:
The investigator should not deviate from the protocol. However, the investigator should take any
measure necessary in deviation from or not defined by the protocol in order to protect clinical
study subjects from any immediate hazard to their health and safety. In this case, this action
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or
sponsor. After implementation of such measure, the investigator must notify the Clinical Project 
Manager (CPM) of the sponsor within 24 hours and follow any local regulatory requirements.
Change #16
Section 13.1 Definition of analysis sets
Definition of the analysis sets has been clarified, 1st paragraph.
The primary analysis set for the efficacy data will be the Full Analysis Set (FAS), and will 
include all subjects who were randomized, received at least 1 dose of study medication, and had 
an End-of-Maintenance Period video-EEG.
The secondary analysis set for the efficacy data will be the Per Protocol Set (PPS), which 
includes all subjects in the FAS who did not have important protocol deviations related to 
efficacy.
The Safety Set (SS) will include all randomized subjects who took at least 1 dose of study 
medication. This is the primary analysis set for the safety variables.
The Pharmacokinetic Per Protocol Set (PK-PPS) will consist of all subjects having provided at 
least 1 measurable postdose plasma sample (with recorded sampling time) on at least 1 visit with 
documented study medication intake times.
Has been changed to:
The Safety Set (SS) will include all randomized subjects who took at least 1 dose of study 
medication. This is the primary analysis set for the safety variables.
The primary analysis set for the efficacy data will be the Full Analysis Set (FAS), which will 
include all subjects in the SS.
The secondary analysis set for the efficacy data will be the Per-Protocol Set (PPS), which 
includes all subjects in the FAS who did not have important protocol deviations related to 
efficacy.
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects having provided at 
least 1 measurable postdose plasma sample (with recorded sampling time) on at least 1 visit with 
documented study medication intake times.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 108 of 144
Change #17
Section 13.1.1.1 Analysis of the primary efficacy variable for the US
This section has been added.
Contingent upon ≤10% of subjects discontinuing early from the study, the primary efficacy 
parameter for the US is the change in ADF of electrographic partial-onset seizures during the 
Maintenance Period compared to the end of the Baseline Period. Seizure ADF will be analyzed 
using analysis of covariance with terms for treatment and center (properly pooled), on log-
transformed seizure ADF using the transformation of ln (X+1), where X is the seizure ADF. 
Log-transformed Baseline seizure ADF will be used as a covariate. The seizure ADF between 
LCM and PBO will be compared using least squares means (LSMs). The percent reduction over 
PBO will be estimated as 100 x (1 – exp [LSM Treatment {TRT} - LSMPBO]). The analysis of 
this efficacy variable will consist of all subjects in the FAS who have at least 48 hours of 
interpretable recordings during both the End-of-Baseline Period video-EEG and the 
End-of-Maintenance Period video-EEG.
The following additional sensitivity analyses on this primary efficacy variable will be conducted 
in order to assess the effect of early discontinuations, protocol deviations, and operational bias on 
this primary endpoint:
x Repeat the primary analysis using the PPS.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using the Baseline 
observation-carried-forward approach. This will be applied for all subjects who discontinued 
early from the study.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced by the overall mean ADF 
of partial-onset seizures from the End-of-Maintenance Period video-EEG from the subject’s 
respective treatment arm. This will be applied for all subjects who discontinued early from 
the study.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using multiple imputation 
by treatment arm and age group (≥1 month to <6 months of age, ≥6 months to <1 year of age,
≥1 year to <2 years of age, and ≥2 years to <4 years of age) using a Markov chain Monte 
Carlo method assuming a log-normal distribution. This will be applied for all subjects who 
discontinued early from the study.
x Repeat the primary analysis using the FAS for all subjects who have at least 24 hours of 
interpretable recordings during both the End-of Baseline Period video-EEG and the 
End-of-Maintenance Period video-EEG.
Contingent upon >10% of subjects discontinuing early from the study, the primary efficacy
parameter for the US is identical to the primary efficacy parameter for the EU, described below. 
The endpoint not designated as primary will still be summarized as a secondary efficacy 
parameter.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 109 of 144
Change #18
Section 13.1.1.2 Analysis of the primary efficacy variable for the EU
This section has been added.
The primary efficacy parameter for the EU is the proportion of responders during the 
Maintenance Period. Subjects with a 50% or more reduction in seizure ADF will be categorized 
as responders; this classification requires at least 48 hours of interpretable recordings during both 
the End-of-Baseline Period video-EEG and the End-of-Maintenance Period video-EEG. The 
proportion of responders between LCM and PBO will be analyzed using logistic regression with
center (properly pooled) as a factor. Subjects who withdraw or drop out before the first 48 hours 
of the End-of-Maintenance Period video-EEG with reasons related to lack of efficacy will be 
considered non responders; all other subjects will be missing for this analysis. The number and 
percentage of subjects with a 50% or more reduction in seizure ADF will be presented by 
treatment group. 
The following additional sensitivity analyses on this primary efficacy variable will be conducted 
in order to assess the effect of early discontinuations, protocol deviations, and operational bias on 
this primary endpoint:
x Repeat the primary analysis using the PPS.
x Repeat the primary analysis using the FAS, except subjects who discontinued from the study 
prior to performance of the 72-hour End-of-Maintenance Period video-EEG with reasons 
related to lack of efficacy will be considered non responders, and subjects who discontinued 
from the study early for any other reason will be considered responders.
x Repeat the primary analysis using the FAS, except all subjects who discontinued from the 
study early will be considered non responders.
x Repeat the primary analysis using the FAS, except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-EEG will be replaced using multiple imputation 
by treatment arm and age group (≥1 month to <6 months of age, ≥6 months to <1 year of age, 
≥1 year to <2 years of age, and ≥2 years to <4 years of age) using a Markov chain Monte 
Carlo method assuming a log-normal distribution. This will be applied for all subjects who 
discontinued from the study early, and the imputed End-of-Maintenance Period ADF of 
partial-onset seizures will be used to determine whether a subject is a responder.
x Repeat the primary analysis using the FAS for all subjects who have at least 24 hours of 
interpretable recordings during both the end of Baseline Period video-EEG and the end of 
Maintenance Period video-EEG.
Change #19
Section 13.2.1 Planned efficacy analyses
This section has been removed.
Subjects evaluable for the EEG-based efficacy endpoints will consist of all subjects in the FAS 
who have at least 48 hours of interpretable recordings during both the end of Baseline Period 
video-EEG and the end of Maintenance Period video-EEG.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 110 of 144
Change #20
Section 13.5 Planned interim analysis and data monitoring
The sample size re-estimation has been further detailed, 2nd and 3rd paragraphs.
A blinded sample size re-estimation will be performed when 50% of subjects have been 
randomized, completed the study, and have data available for analysis to check the validity of 
these assumptions using interim data from the study. The sample size re-estimation with equal 
allocation in each arm will be performed using the related residual variance combined with 
Guenther adjustment (Friede and Kieser, 2011). An assessment of the observed dropout rate will 
also be made as part of this analysis, and the anticipated dropout rate of 14% will be modified 
based on the observed rate. Additionally, an assessment of the observed difference of 
