Conditions: Epilepsy
Keywords: Lacosamide Vimpat Epilepsy Children Primary Generalized Tonic Clonic seizures Idiopathic Generalized Epilepsy Adults
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 242
Healthy volunteers: no

Brief summary:
Evaluating efficacy \& safety of lacosamide versus Placebo in a blinded fashion as add-on Therapy for Primary Generalized Tonic-clonic (PGTC) seizures in subject 4 years of age or greater with idiopathic generalized epilepsy currently taking 1 to 3 antiepileptic drugs. Maximum duration of study drug administration is 28 weeks. Eligible subjects may choose to enter the open-label extension study after completion.

Detailed description:

Arms:
arm 1: Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day are allowed. Maximal dose 400 mg/day for adult subjects and pediatric subjects \>= 50 kg.

Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric subjects \< 30 kg.)

Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric subjects 30 kg to \< 50 kg.) arm 2: Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day are allowed. Maximal dose 400mg/day for adult subjects and pediatric subjects \>= 50kg.

Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric subjects \< 30kg.)

Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric subjects 30kg to \< 50kg.)

Interventions: intervention 1: Lacosamide Tablet intervention 2: Lasosamide Oral Solution intervention 3: Placebo Tablet intervention 4: Placebo Oral Solution
Intervention descriptions: intervention 1: * Active Substance: Lacosamide
* Pharmaceutical Form: Film-coated Tablet
* Concentration: 50 mg
* Route of Administration: Oral use intervention 2: * Active Substance: Lacosamide
* Pharmaceutical Form: Oral Solution
* Concentration: 10 mg/ml
* Route of Administration: Oral use intervention 3: * Active Substance: Placebo
* Pharmaceutical Form: Film-coated Tablet
* Concentration: 50 mg
* Route of Administration: Oral use intervention 4: * Active Substance: Placebo
* Pharmaceutical Form: Oral Solution
* Concentration: 10 mg/ml
* Route of Administration: Oral use

Protocol document:
Prot_001.pdf: 
UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 1 of 267
PROTOCOL SP0982 AMENDMENT 5
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF LACOSAMIDE AS 
ADJUNCTIVE THERAPY FOR UNCONTROLLED PRIMARY 
GENERALIZED TONIC-CLONIC SEIZURES IN SUBJECTS 
WITH IDIOPATHIC GENERALIZED EPILEPSY 
PHASE 3
EudraCT-Number: 2011-003100-21
IND Numbers: 57939 and 73809
Sponsor:
UCB BIOSCIENCES, Inc.,
8010 Arco Corporate Drive,
Raleigh, NC  27617,
UNITED STATES
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
05 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
09 Jan 2015
Non-substantial
Protocol Amendment 4
08 Jun 2016
Substantial
Protocol Amendment 5
07 Nov 2017
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
, NC
, N
NITED
NITED
AC
RE
COPY 
porate 
orate 
NC
This document
o
cannot 
Th
Th
be 
be used 
d to 
t 5
t 5
t
support 
po
su
any 
an marketing 
g
ke
m
authorization 
e D
2761
2761
D STA
STA
D
th
a
application 
nc.,
c.,
Drive
Drive
and any extensions or
CT
CT
variations 
RY
TS
TS
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 2 of 267
STUDY CONTACT INFORMATION
UCB BIOSCIENCES, Inc., 
8010 Arco Corporate Drive, 
Raleigh, NC  27617, USA
Sponsor Study Physician
Name:
 MD
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Email:
Clinical Project Manager
Name:
Address:
Allée de la Recherche 60
1070 Brussels
BELGIUM
Phone:
Email:
Clinical Trial Biostatistician 
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
USA
Phone:
Email:
REDACTED
he 60
he 6
RE
RE
COPY 
PY
0
C
This document cannot 
:
t
an
be 
b
used 
us
to suppo
80
8
pp
u
rt
pport any
cian
ian
a
ma
ma keting 
g
ket
etin
marke
authorization 
ion
a
application 
tio
pp
and 
an
any 
an extensions 
on or
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 3 of 267
Clinical Monitoring Contract Research Organization
Name:
Pharmaceutical Research Associates (PRA), Inc.
Address:
4130 Park Lake Avenue, Suite 400
Raleigh, NC 27612
USA
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
Interactive Response Technology
Name:
Perceptive eClinical Limited
Address:
Lady Bay House
Meadow Grove, Nottingham, NG23HF
UK
Phone:
+44 115 955 7333
Fax:
+44 115 955 7555
COPY 
OP
This document cannot be used to support any marketing authorization application 
on
lic
ap
and any extensions s
ns
ex
or 
o variations 
on
tio
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 4 of 267
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 2421
USA: +1 800 880 6949
or  +1 866 890 3175
Email
Global: DS_ICT@ucb.com
COPY 
This document cannot be used to support any marketing authorization application and any extensions 
sio
or 
or variations 
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 5 of 267
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................11
1
SUMMARY.....................................................................................................................13
2
INTRODUCTION ...........................................................................................................14
3
STUDY OBJECTIVES....................................................................................................16
3.1
Primary objective...................................................................................................16
3.2
Secondary objective...............................................................................................16
4
STUDY VARIABLES.....................................................................................................16
4.1
Efficacy variables...................................................................................................16
4.1.1
Primary efficacy variable.............................................................................16
4.1.2
Secondary efficacy variables .......................................................................16
4.1.3
Other efficacy variables...............................................................................16
4.2
Safety variables......................................................................................................18
4.3
Pharmacokinetic variable.......................................................................................18
5
STUDY DESIGN.............................................................................................................18
5.1
Study description ...................................................................................................18
5.1.1
Study duration per subject ...........................................................................21
5.1.2
Study completers..........................................................................................22
5.1.3
Planned number of subjects and sites ..........................................................22
5.1.4
Anticipated regions and countries................................................................22
5.2
Schedule of study assessments...............................................................................22
5.3
Schematic diagrams for SP0982............................................................................31
5.4
Rationale for study design and selection of dose...................................................36
5.4.1
Rationale for dose ........................................................................................36
5.4.2
Rationale for second PGTC seizure.............................................................37
5.4.3
Rationale for minimum duration of treatment .............................................37
5.4.4
Rationale for selected age range ..................................................................38
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................38
6.1
Inclusion criteria ....................................................................................................38
6.2
Exclusion criteria ...................................................................................................40
6.3
Exit criteria.............................................................................................................43
6.4
Withdrawal criteria ................................................................................................43
6.4.1
Potential drug-induced liver injury IMP discontinuation criteria................44
7
STUDY TREATMENTS.................................................................................................45
7.1
Description of investigational medicinal product..................................................45
7.2
Treatments to be administered...............................................................................45
7.2.1
Titration Period............................................................................................45
7.2.2
Maintenance Period .....................................................................................47
REDACTED 
....