interpretation rate will be made; the anticipated rate of 5% will be modified based on the 
observed rate.
The final sample size will be modified according to the sample size re-estimate and also the 
anticipated dropout rate and anticipated rate of difference of interpretation of the end-of-Baseline 
Period video-EEG; however, an upper bound may be applied to reach a maximum sample size 
based on practical and logistical considerations.
Has been changed to:
A blinded sample size re-estimation will be performed when 50% of subjects have been 
randomized, completed the study, and have data available for analysis to check the validity of 
these assumptions using interim data from the study. The sample size re-estimation with equal 
allocation in each arm will be performed using the related residual variance combined with 
Guenther adjustment (Friede and Kieser, 2011). An assessment of the observed dropout rate will 
also be made as part of this analysis, and the potential dropout rate of 14% used for calculation 
of the initial sample size (see Section 13.6) will be modified based on the observed rate. 
Additionally, an assessment of the observed difference of End-of-Baseline Period EEG 
interpretation rate will be made; the anticipated rate of 5% will be modified based on the 
observed rate.
The final sample size will be modified according to the sample size re-estimate and also the 
anticipated dropout rate and anticipated rate of difference of interpretation of the 
End-of-Baseline Period video-EEG; however, an upper bound will be applied to reach a 
maximum sample size based on practical and logistical considerations. The initial sample size 
re-estimate using Guenther adjustment will not be adjusted above 109 subjects per treatment 
arm, the original estimated overall study drop out rate will not be adjusted above 24%, and the 
difference of End-of-Baseline Period EEG interpretation rate will not be adjusted above 10%.
Change #21
Section 13.6 Determination of sample size
Text for third paragraph has been updated.
Subjects are randomized into the study based on the investigator’s interpretation of the video-
EEG to meet study entry requirements; however, there may be a difference of interpretation of 
the number of seizures counted on the end-of-Baseline Period video-EEG between the central 
reader and the investigator. To account for an anticipated difference of interpretation of the 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 111 of 144
end-of-Baseline Period video-EEG of 5% as well as an anticipated subject dropout rate of 
approximately 14%, the planned number of subjects to enroll is 122 subjects per treatment arm.
Has been changed to:
Subjects are randomized into the study based on the investigator’s interpretation of the video-
EEG to meet study entry requirements; however, there may be a difference of interpretation of 
the number of seizures counted on the End-of-Baseline Period video-EEG between the central 
reader and the investigator. To account for an anticipated difference of interpretation of the 
End-of-Baseline Period video-EEG of 5% as well as the potential subject dropout rate of 
approximately 14%, the planned number of subjects to enroll is 122 subjects per treatment arm.
Change #22:
The following section has been added for electronic signature:
Section 19
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.
17.2
AMENDMENT 2
Rationale for the amendment
The primary purposes of this substantial amendment are to clarify elements of the study design 
including inclusion and exclusion criteria, withdrawal criteria, permitted and prohibited 
concomitant medication, and study procedures to make the protocol more patient-friendly and 
enhance enrollment. The protocol was also updated according to the new UCB protocol 
template, for example, with the addition of text regarding PDILI.
The following table summarizes each change with the associated rationale. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 113 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 1
Lacosamide is being evaluated in pediatric subjects 1 
month to 17 years of age in 3 studies: SP847 (open label, 
Phase 2, safety, tolerability, and PK study), SP848 (open 
label long term safety study), and SP1047 (PK study for 
subjects prescribed LCM). In SP847 and SP848, subjects 
with uncontrolled partial onset seizures receive LCM oral 
solution at doses up to 12mg/kg/day based on tolerability.
Lacosamide is being evaluated in pediatric 
subjects 1 month to 17 years of age with partial-
onset seizures in completed and ongoing studies. 
The completed pediatric studies include: SP847 
(open-label, safety, tolerability, and PK study) 
and SP1047 (PK study for subjects prescribed 
LCM). The ongoing pediatric studies include: 
SP848 and EP0034 (open-label, long-term safety 
studies). In SP847 SP848, and EP0034  subjects 
with uncontrolled partial onset seizures have 
received LCM oral solution at doses up to 
12mg/kg/day based on tolerability.
Updated text according to 
pediatric studies that have 
been completed. 
Section 1
Section 5.1.2
A total of approximately 244 subjects (122 subjects per 
treatment arm) are planned to be randomized at 
approximately 175 sites in North America, Europe, Asia 
Pacific, and Latin America, with possible extension to 
other countries and regions.
A total of approximately 244 subjects (122 
subjects per treatment arm) are planned to be 
randomized at approximately 140 sites in North 
America, Europe, Asia Pacific, and Latin 
America, with possible extension to other 
countries and regions.
Revised number of sites. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 114 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 1
Section 5.1.1
x The maximum duration of study medication 
administration in SP0967 is 55 days, and the maximum 
study duration is 93 days (not withstanding visit 
windows).
x For each subject, the total study duration can be up to 93 
days (not withstanding visit windows), including the 30 
day Safety Follow-Up Period. Each subject’s 
participation in the study begins with a 7-day Baseline 
Period (no administration of study medication). Each 
subject’s total duration of study medication 
administration in SP0967 is up to 55 days. This includes 
a 20-day Titration Period, a 7-day Maintenance Period, 
and a 12-day Transition Period (for subjects who plan to 
enter the open label extension study [EP0034]) or up to a 
16-day Taper Period (for subjects who will not be 
entering EP0034).
x The maximum duration of study medication 
administration in SP0967 is 55 days (this 
includes a 20-day Titration Period, a 7-day 
Maintenance Period, a 12-day Transition 
Period, and/or up to a 16-day Taper Period), 
and the maximum study duration is 93 days (not 
withstanding visit windows).
x For each subject, the maximum total study 
duration can be up to 93 days (not withstanding 
visit windows), including the 30 day Safety 
Follow-Up Period. Each subject’s participation 
in the study begins with a 7-day Baseline Period 
(no administration of study medication). Each 
subject’s maximum total duration of study 
medication administration in SP0967 can be up 
to 55 days. This includes a 20-day Titration 
Period, a 7-day Maintenance Period, a 12-day 
Transition Period (for subjects who plan to 
enter the open label extension study [EP0034]) 
and/or up to a 16-day Taper Period (for subjects 
who will not be entering EP0034).
Clarify that the duration of 
study medication 
administration (55 days) 
and total study duration 
(93 days) are maximum 
durations for a subject who 
enters the Transition 
Period end up also going 
through the Taper Period.
Section 2
Epilepsy is the second most prevalent neurological 
disorder in the world. More than 40 million people suffer 
from epilepsy–about 1% of the world’s population 
(Dichek, 1999).
Epilepsy is the second most prevalent 
neurological disorder in the world. It is estimated 
that almost 70 million people suffer from epilepsy 
(Ngugi et al, 2011).
Updated introductory text 
with newer reference.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 115 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 4.2
Table 5-1
Section 8.1.1
Section 8.2.4
Section 8.3.2
Section 10
Section 13.2.2.1
Section 13.2.2.3
Collection of blood at V1, V5, and V6 (Day 27) to 
investigate the effect of LCM on the steady-state plasma 
concentrations of concomitant
AEDs
Global change:
x Remove variable. Collection of blood samples 
at V1, Visit 5, and V6 (Day 27) for analysis of 
concomitant AEDs will not be performed.
x No clinically significant 
impact of concomitant 
AEDs on LCM plasma 
concentrations or LCM 
efficacy – as shown by 
PK analyses in adults 
and children. 
x Additional blood 
collected for this analysis 
is unnecessary in this 
vulnerable patient 
population.
Table 5-1
Section 8.1.1
Collection of blood sample for analysis of LCM plasma 
concentrations at V1.
Removed from V1. 
x There is no need to 
collect blood to evaluate 
LCM plasma 
concentrations prior to 
subject randomization.
x Collection of blood for 
this analysis puts undue 
burden on this vulnerable 
patient population. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 116 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Table 5-1
Table 5-2
Table 5-3
Section 8.1.1
Section 8.2.1
Section 8.2.4
Section 8.3.2
Section 8.4.3
Section 8.5.2
Section 11.7.4
A 12-lead ECG (2 interpretable recordings) will be 
performed at V1, V3, V5, V6 (Day 27), TV2, Taper Visit, 
and Safety Follow-up Visit (at investigator’s discretion) 
prior to any blood draws and vital signs assessment and, if 
possible, with the subject in the supine position for 5 
minutes preceding the ECG recording. The second 
recording will be conducted 20 to 30 minutes after the first 
recording.
Global changes:
x Insert “approximately” as follows: The second 
recording will be conducted approximately 20 
to 30 minutes after the first recording.
x ECG performed at V3 will be at the discretion 
of the investigator.
x ECG at V1 will serve as Baseline for the 
evaluation of change in ECG measurements. 
x The ECG at the Taper Visit and Safety Follow-
up Visit will be required for subjects with a 
clinically significant abnormal or reading at the 
previous clinic visit. For non-clinically 
significant abnormalities, repeat of this 
assessment is at the discretion of the 
investigator. 
x Allow some flexibility 
for the timing of the 
second ECG recording.
x ECG is performed at V1, 
which will be at most 7 
days prior to V3. 
Therefore, ECG at V3 is 
unnecessary. 
x No changes in 
concomitant AEDs are 
allowed during the 
Baseline Period. Thus, 
there is no need to repeat 
the ECG unless 
medically necessary. 
x If the ECG is normal at 
End of Maintenance, 
there is no need to repeat 
as early as 4 days later at 
the Taper Visit when the 
study drug is being 
tapered. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 117 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 1
Section 4.1
Section 4.1.1
Section 5.1
Table 5-1
Section 5.4
Section 8.1.2
Section 8.2.1
Section 8.3.1
Section 9.1
Section 13.1.1
Section 13.1.1.2
x Video-EEG (72 hours of continuous recording) 
performed at V2, V3, and V6 serves to evaluate both the 
primary and secondary efficacy variables. 
x The ADF of electrographic partial-onset seizures will be 
calculated as (number of partial-onset seizures recorded 
on the 72-hour video-EEG divided by 72 [or number of 
interpretable hours recorded]) multiplied by 24.
Global changes:
x Revise duration of video-EEG to be up to 72 
hours of continuous recording with every 
attempt to obtain at least 48 hours of 
interpretable recording. 
x Localize definition of video-EEG duration to 
Sections 4.1, 5.1, 8.1.2, 8.3.1, 9.1, and 13.1.1, 
and Table 5-1.
Text revised:
x The ADF of electrographic partial-onset 
seizures will be calculated as (number of 
partial-onset seizures recorded on the video-
EEG divided by the number of interpretable 
hours recorded) multiplied by 24.
x Clarify duration of 
video-EEG requirements 
with every attempt to 
obtain at least 48 hours 
of interpretable 
recording. 
x Completion of a full 72-
hour EEG is an 
impediment to patient 
enrollment based on site 
feedback. 
x Seizure data are 
normalized to 24 hours.
x There would be no 
changes to the analyses 
that would affect the 
validity of the data. 
Section 5.1.3
A target of approximately 30% of the randomized subjects 
should consist of subjects originating from sites in North 
America and the EU.
A target of approximately 30% of the randomized 
subjects should consist of subjects originating 
from sites in North America and Europe.
Inclusion of non-EU 
countries into the 30% 
randomization target.
Table 5-1
Table 5-2
Table 5-3
Section 8.2.3
Section 8.2.4
Section 8.4.1
Section 8.4.3
Section 8.5.2
Section 8.6.1
Assessments of healthcare resource use on Visit 3, Visit 4, 
Visit 5, Visit 6, TV1, TV2, Taper Visit, and Safety 
Follow-up Visit.
Global change:
x Remove assessments for healthcare resource 
use on Visit 4, Visit 5, TV1, TV2, Taper Visit, 
and Safety Follow-up Visit. 
Duration of the study is too 
short to administer the 
questionnaire on multiple 
occasions.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 118 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Table 5-1
Section 8.2.1
Section 11.7.8
Section 13.2.1
The Bayley Scales of Infant and Toddler Development, 
Third Edition is to be completed by subjects who are <18 
months of age who originate in English-speaking 
countries.
Text revised:
x Investigators must make every attempt to 
administer the Bayley Scales of Infant and 
Toddler Development, Third Edition, for 
subjects who are <18 months of age who 
originate in English-speaking countries. 
x The investigators may utilize trained pediatric 
psychologists or other appropriately skilled 
individuals to administer the scale.
x Investigators must make every attempt to 
administer Baseline assessment of the Bayley-
III scales; however, due to the short study 
duration of SP0967, the next assessment will be 
collected in subjects entering into the EP0034 
study and analysis of these data will be 
conducted in EP0034.
The administration of 
Bayley Scales is 
complicated and requires 
trained individuals.  The 
revised wording provides 
additional instructions to 
the investigators.  
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 119 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 1
Section 4.3.2
Table 5-1
Section 8.3.2
Section 11.7.7
Section 13.2.1
x The BRIEF-P will be used only for subjects who are ≥2 
years of age at V3 and V6.
x The BRIEF P includes rating forms used by parents to 
assess subjects’ executive functioning. Executive 
functions broadly encompass a set of cognitive skills 
that are responsible for the planning, initiation, 
sequencing, and monitoring of complex goal directed 
behavior. 
x The BRIEF P rating form consists of items that measure 
various aspects of executive functioning: Inhibit, Shift, 
Emotional Control, Working Memory, and 
Plan/Organize. The clinical scales form 3 broad indexes 
(Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and 1 composite score (Global 
Executive Composite).
x The BRIEF P includes validity scales to measure 
negativity and inconsistency of responses.
x The BRIEF-P will be used only for subjects 
who are ≥2 years of age at V3 and this will 
serve as the baseline for assessment in EP0034 
(open-label extension study).
x The Other Safety Variable for change from 
Baseline to end of Maintenance Period in the 
BRIEF-P score for subjects ≥2 years was 
removed.
x The BRIEF P includes rating forms used by 
parents to assess subjects’ executive functioning 
within the context of the subject’s everyday 
environment. It requires that the parent must 
have had recent and extensive contact with the 
child over the past 6 months. 
x The clinical scales form 3 broad overlapping 
indexes: Inhibitory Self-Control (Inhibit and 
Emotional Control), Flexibility (Shift and 
Emotional Control), and Emergent 
Metacognition (Working Memory and 
Plan/Organize) and 1 composite score (Global 
Executive Composite).
x Baseline assessment of the BRIEF-P will be 
performed at Visit 3; however, due to the study 
duration of SP0967, the next assessment will be 
collected in subjects entering into the EP0034 
study. Thus, the analysis of these data will be 
conducted in EP0034. 
x Recall period for BRIEF-
P is 6 months. In a study 
of approximately 1-
month treatment 
duration, the recall 
period at V3 would 
overlap that at V6/ET. 
Therefore, it is not 
possible to reliably 
detect any change from 
Baseline. 
x V3 measures of BRIEF-
P will still serve as 
Baseline for subjects in 
EP0034. 
x Because the V6 
assessment was 
removed, the analysis of 
change from baseline 
will occur in EP0034; 
therefore, the variable 
was removed from 
SP0967.  
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 120 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 1
Section 4.3.2
Table 5-1
Section 8.3.2
Section 11.7.6
Section 13.2.1
x Achenbach CBCL (the CBCL/1½ 5 will be completed 
by parent[s]/legal representative[s]/caregiver[s] of 
subjects ≥18 months of age at V3 and V6/ET)
x In both questionnaires, the occurrence of certain 
problems and behaviors in the past 6 months will be 
scored on the following scale:
 