....
cts and
cts and
nd cou
nd cou
ments
ments
COPY 
.....
.......
.....
This document 
7
cannot 
E
6.4
6.4
be
Exc
Exc
used 
N A
N A
clusio
lusio
to 
atio
AN
AN
support 
for
fo
ale for
ale fo
onale
onale
any
dose
dos
r sec
r se
marketing 
s.....
....
P0982
P0982
sign an
gn an
e
authorization 
....
....... .
d site
d site
untrie
ntrie
application 
.....
...
.......
....
.......
.....
.....
and 
......
....
any 
......
.....
extensions 
......
....
..............
......
....
or
.....
....
variations 
.16
16
1
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 6 of 267
7.2.3
Transition Period (for subjects who enter EP0012).....................................47
7.2.4
Taper Period.................................................................................................48
7.3
Packaging...............................................................................................................49
7.4
Labeling .................................................................................................................50
7.5
Handling and storage requirements .......................................................................50
7.6
Drug accountability................................................................................................50
7.7
Procedures for monitoring subject compliance......................................................51
7.8
Concomitant medication/treatment........................................................................51
7.8.1
Permitted concomitant treatments (medications and therapies) ..................51
7.8.2
Prohibited concomitant treatments (medications and therapies) .................51
7.9
Blinding..................................................................................................................52
7.9.1
Procedures for maintaining and breaking the treatment blind.....................52
7.9.1.1
Maintenance of study treatment blind................................................52
7.9.1.2
Breaking the treatment blind in an emergency situation....................52
7.10
Randomization and numbering of subjects............................................................53
8
STUDY PROCEDURES BY VISIT ...............................................................................53
8.1
Prospective Baseline Period...................................................................................53
8.1.1
Visit 1 (Week -4) .........................................................................................53
8.1.2
Telephone contact (Week -2).......................................................................54
8.2
Treatment Period....................................................................................................54
8.2.1
Visit 2 (Day 0) Randomization....................................................................55
8.2.2
Titration Period............................................................................................56
8.2.2.1
Week 1 to Week 6..............................................................................56
8.2.3
Maintenance Period .....................................................................................57
8.2.3.1
Visit 5 (end of Week 6)......................................................................57
8.2.3.2
Visit 6 (end of Week 8)......................................................................58
8.2.3.3
Visit 7 (end of Week 12)....................................................................59
8.2.3.4
Visit 8 (end of Week 16)....................................................................59
8.2.3.5
Visit 9 (end of Week 20)....................................................................60
8.2.3.6
Visit 10/ET Visit (end of Week 24)...................................................61
8.3
End of Study Period...............................................................................................62
8.3.1
Transition Period..........................................................................................62
8.3.1.1
Transition Clinic Visit/telephone contact ..........................................62
8.3.1.2
Final Clinic Visit................................................................................62
8.3.2
Taper and Safety Follow-up Period.............................................................63
8.3.2.1
End of Taper Visit..............................................................................63
8.3.2.2
Safety Follow-up Visit.......................................................................64
8.3.2.3
Safety Follow-up telephone contact...................................................64
REDACTED 
..
-2)....
-2)....
......
.....
ndomiz
ndomiz
COPY 
......
...
.......
......
This document cannot
E
8.8.
be
8.2.
8.2
E
used 
3.5
3.5
3
to support 
t 5
Visit 6 
isit 6
Visi
Visi
V
any 
erer
5 (end
 (end
marketing 
za
..........
........
Week 6
Week 
riod
riod
authorization 
.....
......
.........
.......
...........
ation
tion
application 
ncy
.......
.....
..........
...
...........
and 
.......
y sit
 sit
y
any
lind
ind
...
extensions
......
.....
........
......
..... .....
.....
d
or 
......
variations 
51
51
5
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 7 of 267
8.4
Unscheduled Visit..................................................................................................65
9
ASSESSMENT OF EFFICACY......................................................................................65
9.1
Primary efficacy variable.......................................................................................65
9.2
Secondary efficacy variables .................................................................................65
9.3
Other efficacy variables.........................................................................................65
9.3.1
Seizure variables..........................................................................................67
9.3.1.1
PGTC seizures ...................................................................................67
9.3.1.2
Absence and myoclonic seizures .......................................................67
9.3.2
Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P)..............................................................................................67
9.3.3
Pediatric Quality of Life Inventory..............................................................67
9.3.4
EQ-5D-3L Quality of Life Assessment .......................................................68
9.3.5
Healthcare resource use ...............................................................................68
9.3.6
Number of working or school days lost due to epilepsy..............................68
9.3.7
Number of days with help from a caregiver due to epilepsy.......................68
9.3.8
Socio-professional data................................................................................68
10
ASSESSMENT OF SAFETY..........................................................................................68
10.1
Adverse events.......................................................................................................68
10.1.1
Definitions ...................................................................................................68
10.1.1.1
Adverse event.....................................................................................68
10.1.1.2
Serious adverse event.........................................................................69
10.1.1.3
Adverse events of special interest......................................................70
10.1.2
Procedures for reporting and recording adverse events...............................71
10.1.2.1
Description of adverse events ............................................................71
10.1.2.2
Rule for repetition of an adverse event..............................................72
10.1.2.3
Additional procedures for reporting serious adverse events..............72
10.1.3
Follow up of adverse events ........................................................................72
10.1.4
Pregnancy.....................................................................................................73
10.1.5
Suspected transmission of an infectious agent via a medicinal product......74
10.1.6
Overdose of investigational medicinal product ...........................................74
10.1.7
Safety signal detection.................................................................................74
10.2
Laboratory measurements......................................................................................74
10.2.1
Evaluation of PDILI.....................................................................................75
10.2.1.1
Consultation with Medical Monitor and local hepatologist...............79
10.2.1.2
Immediate action: determination of IMP discontinuation .................79
10.2.1.3
Testing: identification/exclusion of alternative etiology ...................79
10.2.1.4
Follow-up evaluation .........................................................................81
10.2.2
Pregnancy testing.........................................................................................81
REDACTED 
......