0=not true (as far as known)
 
1=somewhat or sometimes true
 
2=very true or often true
x Achenbach CBCL (the CBCL/1½ 5 will be 
completed by parent[s]/legal 
representative[s]/caregiver[s] of subjects ≥18 
months of age at V3 and this will serve as the 
baseline for assessment in EP0034 (open-label 
extension study))
x The Other Safety Variable for change from 
Baseline to the end of the Maintenance Period 
in the Achenbach CBCL/1½-5 for subjects ≥18 
months was removed.
x Baseline assessment of Achenbach CBCL will 
be performed; however, due to the short study 
duration of SP0967, the next assessment will be 
collected in subjects entering into the EP0034 
study and analysis of these data will be 
conducted in EP0034.
x In both questionnaires, the occurrence of certain 
problems and behaviors at the time of 
administering the questionnaire or within the 
past 2  months will be scored on the following 
scale: 
 
0=not true (as far as known)
 
1=somewhat or sometimes true
 
2=very true or often true
x Recall period for 
Achenbach CBCL is 2 
months. In a study of 
approximately 1-month 
treatment duration, the 
recall period at V3 
would overlap that at 
V6/ET. Therefore, it is 
not possible to reliably 
detect any change from 
Baseline. 
x V3 measures of 
Achenbach CBCL will 
still serve as Baseline for 
subjects in EP0034.
x Because the V6 
assessment was 
removed, the analysis of 
change from baseline 
will occur in EP0034; 
therefore, the variable 
was removed from 
SP0967. 
Table 5-2
Section 8.4.3
Height and head circumference will be measured at TV2. 
Removed from TV2
Height and head 
circumference are 
measured at V6 (Day 27). 
There is no need to repeat 
2 weeks later. 
Table 5-3
No dosing instructions provided to the caregiver at the 
Taper Visit.
At the Taper Visit, dosing instructions will be 
provided to the caregiver(s). 
Provide the caregiver with 
dosing instructions.
REDACTED 
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05 Apr 2018
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Lacosamide
SP0967
Confidential
Page 121 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Table 5-3
Section 8.5.2
x Blood sample for clinical chemistry/hematology drawn 
at Taper Visit and Safety Follow-up Visit.
x At the Safety Follow-up Visit, the assessment will be 
required only for subjects with an abnormal value 
(clinical chemistry or hematology) or reading (ECG) at 
the previous clinic visit.
x Blood sample for clinical chemistry/hematology 
drawn at Taper Visit and Safety Follow-up 
Visit.
x For both the Taper Visit and Safety Follow-up 
Visit: blood sample for clinical 
chemistry/hematology collection will be 
required for subjects with a clinically 
significant abnormal value at the previous clinic 
visit. For non-clinically significant 
abnormalities, repeat of these assessments are at 
the discretion of the investigator.
If the laboratory values are 
normal at End of 
Maintenance, there is no 
need to repeat as early as 4 
days later at the Taper 
Visit when the study drug 
is being tapered. 
Section 6.1
Inclusion Criterion 6: 
x Subject has uncontrolled partial-onset seizures after an 
adequate course of treatment (in the opinion of the 
investigator) with ≥2 AEDs (concurrently or 
sequentially).
Remove Inclusion Criterion 6
x Inclusion Criterion 9 
targets the population of 
interest with regard to 
concomitant AEDs. 
x Requiring subjects to fail 
2 or more AEDs is an 
impediment for 
recruiting younger 
subjects.
Section 6.1
Inclusion Criterion 8: 
x Subject has ≥2 partial-onset seizures with or without 
secondary generalization during the 72-hour Baseline 
video-EEG.
Revise Inclusion Criterion 8a: 
x Subject has ≥2 partial-onset seizures with or 
without secondary generalization during the 
End-of-Baseline video-EEG.
Duration of End-of-
Baseline video-EEG is 
explained elsewhere. 
Section 6.2
Exclusion Criterion 1: 
x Subject has previously participated in this study.
Revise Exclusion Criterion 1a: 
x Subject has been previously randomized in this 
study (re-screening for screen-failed subjects is 
only allowed with prior consultation and 
permission of the medical monitor). 
Clarify that re-screening is 
allowed for screen failed 
subjects who have not been
previously randomized in 
SP0967 (see Exclusion 
Criterion 4a).
Section 6.2
Exclusion Criterion 4: 
x Subject has been previously treated with LCM.
Revise Exclusion Criterion 4a: 
x Subject has been previously treated with LCM 
and the LCM treatment was stopped due to lack 
of efficacy or adverse event(s).
Clarify exclusion of 
subjects previously treated 
with LCM  
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 122 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.2
Exclusion Criterion 8: 
x Subject is on a ketogenic or other specialized diet for the 
treatment of epilepsy. If the subject was on a ketogenic 
or other specialized diet in the past, they must be off this 
diet for ≥2 months prior to Visit 1.
Revise Exclusion Criterion 8a: 
x Subject is on a ketogenic diet that has either 
changed within the 4 weeks prior to Visit 1 or is 
expected to change during the study.
x As long as a ketogenic 
diet is stable, the subject 
should be allowed into 
the study. 
x Treatment of ketogenic 
diet eligibility should be 
similar to VNS use 
eligibility (Inclusion 
Criterion 10).
Section 6.2
Exclusion Criterion 9: 
x Subject has an alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or total bilirubin level 
≥2 times the upper limit of normal (ULN), or creatinine 
clearance <30mL/minute.
Revised Exclusion Criterion 9a: 
x Subject has creatinine clearance <30mL/minute.
x Update to UCB protocol 
template text.
x Exclusion of subjects 
with abnormal ALT, 
AST, or bilirubin now 
covered by new 
Exclusion Criterion 22.
Section 6.2
Exclusion Criterion 15: 
x Subject has a current diagnosis of Lennox-Gastaut 
syndrome, epilepsia partialis continua, primary 
generalized epilepsy, or seizures that are not of partial-
onset origin.
Revise Exclusion Criterion 15a: 
x Subject has a current diagnosis of Lennox-
Gastaut syndrome, epilepsia partialis continua, 
primary generalized epilepsy, Dravet 
Syndrome, or seizures that are not of partial-
onset origin.
A subject could have 
partial-onset seizures but 
also have generalized 
seizures. LCM can 
exacerbate generalized 
seizures in subjects with 
Dravet Syndrome in this 
age category.
Section 6.2
Exclusion Criterion 16: 
x Subject has a history of status epilepticus ≤2 months 
prior to Screening (Visit 1).
Revise Exclusion Criterion 16a: 
x Subject has a history of generalized convulsive 
status epilepticus ≤2 months prior to Screening 
(Visit 1).
x Clarify type of status 
epilepticus history that 
would be excluded
x Generalized convulsive 
status epilepticus has the 
highest associated 
morbidity and mortality; 
therefore, only subjects 
with a history of this 
type of status epilepticus 
will be excluded. 
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 123 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.2
Exclusion Criterion 17: 
x Subject has been treated with ethosuximide.
Remove Exclusion Criterion 17 
x Subjects with IGE are 
excluded per Exclusion 
Criterion 15. 
x Ethosuximide is 
generally only used for 
treatment of generalized 
seizures. 
Section 6.2
Exclusion Criterion 18: 
x Subject is currently being treated with vigabatrin or has 
discontinued use <12 months prior to Visit 1. Subjects 
who were previously treated with vigabatrin and have 
discontinued use >12 months prior to Visit 1 are eligible.
Remove Exclusion Criterion 18.
x The risks with vigabatrin 
use are higher with long-
term treatment. SP0967 
is only 27 days of LCM 
treatment. 
x This criterion was 
removed from long-term, 
open-label extension to 
SP0967 (EP0034).
Section 6.2
Exclusion Criterion 21: 
x Subject has a known sodium channelopathy, such as 
Brugada syndrome
Revise Exclusion Criterion 21a: 
x Subject has a known cardiac sodium 
channelopathy, such as Brugada syndrome
Clarification of the 
exclusion criterion. 
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 124 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.2
NA
New Exclusion Criterion 22:
x Subject has >2x upper limit of normal (ULN) of 
any of the following: alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), or >ULN total 
bilirubin (≥1.5xULN total bilirubin if known 
Gilbert’s syndrome). If subject has elevations 
only in total bilirubin that are >ULN and 
<1.5xULN, fractionate bilirubin to identify 
possible undiagnosed Gilbert’s syndrome (ie, 
direct bilirubin <35%).
x For randomized subjects with a Baseline result 
>ULN for ALT, AST, ALP, or total bilirubin, a 
Baseline diagnosis and/or the cause of any 
clinically meaningful elevation must be 
understood and recorded in the electronic Case 
Report form (eCRF).
x If subject has >ULN ALT, AST, or ALP that 
does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to 
ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant 
increase, inclusion of the subject must be 
discussed with the Medical Monitor.
x Tests that result in ALT, AST, or ALP up to 
25% above the exclusion limit may be repeated 
once for confirmation. 
Provide more detailed 
eligibility criteria to align 
with FDA guidance 
regarding PDILI.
REDACTED 
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05 Apr 2018
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Lacosamide
SP0967
Confidential
Page 125 of 144
Protocol 
Section(s) 
impacted
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Key components of revised protocol text
Rationale
Section 6.3
Section 7.2.2
Section 8.3
Must Withdrawal Criterion 1:
x Subject experiences intolerable AEs, including clinically 
relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation 
in the study. 
x Subjects who are unable to tolerate study medication 
will be withdrawn from the study as follows:
 Subjects unable to achieve or maintain target dose 
for the final 3 days of the Titration Period
 Subjects who require dose reduction during the 
Maintenance Period
Section 7.2.2 and Section 8.3:
x Subjects who require dose reduction during the 
Maintenance Period will be withdrawn from the study 
and enter the blinded Taper Period.
Revise must Withdrawal Criterion 1:
x Subject experiences intolerable AEs, including 
clinically relevant abnormal laboratory findings 
that, in the opinion of the investigator, preclude 
further participation in the study. 
x Subjects who are unable to tolerate study 
medication will be withdrawn from the study as 
follows:
 Subjects unable to achieve or maintain 
target dose for the final 3 days of the 
Titration Period
x Text removed from Section 7.2.2 and Section 
8.3 
x The patient can still 
contribute valuable 
efficacy and safety data 
even if they need a dose 
reduction. 
x This patient will be 
included the Full 
Analysis Set but not 
included in the Per-
Protocol set.
Section 6.3
x Must Withdrawal Criterion 8:
 Subject has liver function test (LFT) results for 
transaminases (AST, ALT, or both) ≥3xULN to 
<5xULN and total bilirubin ≥2xULN, or 
transaminases (AST, ALT, or both) ≥5xULN. In 
such instances, the study medication 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.
x May Withdrawal Criterion 4:
 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 
study medication.
x Remove must Withdrawal Criterion 8.
x Remove may Withdrawal Criterion 4.
x Withdrawal criteria 
related to liver function 
tests now covered in new 
Section 6.3.1.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 126 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.3
Must Withdrawal Criterion 9:
x Subject requires a change in concomitant AED daily 
dose or a change in VNS setting.
Remove must Withdrawal Criterion 9.
x The patient can still 
contribute valuable 
efficacy and safety data 
even if they need a 
change in dose or VNS 
setting. 
x This patient will be 
included the Full 
Analysis Set but not 
included in the Per-
Protocol set.
Section 6.3
Must Withdrawal Criterion 10:
x Subject initiates a ketogenic diet.
Remove must Withdrawal Criterion 10.
x Per Exclusion Criterion 
8, a patient’s ketogenic 
diet must remain stable. 
x Due to the short duration 
of this study, it is 
unlikely that a subject 
would initiate a 
ketogenic diet. 
x Should a ketogenic diet 
be initiated in violation 
of the exclusion 
criterion, the patient will 
be included in the Full 
Analysis Set but not 
included in the Per-
Protocol set.
Section 7.8.1
However, use of BZDs for any reason other than a stable 
daily dosage regimen as concomitant AED within 24 
hours prior to or during the video-EEG is not permitted 
and may lead to the subject being withdrawn from the 
study (Withdrawal Criterion 15; Section 6.3).
Text revised:
x However, use of BZDs for any reason other 
than a stable daily dosage regimen as 
concomitant AED within 24 hours prior to or 
during the video-EEG is not permitted and may 
lead to the subject being withdrawn from the 
study (MAY Withdrawal Criterion 5; Section 
6.3).
Correct Withdrawal 
Criterion cross reference 
number. 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 127 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.3
x Investigators should attempt to obtain information for 
subjects who withdraw or discontinue. 
x The Case Report form (CRF) must document the 
primary reason for withdrawal or discontinuation.
Text revised: 
x Investigators should attempt to obtain 
information for subjects who withdraw. 
x The eCRF must document the primary reason 
for withdrawal.
Update to UCB protocol 
template text.
New Section 
6.3.1
NA
New Section 6.3.1: Potential drug-induced liver 
injury IMP discontinuation criteria
x Subjects with potential drug-induced liver 
injury (PDILI) must be assessed to determine if 
IMP must be discontinued. In addition, all 
concomitant medications and herbal 
supplements that are not medically necessary 
should also be discontinued. 
x The PDILI criteria below require immediate 
and permanent discontinuation of IMP: 
 Subjects with either of the following:
◦ ALT or AST ≥5xULN
◦ ALT or AST ≥3xULN and coexisting total 
bilirubin ≥2xULN 
x Update to UCB protocol 
template text.
x Sponsor language for 
monitoring of PDILI 
events was added to 
increase clarity for the 
sites and to align across 
programs. Addition of 
this language is to align 
with FDA guidance 
regarding monitoring of 
PDILI events and does 
not reflect a change in 
the liver safety signal for 
LCM.
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 128 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
New Section 
6.3.1 (continued)
NA
New Section 6.3.1: Potential drug-induced liver 
injury IMP discontinuation criteria 
(continued)
x The PDILI criterion below requires immediate 
discontinuation of IMP:
 Subjects with ALT or AST ≥3xULN who 
exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis 
symptoms include fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness. 
Hypersensitivity symptoms include fever 
(without clear alternative cause), rash, or 
eosinophilia (ie, >5%).
 The PDILI criterion below allows for 
subjects to continue on IMP at the discretion 
of the investigator. 
 Subjects with ALT or AST ≥3xULN (and 
≥2x Baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with 
no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness).
(continued)
REDACTED 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 129 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
New Section 
6.3.1 (continued)
NA
New Section 6.3.1: Potential drug-induced liver 
injury IMP discontinuation criteria 
(continued)
x Evaluation of PDILI must be initiated as 
described in Section 8.3.2. If subjects are 
unable to comply with the applicable 
monitoring schedule, IMP must be discontinued 
immediately.
x Investigators should attempt to obtain 
information on subjects in the case of IMP 
discontinuation to complete the final evaluation. 
Subjects with PDILI should not be withdrawn 
from the study until investigation and 
monitoring are complete. All results of these 
evaluations and observations, as well as the 
reason(s) for IMP discontinuation and subject 
withdrawal (if applicable), must be recorded in 
the source documents. The eCRF must 
document the primary reason for IMP 
discontinuation.
(continued)
Section 7.2.4
NA
x Text added:
x Taper of LCM may not be required for some 
subjects who are on the lowest dose of study 
medication or who need to discontinue study 
medication abruptly, depending on the 
treatment option selected by the investigator in 
consultation with the medical monitor.
x If a subject received 
study medication at a 
dose of 2mg/kg/day and 
discontinued, a taper 
would not be required. 
x In case there is a need to 
immediately switch the 
subject to a different 
AED, the protocol would 
allow immediate 
discontinuation from 
LCM. 
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 130 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 7.5
x Investigational medicinal product stored by the
investigator is to be kept in a secured area with limited 
access.
x Appropriate storage conditions must be ensured either 
by controlled room temperature or by completion of a 
temperature log in accordance with local requirements 
on a regular basis, showing minimum and maximum 
temperatures reached over the time interval.
x In case an out of range temperature is noted, it must be 
immediately communicated in accordance with the 
pharmacy manual.
Text revised:
x Investigational medicinal product stored by the 
investigator is to be kept in a secured area with 
limited access according to the storage 
conditions mentioned on the label.
x Appropriate storage conditions must be ensured 
either by controlling the temperature or by 
completion of a temperature log in accordance 
with local requirements on a regular basis, 
showing minimum and maximum temperatures 
reached over the time interval.
x In case an out-of-range temperature is noted, it 
must be immediately reported as per 
instructions contained in the IMP Handling 
Manual.
Update to UCB protocol 
template text.
Section 7.6
x Details of any IMP lost (due to breakage or wastage), 
not used, or returned to the sponsor or designee must 
also be recorded on the appropriate forms. 
x 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’s designee, preferably in their original 
package. 
Text revised:
x Details of any IMP lost, damaged (due to 
breakage or wastage), not used, partially used, 
disposed of at the study site, or returned to the 
sponsor or designee must also be recorded on 
the appropriate forms.
x Periodically, and/or after completion of the 
clinical phase of the study, all used (including 
empty containers/partially used), unused, 
damaged, and/or expired IMP must be 
reconciled and either destroyed at the site 
according to local laws, regulations, and UCB 
SOPs or returned to UCB’s designee. 
Update to UCB protocol 
template text.
Section 7.8.1
Subjects must have been maintained on a stable dosage 
regimen of 1 to 3 marketed AEDs for ≥2 weeks prior to 
Visit 1 (ie, prior to entry into the Baseline Period). 
Text revised:
x Subjects must have been maintained on a stable 
dosage regimen of 1 to 3 marketed AEDs for ≥2 
weeks prior to Visit 1 (ie, prior to initiation of 
Baseline video-EEG monitoring) 
Timing of stable AED 
dosing clarified. 
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 131 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 7.8.1
x The following concomitant medications are prohibited 
during the study:
 