......
......
....
se eve
se eve
nts 
nts 
COPY 
.....
.... .
......
....
This document cannot
0.1
0.1
0.2
0.2
be 
.6
7
used
Su
Su
to
regn
regn
support
dditio
dditio
ow up 
w up
nan
any 
for rep
or re
marketing 
of spe
of spe
orting 
orting
on of a
n of
authorization 
......
....
......
......
......
......
ntnt....
application
e to ep
e to e
........
.....
.......
......
and 
....
epsy
psy
any 
...
.....
..
extensions 
........
.......
.........
.......
.....
or 
......
variations 
67
67
67
6
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 8 of 267
10.3
Other safety measurements....................................................................................81
10.3.1
12-lead ECG ................................................................................................81
10.3.1.1
Overall ECG interpretation................................................................82
10.3.2
Vital signs, body weight, and height............................................................82
10.3.3
New seizure types ........................................................................................82
10.3.4
Physical examination...................................................................................82
10.3.4.1
Complete physical examination.........................................................82
10.3.4.2
Brief physical examination ................................................................83
10.3.5
Tanner Stage ................................................................................................83
10.3.6
Neurological examination............................................................................83
10.3.6.1
Complete neurological examination ..................................................83
10.3.6.2
Brief neurological examination..........................................................83
10.3.7
Assessment of suicidality.............................................................................83
10.3.8
Achenbach CBCL........................................................................................84
10.3.9
BRIEF ..........................................................................................................84
11
ASSESSMENT OF PHARMACOKINETICS................................................................85
12
STUDY MANAGEMENT AND ADMINISTRATION.................................................85
12.1
Adherence to protocol............................................................................................85
12.2
Monitoring .............................................................................................................85
12.2.1
Definition of source data..............................................................................85
12.2.2
Source data verification ...............................................................................86
12.3
Data handling.........................................................................................................86
12.3.1
Case report form completion .......................................................................86
12.3.2
Database entry and reconciliation................................................................86
12.3.3
Subject Screening and Enrollment log/Subject Identification Code list......87
12.4
Termination of the study........................................................................................87
12.5
Archiving and data retention..................................................................................87
12.6
Audit and inspection ..............................................................................................87
12.7
Good Clinical Practice...........................................................................................88
13
STATISTICS ...................................................................................................................88
13.1
Definition of analysis sets......................................................................................88
13.1.1
Screened Set.................................................................................................88
13.1.2
Randomized Set...........................................................................................88
13.1.3
Safety Set .....................................................................................................88
13.1.4
Full Analysis Set..........................................................................................88
13.1.5
Per Protocol Set ...........................................................................................88
13.2
General statistical considerations...........................................................................88
13.3
Planned efficacy analyses ......................................................................................89
REDACTED 
......
......
tata......
ation .
tion .
COPY 
RATI
RATI
....
....
This document cannot
D
13
13
be
IST
ST
D
used 
an
an
od Cl
d Cl
IC
IC
to
nd in
nd i
support 
re
f the s
f the 
and da
and d
any 
a
ening
enin
marketing 
..
.......
.....
comple
ompl
and r
nd 
authorization 
......
.....
......
....
......
.....
.......
......
application 
.
.......
....
........
....
ON
ON.
and 
.......
......
any
.....
....
......
extensions
......
.....
..........
....
..... .....
.....
or 
......
variations 
82
83
8
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 9 of 267
13.3.1
Analysis of the primary efficacy variable....................................................89
13.3.2
Secondary efficacy analyses ........................................................................89
13.3.2.1
Key secondary efficacy variable........................................................89
13.3.2.2
Other secondary efficacy variables....................................................90
13.3.3
Other efficacy analysis.................................................................................90
13.4
Planned safety and other analyses..........................................................................90
13.5
Handling of protocol deviations.............................................................................90
13.6
Handling of dropouts or missing data....................................................................91
13.7
Planned interim analysis and data monitoring.......................................................91
13.8
Determination of sample size.................................................................................92
14
ETHICS AND REGULATORY REQUIREMENTS......................................................92
14.1
Informed consent/assent.........................................................................................92
14.2
Subject identification cards....................................................................................93
14.3
Institutional Review Boards and Independent Ethics Committees........................93
14.4
Subject privacy.......................................................................................................94
14.5
Protocol amendments.............................................................................................94
15
FINANCE, INSURANCE, AND PUBLICATION.........................................................94
16
REFERENCES ................................................................................................................94
17
APPENDICES .................................................................................................................96
17.1
Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) ............................96
17.2
EuroQol-5D Quality of Life Assessment.............................................................106
17.3
Protocol Amendment 1 ........................................................................................108
17.4
Protocol Amendment 2 ........................................................................................128
17.5
Protocol Amendment 3 ........................................................................................200
17.6
Protocol Amendment 4 ........................................................................................202
17.7
Protocol Amendment 5 ........................................................................................240
17.8
International Classification of Epileptic Seizures (1981)....................................264
17.9
Contraception table..............................................................................................265
18
DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................266
19
SPONSOR DECLARATION ........................................................................................267
LIST OF TABLES
Table 5‒1: Schedule of study assessments for SP0982 (Prospective Baseline, Titration 
Period, Maintenance Period, ET Visit, and Unscheduled Visits).........................23
Table 5‒2: Schedule of study assessments for SP0982 (Transition Period)...........................27
Table 5‒3: Schedule of study assessments for SP0982 (Taper Period and Safety 
Follow-up Period).................................................................................................29
REDACTED 
......