Neuroleptics 
 
Monoamine oxidase inhibitors 
 
Barbiturates (except as AEDs)
 
Narcotic analgesics 
Text revised:
x The following concomitant medications are 
prohibited during the study:
 
Clozapine
 
Monoamine-A oxidase inhibitors 
 
Barbiturates (except as AEDs)
 
Cannabidiols (not approved or indicated 
for epilepsy by local health authority)
x Neuroleptics (except for clozapine) are allowed 
during the study but the investigator should 
make every effort to keep the dose stable. 
x Other medications are permitted according to 
current clinical standards (eg, topical 
anesthetic).
x Clozapine is the only 
neuroleptic that lowers 
seizure threshold.
x Clarification made to 
note that prohibited 
medication refers to 
MAO-A inhibitors.
x Majority of narcotic 
analgesics do not lower 
seizure threshold and, 
therefore, should not 
interfere with efficacy 
evaluations. In the rare 
instance they are used in 
association with an AE, 
the reason for use would 
be recorded.
x Cannibidiols that are 
approved or indicated 
will count as a 
concomitant AED.
x Revisions in prohibited 
medications to allow use 
of medications to those 
patients who may need 
it.
Section 7.8.1 
(continued)
x The following medications are not allowed unless used 
as described: 
 
Amphetamines and sedative antihistamines: 
stable use only.
Text revised:
x The following medications are not allowed 
unless used as described: 
 