......
nvento
vent
fe As
fe As
COPY 
ION
ON
....
....
This document 
Tabl
Tab
cannot be
SOR
O
used 
ace
c
RATIO
ATIO
R
to
epti
ept
support 
m
ndmen
ndme
nal Cla
al Cla
any 
3
ent 4
ent 4
marketing 
se
.......
.....
........
.....
3 ....
authorization 
......
......
......
....
ory
ry-Fo
Fo
essm
essm
application 
om
.....
.......
........
....
......
.....
and 
.......
mmitt
mit
any 
.....
...
...
extensions
......
.....
........
......
.........
.......
or 
......
variations 
90
90
91
9
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 10 of 267
Table 7‒1: Recommended dosing schedule for LCM (or matching placebo) during the 
Titration Period.....................................................................................................46
Table 7‒2: Dosing of LCM (or matching placebo) with flexibility based on tolerability 
during the Titration Period....................................................................................46
Table 7‒3: Required LCM (or matching placebo) dose for at least the final 3 days of 
Week 6..................................................................................................................47
Table 7‒4: Transition Period LCM dosing schedule for subjects randomized to placebo.....48
Table 7‒5: Taper Period dosing of LCM (or matching placebo)............................................49
Table 10‒1:
Anticipated SAEs for the epilepsy population.............................................70
Table 10‒2:
Laboratory measurements............................................................................75
Table 10-3: Required investigations and follow up for PDILI ................................................77
Table 10‒4:
PDILI laboratory measurements..................................................................80
Table 10‒5:
PDILI information to be collected...............................................................81
LIST OF FIGURES
Figure 5-1: Combined Baseline Period seizure eligibility for SP0982 ...................................31
Figure 5‒2: SP0982 Prospective Baseline Period through the Taper Period schematic 
diagram .................................................................................................................32
Figure 5‒3: SP0982 Transition Period schematic diagram......................................................34
REDACTED 
ure elig
ure eli
ne Peri
e Per
.....
.... .
d s
d
COPY 
FIGU
FIGU
This document cannot be used to support any marketing 
.
schem
chem
authorization
URE
URE
igibilit
gibilit
iod th
od th
......
application 
..
ES
ES
and 
....
....
any 
.
.....
extensions 
........
.......
......
.....
....
or
.....
....
variations 
48
48
4
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 11 of 267
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AST
aspartate aminotransferase 
AV
atrioventricular
bid
twice daily
BP
blood pressure
BRIEF®
Behavior Rating Inventory of Executive Function®
BRIEF®-P
Behavior Rating Inventory of Executive Function®-Preschool Version
CBCL
Child Behavior Checklist
CDMS
Clinical Data Management System
CLcr
creatinine clearance
CPM
Clinical Project Manager
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
DMC
data monitoring committee
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EEG
electroencephalogram
EI-AED
enzyme-inducing antiepileptic drug
EQ-5D-3L
EuroQol-5 Dimension
ET
Early Termination
FAS
Full Analysis Set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HDPE
High-density polyethylene
HLA
Human leukocyte antigen
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
REDACTED 
Rating
Rating
mitte
mitte
COPY 
This document 
CP
CP
GM
GM
cannot 
P
be used
enzy
nzy
Eu
E
to 
ym
ym
support 
se
ic data 
data
roence
oence
any 
e repo
repo
marketing 
ee
ee
tical M
ical M
authorization 
g Scale
Scale
application and 
o
any 
l Ver
Ver
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 12 of 267
IDMC
independent data monitoring committee
IEC
Independent Ethics Committee
IGE
idiopathic generalized epilepsy
ILAE
International League Against Epilepsy
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
interactive response technology
iv
intravenous
KM
Kaplan-Meier
LCM
lacosamide
LFT
liver function test
MAO-A
monoamine oxidase A
MRI
magnetic resonance imaging
PDILI
potential drug-induced liver injury
PedsQL™
Pediatric Quality of Life Inventory
PET
polyethylene terephthalate
PGTC
primary generalized tonic-clonic
PK
pharmacokinetic
PPS
Per Protocol Set
PS
patient safety
QC
quality control
QOLIE-31-P
Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31
RS
Randomized Set
SAE
serious adverse event
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SS
Safety Set
TEAE
treatment emergent adverse event
TFL
tables, figures, and listings
ULN
upper limit of normal
VNS
vagus nerve stimulation
REDACTED 
nic
nic
COPY 
This document 
ULN
ULN
V
cannot 
L
be used 
Stan
Stan
to
atisti
atist
support 
ed Se
d Se
s adver
adve
ica
i
any
ed Qu
ed Q
et
marketing 
ua
authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 13 of 267
1
SUMMARY
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy and safety of oral lacosamide (LCM) (VIMPAT®; SPM 927; 
previously referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, 
ADD 234037) twice daily [bid]) vs placebo as adjunctive therapy for uncontrolled primary 
generalized tonic-clonic (PGTC) seizures in subjects ≥4 years of age with idiopathic generalized 
epilepsy (IGE) currently taking 1 to 3 concomitant antiepileptic drugs (AEDs) independent of the 
number of prior failed AEDs (see Section 7.8).
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study. 
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 36 weeks per subject. 
The study is comprised of the following: a 4-week Prospective Baseline Period and a 6-week 
(minimum) to 24-week (maximum) Treatment Period, which includes a 6-week Titration Period 
and an 18-week (maximum) Maintenance Period. Eligible subjects who choose to enter the 
open-label extension study (EP0012) after the completion of Visit 10 (Week 24) or the Early 
Termination (ET) Visit will complete a 4-week blinded transition. Subjects who choose not to 
continue in EP0012 must complete an up to 4-week blinded taper followed by a 30-day Safety 
Follow-up Period. 
The primary study objective is to demonstrate the efficacy of oral LCM vs placebo as adjunctive 
therapy for uncontrolled PGTC seizures in subjects with IGE taking 1 to 3 concomitant AEDs
(See Section 7.8).
The primary efficacy variable is the time to the second PGTC seizure (also defined as an event) 
during the 24-week Treatment Period. Once the 125th event occurs, the study will have met its 
protocol-defined endpoint or milestone; all subjects will transition into EP0012 or taper off study 
medication.
The key secondary efficacy variable is seizure freedom for PGTC seizures for the 24-week 
Treatment Period, which will use a gatekeeping strategy to assess statistical significance (see 
Section 13.3.1). The other secondary efficacy variable is time to the first PGTC seizure during 
the Treatment Period. 
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs) as reported 
spontaneously by the subject and/or caregiver or observed by the investigator. Other safety 
variables are withdrawal due to AEs; incidence of new seizure types, increase in absence seizure 
days per 28 days or myoclonic seizure days per 28 days during the Treatment Period; and 
changes in physical and neurological examination findings; changes in hematology, chemistry, 
endocrinology, and urinalysis parameters; changes in 12-lead electrocardiograms (ECGs); 
changes in vital sign measurements; for pediatric subjects <18 years of age, safety will be 
evaluated using a behavioral assessment (Achenbach Child Behavior Checklist [CBCL]) and a 
cognitive function assessment (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/Behavior Rating Inventory of Executive Function Preschool Version [BRIEF-P]).
REDACTED 
ate the
ate the
in sub
n sub
tim
tim
COPY 
d d
k blin
k blin
This document 
ay
ays
chan
chan
e
cannot
neous
eous
ables a
bles a
s pe
s pe
be
ed PG
ed P
l
used 
rioio
y obje
obje
y
G
to 
e o
od. 
od.
support
cy var
va
y
ch will 
h wil
other 
ther 
any 
ria
marketing 
me to th
e to th
d. Onc
On
stone;
stone
authorization 
d
e effic
effic
bjects 
jects 
application
cts wh
cts w
Visit 
Visit 10
1
nsition
sition
ded tap
ed ta
and 
ne P
e P
es s a a 6
h
any 
Perio
Per
extensions
th po
h p
dy. .
will las
ll la
or 
os
variations 
ed d 
of the
of the
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 14 of 267
The plasma concentrations of LCM will also be assessed.
2
INTRODUCTION
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated to affect 
almost 70 million people worldwide (Ngugi et al, 2011). Epileptic seizures occur in the context 
of a wide range of epilepsy syndromes that may be of genetic, structural/metabolic, or of 
unknown origin. The most common seizure type in patients with epilepsy is partial seizures 
(57%), followed by tonic-clonic (23%), absence (6%), and myoclonic (3%); the latter 3 seizure 
types comprise the majority of generalized seizures (convulsive and nonconvulsive) 
(Hauser et al, 1993). 
Generalized seizures are those in which the first clinical changes indicate initial involvement of 
both brain hemispheres. Consciousness may be impaired and this impairment may be the initial
manifestation. Motor manifestations are typically bilateral. Generalized seizures typically occur 
with idiopathic generalized (genetic) or symptomatic generalized epilepsy syndromes. Idiopathic 
generalized epilepsy is a category of disorders defined by strict clinical and 
electroencephalogram (EEG) features proposed by the International League Against Epilepsy 
(ILAE) classification of epileptic syndromes (ILAE, 1989). Clinical experience has shown that 
IGEs represent a heterogeneous condition in which many factors interact (such as age at onset, 
external factors, role of medications, and sleep) (Jallon and Latour, 2005). Idiopathic generalized 
epilepsies are assumed to have a genetic etiology and onset almost always occurs during 
childhood or adolescence, although there are exceptions; some patients develop these kinds of 
epilepsies after the second decade of life or, rarely, even later.
Treatment of PGTC seizures is complex because the patient population with PGTC seizures is 
heterogeneous, as PGTC seizures can occur as an isolated seizure type or in association with 
other generalized seizure types.
Although some forms of epilepsy may not require any treatment at all, most patients with 
epilepsy require appropriate pharmacological therapy (Perucca, 1996). In the past decade, several 
new options for the medical treatment of epilepsy have been introduced, including novel AEDs 
and vagus nerve stimulation (VNS). The newer AEDs differ from older agents in several 
important ways, including mechanism of action, spectrum of activity, and pharmacokinetic (PK) 
characteristics (Herman and Pedley, 1998). 
Between 15% and 40% of patients with generalized epilepsy remain refractory to therapy or do 
not tolerate the currently available AEDs used in this population (phenobarbital, valproate, 
ethosuximide, lamotrigine, topiramate, and levetiracetam) (Bartolomei et al, 1997; 
Verrotti et al, 2007); some of these AEDs can induce serious, life-threatening AEs (eg, aplastic 
anemia, rash, hepatic failure). Generalized tonic-clonic seizures may respond to drugs that 
aggravate typical absences and/or myoclonic jerks (Genton, 2000; Verrotti et al, 2007). Two IGE 
seizure types, typical absences and myoclonic seizures, are particularly prone to aggravation by 
certain AEDs (carbamazepine, vigabatrin, tiagabine, phenytoin, phenobarbital, and lamotrigine).
Lacosamide belongs to a novel class of functionalized amino acids that were specifically 
synthesized as anticonvulsive drug candidates. 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 bid dose 
REDACTED
xce
rarel
rarely
becau
beca
n occu
occu
COPY
on
on a
and on
nd on
eptio
eptio
This document
ggr
g
seizu
seizu
ce
ce
cannot
etet a
mia, ras
a, ras
rava
rava
be
ide, l
ide, 
alal
used
nd 40
d 4
e curr
curr
lala
to 
40%
40%
support 
n (V
(V
ng mec
ng me
an and
an an
any
eatme
eatm
VN
VN
marketing 
ur 
may
ay not
 no
y
macol
maco
authorization 
ns
ons; s
ons; s
y, even
, even
use th
use th
as a
as a
application
ical e
ical e
tors int
tors in
d Latou
Lato
set alm
et alm
and 
l an
an
Leag
Leag
any 
y sy
sy
y
n
y
nd 
nd
extensions 
nvolve
volve
may be
may be
ures t
res t
d
or variations 
ure
ure
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 15 of 267
regimen. It also displays dose-proportional PK following administration over a range of doses up 
to 800mg in adults.