Amphetamines: stable use only. 
x Antihistamines should be 
allowed for treatment of 
URTI. 
x They are not expected to
have an effect on 
efficacy or safety 
evaluations.
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 132 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 7.8.1
Subjects who have been treated with ethosuximide are 
excluded from the study. Subjects who are currently being 
treated with vigabatrin or have discontinued vigabatrin use 
<12 months prior to Visit 1 are excluded from the study. 
Subjects who were previously treated with vigabatrin and 
have discontinued use >12 months prior to Visit 1 are 
eligible. Concomitant use of either vigabatrin or 
ethosuximide during the course of the study is prohibited.
Text removed.
Text removed for 
consistency with changes 
to Exclusion Criteria 17 
and 18. 
New Section 
11.1.6
NA
New Section 11.1.6: Suspected transmission of 
an infectious agent via a medicinal product
x For the purposes of reporting, any suspected 
transmission of an infectious agent via a 
medicinal product should be considered as an 
SAE; such cases must be reported immediately, 
recorded in the AE module of the eCRF, and 
followed as any other SAE. Any organism, 
virus, or infectious particle (eg, prion protein 
transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, 
is considered an infectious agent.
x Subsequent Sections 11.1.7 and 11.1.8 
renumbered.
Update to UCB protocol 
template text.
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 133 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 11.2.1
(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.)
Text revised:
x (Important medical events may include, but are 
not limited to, potential Hy’s Law [see Section 
11.3], 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.)
x Update to UCB protocol 
template text.
x Sponsor language for 
monitoring of PDILI 
events was added to 
increase clarity for the 
sites and to align across 
programs. Addition of 
this language is to align 
with FDA guidance 
regarding monitoring of 
PDILI events and does 
not reflect a change in 
the liver safety signal for 
LCM.
Section 11.2.3
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. 
Text revised:
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. This follow-up 
requirement applies to AEs, SAEs, and AEs of 
special interest; further details regarding follow 
up of PDILI events are provided in Section 
11.6.1.4.
x Update to UCB protocol 
template text.
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 134 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 11.3
NA
New text:
x Potential Hy’s Law, defined as ≥3xULN ALT 
or AST with coexisting ≥2xULN total bilirubin 
in the absence of ≥2xULN ALP, with no 
alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to 
UCB as an AE of special interest (ie, without 
waiting for any additional etiologic 
investigations to have been concluded). Follow-
up information should then be reported if an 
alternative etiology is identified during 
investigation and monitoring of the subject.
x Update to UCB protocol 
template text.
x Sponsor language for 
monitoring of PDILI 
events was added to 
increase clarity for the 
sites and to align across 
programs. Addition of 
this language is to align 
with FDA guidance 
regarding monitoring of 
PDILI events and does 
not reflect a change in 
the liver safety signal for 
LCM.
Section 11.5
x 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 
(Table 11‒1) will remain in effect for the duration of the 
protocol.
x Pregnancy, puerperium and perinatal disorders: Abortion 
spontaneous
x Reproductive system and breast disorders: Menstrual 
disorder
Text revised:
x The following list of Anticipated SAEs (Table 
11‒1) is anticipated to occur in the population 
studied in this protocol at some frequency that 
is independent of drug exposure.
x Removal of pregnancy, puerperium and 
perinatal disorders: Abortion spontaneous 
x Removal of reproductive system and breast 
disorders: Menstrual disorder
x Update to UCB protocol 
template text.
x Updated based on patient 
population of this study
Section 14.1
Prior to participation in the study, the written Informed 
Consent form should be signed and personally dated by 
the subject’s legal representative(s), and by the person 
who conducted the informed consent discussion 
(investigator or designee).
Text revised:
x Prior to participation in the study, the Informed 
Consent form should be signed and personally 
dated by the subject’s legal representative(s), 
and by the person who conducted the informed 
consent discussion (investigator or designee).
Update to UCB protocol
template text.
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 135 of 144
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 11.6.1 
(formerly Section 
11.7)
Section 11.7  Liver function tests
x Refer to Section 6.3 for LFT withdrawal criteria.
x Transaminases (AST, ALT, or both) ≥3×ULN but 
<5×ULN, in the presence of total bilirubin ≥2×ULN, or 
transaminases (AST, ALT, or both) ≥5×ULN will result 
in immediate discontinuation of study medication 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.
x 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 study 
medication.
x In all cases of transaminases (AST, ALT, or both) 
≥3xULN, testing for hepatitis A, B, and C will be done.
x 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 study medication.
Section 11.6.1  Liver function tests and 
evaluation of PDILI
x Original text removed and replaced with more 
detailed text about the evaluation of PDILI:
 Table 11‒1: Required investigations and 
follow up of PDILI
 Section 11.6.1.1 Consultation with Medical 
Monitor and local hepatologist
 Section 11.6.1.2 Immediate action: 
determination of IMP discontinuation
 Section 11.6.1.3 Testing: 
identification/exclusion of alternative 
etiology
 Table 11‒2: PDILI laboratory measurements
 Table 11‒3: PDILI information to be 
collected
 Section 11.6.1.4 Follow-up evaluation
x Subsequent sections renumbered.
x Update to UCB protocol 
template text.
x Sponsor language for 
monitoring of PDILI 
events was added to 
increase clarity for the 
sites and to align across 
programs. Addition of 
this language is to align 
with FDA guidance 
regarding monitoring of 
PDILI events and does 
not reflect a change in 
the liver safety signal for 
LCM.
Administrative 
updates
x CRF
x Drug Safety
x ICH=International Conference on Harmonisation
x More than 40 million people suffer from epilepsy–about 
1% of the world’s population (Dichek, 1999).
Text revised:
x eCRF
x Patient Safety
x ICH=International Council for Harmonisation
x Updated list of abbreviations
x Updated list of references
x It is estimated that almost 70 million people 
suffer from epilepsy (Ngugi et al, 2011).
NA
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05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 136 of 144
17.3
AMENDMENT 3
Rationale for the amendment
The primary purpose of this substantial amendment is to address the high variability in video-
EEG seizure counts between the site and central reader by removing the central reader. This 
change was proposed by the FDA as part of a Type C meeting written response obtained on 
25 January 2018.
Additional changes in Protocol Amendment 3 included the following:
x Update clinical trial biostatistician contact
x Update of the regulatory status of LCM in the US and EU
x Clarify the planned number of subjects per age group to reflect UCB’s commitment to make 
every attempt to enroll subjects <2 years of age while recognizing the difficulty of enrolling 
this age group
x Prevent ineligibility of an otherwise eligible subject who has undergone the baseline EEG 
due to the narrow visit window for central laboratory measurements
x Clarify that “seizure-free” status during the Maintenance Period will be summarized by 
(1) all seizure types and (2) partial-onset seizure types only
x Update hematology and chemistry measurements for the assessment of PDILI events
x Replace Markov chain Monte Carlo multiple imputation method with a more appropriate 
monotone regression method 
x Add age group to the analysis of the primary efficacy variable since randomization is 
stratified by age group
The following table summarizes each change with the associated rationale.
REDACTED 
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 137 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
STUDY 
CONTACT 
INFORMATION
Clinical Trial Biostatistician
, MA
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES
Clinical Trial Biostatistician
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES
Update clinical trial 
biostatistician contact
Section 1.0
Section 5.1
Table 5-1
Section 9.1
Section 13.1.1
a central reader
locally by the investigator, subinvestigator, or 
qualified designated reader
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the 
video-EEG seizure count
Section 2.0
Lacosamide has been approved as monotherapy or 
adjunctive therapy in the treatment of partial-onset 
seizures in patients 17 years of age and older in the US 
(tablets, oral solution, and solution for intravenous [iv] 
infusion) and as adjunctive therapy in the treatment of 
partial-onset seizures with or without secondary 
generalization in adult and adolescent (16 to 18 years of 
age) patients with epilepsy in the EU (tablets, oral 
solution, and solution for iv infusion).
In the US, LCM has been approved as 
monotherapy and adjunctive therapy in the 
treatment of partial-onset seizures in patients 
4 years of age and older for tablets and oral 
solution, and 17 years of age and older for 
intravenous [iv] infusion. In the EU, LCM has 
been approved as monotherapy and adjunctive 
therapy in the treatment of partial-onset seizures 
with or without secondary generalization in 
adults, adolescents, and children from 4 years of 
age with epilepsy (tablets, oral solution, and 
solution for iv infusion).
Update of the regulatory 
status of LCM in the US 
and EU
Section 4.1.2
x 
Proportion of subjects who achieved “seizure-free” 
status (yes/no) for subjects who completed at least 48 
hours of interpretable video-EEG recording during the 
End-of-Maintenance Period video-EEG
x 
Proportion of subjects who achieved 
“seizure-free” status (yes/no) from all seizure 
types, and from partial-onset seizure types 
only for subjects who completed at least 48 
hours of interpretable video-EEG recording 
during the End-of-Maintenance Period video-
EEG
Clarify that “seizure-free” 
status during the 
Maintenance Period will 
be summarized by (1) all 
seizures types and (2) 
partial-onset seizures only
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 138 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 5.1
Assessment of video-EEG seizure count for verification of 
selection criteria will be performed by the investigator, but 
for the purpose of study analyses will be performed by a 
central EEG reader.
Assessment of video-EEG seizure count will be 
performed locally by the investigator, 
subinvestigator, or qualified designated reader for 
the purpose of both assessment of eligibility and 
study analyses.
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the 
video-EEG seizure count
Section 5.1.2
Of these (n=122), a minimum target of 20% (n=25) of 
subjects will be enrolled in each of the 3 age categories: 
≥1 month to <6 months, ≥6 months to <1 year, and ≥1 
year to <2 years.
Subjects will be enrolled in the following age categories as 
detailed below:
Of these (n=122), every attempt will be made to 
enroll a minimum target of 20% (n=25) of 
subjects in each of the 3 age categories: ≥1 month 
to <6 months, ≥6 months to <1 year, and ≥1 year 
to <2 years.
Every attempt will be made to enroll subjects in 
the following age categories as detailed below:
Clarify the planned 
number of subjects per age 
group to reflect UCB’s 
commitment to make every 
attempt to enroll subjects 
<2 years of age while 
recognizing the difficulty 
of enrolling this age group
Table 5-1
(footnote i)
The video-EEG (up to 72 hours of continuous recording 
with every attempt to obtain at least 48 hours of
interpretable recording) will be conducted in an inpatient 
setting. Upon completion of the End-of-Baseline video-
EEG (Visits 2 and 3), the investigator will assess the 
electrographic seizure count and confirm the selection 