Lacosamide has been approved in the European Union (oral tablets, oral solution [syrup], and 
solution for intravenous [iv] infusion) as monotherapy or adjunctive therapy in the treatment of 
partial-onset seizures with or without secondary generalization in patients 4 years of age and 
older. Lacosamide has also been approved in the US (oral tablets, oral solution [syrup], and 
solution for iv infusion) as monotherapy or adjunctive therapy in the treatment of partial-onset 
seizures in patients 17 years of age and older. The safety and efficacy of LCM has been 
evaluated in Phase 2/3 studies as adjunctive oral therapy in over 1300 adult subjects with partial-
onset seizures. Excluding blinded ongoing studies and indications not currently pursued, as of 
the data cutoff of 31 Aug 2016, 4938 subjects have been exposed to LCM in the clinical 
development program.
Preliminary recent safety and PK data suggest that the exposure-response in pediatric and adult 
subjects treated with LCM will be similar. Lacosamide has been evaluated in 3 completed 
pediatric studies; 2 studies in subjects aged 1 month to 17 years, and in subjects with epilepsy ≥4 
years to <17 years of age with uncontrolled partial-onset seizures. Subjects who completed the 
Maintenance Period were offered the opportunity to participate in the open-label extension study.
In addition, LCM is being evaluated in the following ongoing pediatric efficacy and safety
studies: 
•
SP0967 (ages ≥1 month to <4 years) as adjunctive therapy in partial-onset seizures
•
EP0034, open-label extension study to SP0967 and SP0969
•
SP0966 (ages ≥1 month to <18 years) as adjunctive therapy, exploratory study in subjects 
with epilepsy syndromes associated with generalized seizures
Further information on LCM nonclinical results, as well as the PK, efficacy, and safety profiles, 
can be obtained from the current version of the LCM Investigator’s Brochure.
Considering the significant unmet medical need for new treatment options for patients with IGE 
and PGTC seizures, the efficacy and tolerability profiles for LCM were evaluated in a series of 
animal models followed by a Phase 2 pilot study of subjects with IGE and uncontrolled PGTC 
seizures.
Lacosamide demonstrated significant seizure protection in animal models of seizures and 
epilepsy mimicking generalized epilepsy in humans. Of particular relevance for the PGTC 
indication are the anticonvulsant properties of LCM treatment obtained against generalized 
tonic-clonic seizures induced by a maximal electroshock in both mice and rats, and 
sound-stimulation in audiogenic seizure-susceptible mice. In these models, LCM treatment 
significantly protected against generalized tonic-clonic seizures. The elevation of seizure 
threshold by LCM following iv infusion of pentylenetetrazol in mice may also be indicative of a 
potential efficacy against myoclonic seizures, where LCM treatment significantly delayed time 
to first myoclonic seizure. However, LCM had no protective effect in animal models of absence 
seizures in the Genetic Absence Epilepsy Rat from Strasbourg model of absence epilepsy.
The Phase 2, multicenter, open-label, pilot study (SP0961) designed to assess the safety of 
adjunctive LCM (400mg/day) for uncontrolled PGTC seizures in subjects aged 16 to 65 years 
REDACTED
junc
un
SP09
SP09
ars) a
ars) a
ated w
ated w
COPY 
ong
on
nctiv
cti
This document 
igni
gni
thre
thre
p
cannot
lonic
onic
d-stim
stim
nific
ific
be
are t
are t
used
mons
mons
ickin
ckin
h
to 
strt
support
fficac
ficac
d by
d by a a
y
any 
nmet m
met 
y
marketing
with g
with 
nical re
nical 
version
ersio
authorization 
ve the
ve the
967 an
67 an
s adju
adju
application
Sub
Su
in the 
in the
ing
ng ped
pe
and
in su
n su
ubje
ubje
any 
n p
n p
ed in 3
d in 
bjb
extensions
ued, 
ed, 
linica
nica
pedi
ped
or
h pa
h p
a
variations 
t 
part
ar
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 16 of 267
with IGE is complete. The results of this pilot study showed reductions in PGTC and myoclonic 
seizure frequencies, with a small reduction in absence seizure frequency. A minority of subjects 
(~10%) in SP0961 showed an increase in absence seizures (reported as treatment-emergent 
adverse events [TEAEs]) that, in this uncontrolled study, these changes cannot be distinguished 
between the drug vs the natural course of the disease. The AE profile was similar to what has 
been observed with adjunctive LCM for the treatment of subjects with partial-onset seizures, 
with the exception of seizure-related AEs.
The purpose of this study (SP0982) is to evaluate the efficacy and safety of LCM
(LCM 8mg/kg/day to 12mg/kg/day for pediatric subjects weighing <30kg, LCM 6mg/kg/day to 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 300mg/day to 400mg/day 
for adult subjects [≥18 years of age] and pediatric subjects [<18 years of age] weighing ≥50kg)
(see Table 7‒3) for uncontrolled PGTC seizures in subjects ≥4 years of age with IGE.
3
STUDY OBJECTIVES
3.1
Primary objective
The primary study objective is to demonstrate the efficacy of oral LCM (Table 7‒3) vs placebo 
as adjunctive therapy for uncontrolled PGTC seizures in subjects with IGE currently taking 1 to 
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
3.2
Secondary objective
The secondary study objective is to assess the safety and tolerability of LCM in subjects with 
IGE with uncontrolled PGTC seizures.
4
STUDY VARIABLES
4.1
Efficacy variables
4.1.1
Primary efficacy variable
The primary efficacy variable is the time to the second PGTC seizure during the 24-week 
Treatment Period.
4.1.2
Secondary efficacy variables
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures during the 24-week Treatment Period, estimated using 
Kaplan-Meier analysis
The other secondary efficacy variable is:
•
Time to the first PGTC seizure during the Treatment Period
4.1.3
Other efficacy variables
Other efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline)
safe
saf
ES
ES
es
COPY 
fety
fety
This document
4.1.3
.1.3
O
cannot 
r se
se
Time t
ime t
3
be 
seco
seco
used 
dom
om
eier 
eier 
to 
eff
f
support 
ary
ary ef
e
y
ficacy
ficac
any 
thth
marketing 
variab
aria
he ti
he
authorization 
y and 
and 
y
application 
LC
LC
cts with
ts wit
led AE
ed A
and 
CM
CM
any extensions
o 400
40
ghing
hing
h IGE
IGE
or
g/da
g/da
0m
0
variations 
ay
ay
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 17 of 267
•
The percent change in PGTC seizure frequency per 28 days during the first 12 weeks of the 
Treatment Period relative to the Combined Baseline
•
The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline
•
Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline
•
Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Prospective Baseline
•
Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline
•
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period 
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Titration Period compared to Combined Baseline
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
first 12 weeks of the Treatment Period compared to Combined Baseline 
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Treatment Period compared to Combined Baseline 
•
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period
•
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period 
•
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy 
Inventory-Form 31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social 
Functioning, Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, 
Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age 
or change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale 
REDACTED 
50% re
0% r
PGT
PGT
COPY
Pro
Pr
res pe
res pe
This document
P
cannot
atme
atme
Seiz
Seiz
be
e-fre
fre
used
f su
su
t Perio
Perio
to 
ubje
ubj
support 
ed
cts with
ts wit
the Tre
he Tre
any
at l
at 
d to C
to C
marketing
TC sei
TC sei
PGTC
PGTC
leas
lea
authorization
er 28
r 28
reduct
reduct
application 
ays s duri
du
pective
ectiv
8 da
8 da
and
Treatm
eatm
any extensions 
Perio
Perio
ay
ays c
s c
or variations 
he
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 18 of 267
(Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning)
and total scores in subjects <18 years of age
•
Change from Baseline to end of treatment or ET in the 3-Level EuroQol-5 Dimension 
Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age)
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject due to epilepsy
•
Number of days with help from a caregiver due to epilepsy
4.2
Safety variables
The safety variable is:
•
AEs as reported spontaneously by the subject and/or caregiver or observed by the 
investigator.
Other safety variables are:
•
Subject withdrawal due to AE
•
Incidence of new seizure types during the Treatment Period
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
•
Changes in 12-lead ECGs
•
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings
•
Behavioral assessment (Achenbach CBCL/1½-5 or CBCL/6-18) for pediatric subjects only
•
Cognitive function assessment (BRIEF-P or BRIEF) for pediatric subjects only
4.3
Pharmacokinetic variable
The plasma concentrations of LCM will be assessed.
5
STUDY DESIGN
5.1
Study description
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy of oral LCM (see Table 7‒3) vs placebo as adjunctive therapy for 
uncontrolled PGTC seizures in subjects ≥4 years of age with IGE currently taking 1 to 
REDACTED
the T
the T
25%, 
25%
day
days
COPY
ment 
ment
% 
% to 5
to 
T
This document 
5
5
cann
p
not 
lasm
lasm
be used 
ses
se
func
func
to
essm
ssm
support 
n measu
mea
) and 
and p
any marketing
durin
durin
mistry
stry
authorization
50%,
50%,
reatm
eatm
>25%
>25%
application 
Period
eriod
>
and any
rved
rved
extensions 
d
or variations 
ts
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 19 of 267
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8). This 
study will also assess the safety, tolerability, and PK of LCM use in this population. 
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study.
The study will last a maximum of 36 weeks per subject. The study is comprised of the following: 
a 4-week Prospective Baseline Period and a 6-week (minimum) to 24-week (maximum) 
Treatment Period, which includes a 6-week Titration Period and an 18-week (maximum) 
Maintenance Period. Eligible subjects who choose to enter the open-label extension study 
(EP0012) after the completion of Visit 10 (Week 24) or the Early Termination (ET) Visit will 
complete a 4-week blinded transition. Subjects who choose not to continue in EP0012 must 
complete an up to 4-week blinded taper followed by a 30-day Safety Follow-up Period. 
Eligibility to enter SP0982 will be based on a 12-week Historical Baseline prior to screening at 
Visit 1. In rare cases where there is a gap between consenting and Visit 1 procedures, the 
12-week Historical Baseline will be calculated from the date of Informed Consent/Assent. 
Prior to randomization, the following 3 criteria concerning PGTC seizure frequency must be met: 
•
The subject must have experienced at least 3 PGTC seizures during the 16-week Combined 
Baseline Period, 
•
The subject must have experienced at least 2 PGTC seizures during the 12-week Historical 
Baseline Period, 
•
Of the above seizures, at least 1 PGTC seizure should have occurred during the first 8 weeks 
and at least 1 PGTC seizure should have occurred during the second 8 weeks of the 16-week 
Combined Baseline Period. 
Examples of different scenarios and the subjects´ eligibility in terms of Baseline Period seizures 
are presented in a table in Inclusion Criterion 5. A schematic diagram for the Combined Baseline 
Period seizure eligibility is provided in Figure 5-1.
At Visit 1, subjects and/or caregivers will be given a seizure diary to document all types of 
seizures, concomitant AEDs, and any other pertinent health status information. Seizure 
frequency and type eligibility will be verified by reliably documented seizure history collected 
(eg, in a seizure diary) 12 weeks prior to Visit 1. In addition, prior to Visit 1, subjects are 
required to have had an EEG showing discharges consistent with IGE (eg, generalized ≥3Hz 
epileptiform discharges and a normal EEG background). A confirmatory EEG may be performed 
during the Prospective Baseline, if approved by the Central Reviewer. Investigators will send a 
copy of the EEG report to the Central Reviewer. The report should include a detailed description 
of the background activity and abnormalities in the EEG as well as a clinical interpretation. The 
information provided will be reviewed and any questions regarding the subject’s eligibility will 
be discussed with the investigator prior to the subject being randomized.