criteria have been met. If the subject meets all selection 
criteria, including the requisite number of seizures based 
on the video-EEG data, the subject may be randomized at 
Visit 3. All video EEG data recordings will be transmitted 
to a central reader for the purposes of data analysis. The 
End-of-Maintenance Period video-EEG will be done at 
Visit 6. Subjects who discontinue on or before Day 20 will 
not require a video-EEG.
The video-EEG (up to 72 hours of continuous 
recording with every attempt to obtain at least 
48 hours of interpretable recording) will be 
conducted in an inpatient setting. Upon 
completion of the End-of-Baseline video-EEG 
(Visits 2 and 3), the investigator will assess the 
electrographic seizure count and confirm the 
selection criteria have been met. If the subject 
meets all selection criteria, including the requisite 
number of seizures based on the video-EEG data, 
the subject may be randomized at Visit 3. 
Assessment of video-EEG seizure count will be 
performed locally by the investigator, 
subinvestigator, or qualified designated reader for 
the purpose of both assessment of eligibility and 
study analyses. The End-of-Maintenance Period 
video-EEG will be done at Visit 6. Subjects who 
discontinue on or before Day 20 will not require a 
video-EEG.
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the 
video-EEG seizure count
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 139 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 6.1 
(IC 8a)
Subject has ≥2 partial-onset seizures with or without 
secondary generalization during the End-of-Baseline 
video-EEG.
Subject has ≥2 partial-onset seizures with or 
without secondary generalization during the 
End-of-Baseline video-EEG. Electrographic 
seizures are defined as recognizable ictal patterns 
on an EEG involving ≥2 contiguous electrodes. 
The seizures are initiated as a unilateral or 
strongly asymmetric abnormal epileptiform 
discharge lasting a total of >10 seconds.
Provide clarity by 
including the definition of 
electrographic seizures
Section 8.1.2
From Visit 2 (Day -3 to Day -1) to Visit 3 (Day 1), an 
End-of-Baseline video-EEG (up to 72 hours of continuous 
recording with every attempt to obtain at least 48 hours of 
interpretable recording) will be performed. The Day -3
assessments should be conducted prior to the start of 
video-EEG monitoring. The video-EEG will be conducted 
in an inpatient setting.  Upon completion of the End-of-
Baseline video-EEG (Visits 2 and 3), the investigator will 
assess the electrographic seizure count and confirm the 
selection criteria have been met. If the subject meets all 
selection criteria, including the requisite number of 
seizures based on the End-of-Baseline video-EEG data, 
the subject may be randomized at Visit 3.
From Visit 2 (Day -3 to Day -1) to Visit 3 (Day 
1), an End-of-Baseline video-EEG (up to 72 hours 
of continuous recording with every attempt to 
obtain at least 48 hours of interpretable recording) 
will be performed. The Day -3 assessments 
should be conducted prior to the start of video-
EEG monitoring. The video-EEG will be 
conducted in an inpatient setting.  Upon 
completion of the End-of-Baseline video-EEG 
(Visits 2 and 3), the investigator will assess the 
electrographic seizure count and confirm the 
selection criteria have been met. If the subject 
meets all selection criteria, including the requisite 
number of seizures based on the End-of-Baseline 
video-EEG data, the subject may be randomized 
at Visit 3. Assessment of the video-EEG seizure 
count will also be performed locally by the 
investigator, subinvestigator, or qualified 
designated reader for the purpose of study 
analyses; however, completion of this review is 
not required prior to randomization.
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the
video-EEG seizure count
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 140 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 8.3.1
The Day 24 assessments should be conducted prior to the 
start of the End-of Maintenance Period video-EEG 
monitoring (up to 72 hours of continuous recording with 
every attempt to obtain at least 48 hours of interpretable 
recording). The following assessments will be performed 
on Day 24 for all subjects:
The Day 24 assessments should be conducted 
prior to the start of the End-of Maintenance 
Period video-EEG monitoring (up to 72 hours of 
continuous recording with every attempt to obtain 
at least 48 hours of interpretable recording). 
Assessment of video-EEG seizure count will be 
performed locally by the investigator, 
subinvestigator, or qualified designated reader for 
the purpose of the study analyses. The following 
assessments will be performed on Day 24 for all 
subjects:
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the 
video-EEG seizure count
Section 9.1
Section 13.1.1
The video-EEG recordings will be evaluated by a central 
reader.
The video-EEG recordings will be evaluated for 
seizure counts locally by the investigator, 
subinvestigator, or qualified designated reader.
Address the high 
variability in video-EEG 
seizure counts between the 
site and the central reader; 
clarify who is responsible 
for the assessment of the 
video-EEG seizure count
Section 11.6
Blood specimens for routine assay of hematology and 
clinical chemistry testing will be collected according to the 
tabular schedule of study procedures (Section 5.2). A 
central laboratory will perform the routine analysis of 
blood specimens. The procedures for handling and 
shipping these specimens will be provided to the sites.
Blood specimens for routine assay of hematology 
and clinical chemistry testing will be collected 
according to the tabular schedule of study 
procedures (Section 5.2). A central laboratory will 
perform the routine analysis of blood specimens. 
The procedures for handling and shipping these 
specimens will be provided to the sites. In 
exceptional circumstances, local laboratory 
analysis may be performed. The medical monitor 
should be contacted beforehand to discuss these 
circumstances.
Prevent ineligibility of an 
otherwise eligible subject 
who has undergone the 
baseline EEG due to the 
narrow visit window for 
central laboratory 
measurements
Table 11-4
Hematology measurements: Eosinophil count
Hematology measurements: Hematocrit, 
Hemoglobin, Platelet count, RBC count, WBC 
count, and Differential count
Update hematology 
measurements for the 
assessment of PDILI 
events
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 141 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Table 11-4
Chemistry measurements: Amylase, If total bilirubin 
≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin, and Serum CPK and LDH to evaluate possible 
muscle injury causing transaminase elevation
Chemistry measurements: Amylase, Bilirubin (if 
total bilirubin ≥1.5xULN, obtain fractionated 
bilirubin to obtain % direct bilirubin), Serum CPK 
and LDH to evaluate possible muscle injury 
causing transaminase elevation, AST, ALT, ALP, 
GGT, and Albumin
Clarify and add chemistry 
measurements for the 
assessment of PDILI 
events
Section 13.1.1.1
Seizure ADF will be analyzed using analysis of covariance 
with terms for treatment and center (properly pooled), on 
log-transformed seizure ADF using the transformation of 
ln (X+1), where X is the seizure ADF.
Seizure ADF will be analyzed using analysis of 
covariance with terms for treatment, age category 
(4 age stratification categories, pooled as 
appropriate), center (properly pooled), on log-
transformed seizure ADF using the 
transformation of ln (X+1), where X is the seizure 
ADF.
Add age group to the 
analysis of the primary 
efficacy variable since 
randomization is stratified 
by age group
Section 13.1.1.1
Section 13.1.1.2
x 
Repeat the primary analysis using the FAS, except 
missing ADF of partial-onset seizures from the End-
of-Maintenance Period video-EEG will be replaced 
using multiple imputation by treatment arm and age 
group (≥1 month to <6 months of age, ≥6 months to 
<1 year of age, ≥1 year to <2 years of age, and ≥2 
years to <4 years of age) using a Markov chain Monte 
Carlo method assuming a log-normal distribution.
x 
Repeat the primary analysis using the FAS, 
except missing ADF of partial-onset seizures 
from the End-of-Maintenance Period video-
EEG will be replaced using multiple 
imputation by treatment arm and age group 
(≥1 month to <6 months of age, ≥6 months to 
<1 year of age, ≥1 year to <2 years of age, 
and ≥2 years to <4 years of age) using 
monotone regression.
Replaced Markov chain
Monte Carlo multiple 
imputation method with a 
more appropriate 
monotone regression 
method; further details to 
be described in the 
statistical analysis plan
Section 13.1.1.2
The proportion of responders between LCM and PBO will 
be analyzed using logistic regression with center (properly 
pooled) as a factor.
The proportion of responders between LCM and 
PBO will be analyzed using logistic regression 
with age category (4 age stratification categories, 
pooled as appropriate) and center (properly 
pooled) as factors.
Add age group to the 
analysis of the primary 
efficacy variable since 
randomization is stratified 
by age group
Section 13.1.2
For subjects who complete the Maintenance Period, the 
number and percentage of subjects who achieved “seizure-
free” status during the Maintenance Period will be 
tabulated and presented by treatment group.
For subjects who complete the Maintenance 
Period, the number and percentage of subjects 
who achieved “seizure-free” status from all 
seizure types, and from partial-onset seizure types 
only during the Maintenance Period will be 
tabulated and presented by treatment group.
Clarify that “seizure-free” 
status during the 
Maintenance Period will 
be summarized by (1) all 
seizures types and (2) 
partial-onset seizures only
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 142 of 144
Appendix Table 2: Summary of changes in SP0967 Amendment 3
Protocol 
Section(s) 
impacted
Key components of previous protocol text
Key components of revised protocol text
Rationale
Section 13.6
Subjects are randomized into the study based on the 
investigator’s interpretation of the video EEG to meet 
study entry requirements; however, there may be a 
difference of interpretation of the number of seizures 
counted on the End-of-Baseline Period video-EEG 
between the central reader and the investigator.
Subjects are randomized into the study based on 
the initial interpretation of the video-EEG to meet 
study entry requirements. However, the 
subsequent detailed assessment of seizure types 
and counts needed for the efficacy analyses could 
lead to a discrepancy in seizure counts (ie, a 
subject initially thought to be eligible is later 
found to have fewer than the required number of 
partial-onset seizures during the End-of-Baseline 
Period video-EEG). To account for an anticipated 
difference of interpretation of the End of Baseline 
Period video-EEG of 5% as well as the potential 
subject dropout rate of approximately 14%, the 
planned number of subjects to enroll is 
122 subjects per treatment arm.
To address removal of the 
central reader
AC
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UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 143 of 144
18
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 
Date/S
Date/S
PY
This document cannot be used to support any marketing authorization
Signa
ign
application 
atu
at
pp
and any extensions
be 
ation 
ation
ents w
nts w
or
trea
tre
variations thereof. 

UCB
05 Apr 2018
Clinical Study Protocol
Lacosamide
SP0967
Confidential
Page 144 of 144
19
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.
COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Approval Signatures
Name:
sp0967-protocol-amend-3
Version:
2. 0
Document Number:
CLIN-000116615
Title:
SP0967 protocol amendment 3
Approved Date:
15 Jun 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Jun-2018 11:27:25 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Jun-2018 12:02:34 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Jun-2018 13:00:15 GMT+0000
DACTED 
REDA
DA
OPY
App
App
CO
CO
This document cannot be used to supp
pport 
pp
any marketing 
ma
ma
n
p
uthorization 
n
ori
Nam
Ca
aut
ut
application 
p
roval
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and any extensions or variations thereof.