The Prospective Baseline begins with subject screening at Visit 1 (Week -4) and will last 
4 weeks. Visit 1 will be conducted to evaluate subject eligibility for enrollment into the study. It 
is acceptable for this visit to be conducted on more than 1 day; although, it should not extend 
over a period longer than 7 consecutive days. Seizure count eligibility will be verified by data 
collected in a study seizure diary during the 4-week Prospective Baseline. Subjects and/or 
REDACTED 
C seizu
seizu
have o
have 
h
COPY 
PGTC
PGTC
This document 
nfor
for
be d
be d
cannot
f the 
the 
he bac
e bac
orma
rma
be
Pros
Pros
E
us
d
sed
e had
had
ischa
ischa
to
ary
ry) )
d a
d
support 
care
ar
EDs, an
Ds, 
igibilit
gibili
) 12
1
any 
ide
d
egiv
egi
marketing 
he subj
he sub
n Crite
Crite
ded in
ed 
authorization
C se
se
ure sho
re sh
occur
occur
application 
sei
es duri
es dur
eizur
eizu
and 
ed
ed
izur
zur
any
proc
proc
d Co
extensions
isi
12 mu
12 m
Period
Period
rior to
ior to
ce
or
it w
t w
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 20 of 267
caregivers will be contacted via telephone 2 weeks following Visit 1 to assess continued 
eligibility and will be reminded of the importance of accurate seizure diary completion. At 
Visit 2, subjects who complete the Prospective Baseline and meet all entry criteria except the 
minimum PGTC seizure criteria required for randomization (Baseline failures) may choose to 
enter EP0012. In this case, at the end of the Prospective Baseline, Visit 1 of EP0012 will be 
performed.
At the end of the Prospective Baseline (Visit 2), eligible subjects will be randomized to receive 
LCM or placebo (see Table 7‒1) in a 1:1 fashion (active:placebo) and stratified by Baseline 
PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline 
Period prior to randomization) and by age at informed consent (≥4 to <12 years of age, ≥12 to 
<18 years of age, and ≥18 years of age). The Treatment Period starts at the time of the 
Randomization Visit (Visit 2).
At the Randomization Visit (Visit 2) eligible subjects will complete the Visit 2 assessments and 
take the first dose of study drug at the clinic and enter a 6-week Titration Period. The 
recommended LCM (or matching placebo) dosing during the Titration Period to achieve the 
target Maintenance Period doses is provided in Table 7‒1. All subjects should follow the 
recommended dosing schedule, unless dose adjustments based on tolerability are needed. 
Table 7‒2 provides LCM (or matching placebo) dosing with flexibility based on tolerability 
during the Titration Period. During the Titration Period, subjects must achieve a target 
Maintenance Period dose range (see Table 7‒3). 
During the Maintenance Period, a single dose reduction of study drug or placebo is permitted as 
long as the minimum target dose is maintained (Table 7‒3). No other dose reductions are 
allowed. If a dose reduction is required, an (un)scheduled visit, either telephone or clinic visit, is 
required. If the subject is not able to tolerate the study drug after 1 dose reduction, the subject 
must enter the Taper Period and be withdrawn from the study. All dose reductions should be 
discussed with the Medical Monitor. Once the dose has been reduced, it cannot be increased.
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
•
The 125th event occurs in the study. A second PGTC seizure is defined as an event.
Subjects who experience >2 PGTC seizures and who also complete ≥6 weeks (ie, ≥42 days) of 
the treatment period after randomization will be required to exit and complete the ET Visit
(Section 6.3). The seizures may occur on the same day, but the initiation and completion of each 
individual seizure must be distinguishable allowing reliable counting of individual seizures. 
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment
Period or after completing the 24-week Treatment Period or if the 125th event occurs in the study
(whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012. Subjects completing Visit 10 (Week 24) or the ET 
Visit must complete a 4-week blinded transition followed by a Final Clinic Visit. The Final 
Clinic Visit is the same as Visit 1 of EP0012 (see Section 7.2.3). During the 4-week blinded 
transition, subjects receiving placebo during SP0982 will have their dose titrated to LCM (see 
Table 7‒4). 
REDACTED
e redu
e red
ained (
ined 
d, a
, an (u
n (u
tolera
tolera
wit
wi
COPY
g
riod, 
iod, 
This document 
After
fte
Peri
Peri
(w
(
cannot 
6.3
6.
idual s
dual 
er c
er c
be
nt p
t p
3)
used 
experi
xperi
per
per
to
t occ
oc
support 
s o
weeks o
eeks
cu
any 
un
un
of th
f th
marketing
ate t
te t
thdraw
hdraw
r. Once
 Onc
until 
ntil
authorization 
uction
uction
(Tabl
Tabl
un
un)sch
sch
the
th
application
bject
ec
on tole
tol
h flexib
flexi
subject
ubjec
and
on Pe
n Pe
cts s
ts
any 
it 
it 
Perio
Peri
rio
extensions
ge, ≥
f the
the
t 2 a
2 a
or 
ase
as
≥12
≥1
variations 
e
e
seli
sel
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 21 of 267
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24), and an up to 4-week 
blinded taper followed by an End of Taper Visit. Following the End of Taper Visit, there will be 
a 30-day Safety Follow-up Period (see Section 7.2.4). In case the 125th event occurs in the study, 
the subjects discontinuing treatment will complete the ET Visit or Visit 10 (Week 24), and an up 
to 4-week blinded taper followed by an End of Taper Visit. However, the End of Taper Visit will 
be the same as Visit 1 of EP0012. The 30-day Safety Follow up Period will be done as part of 
EP0012, except if the subject refuses to sign the EP0012 informed consent form. If the subject
signs the informed consent form for a short Safety Follow-up as part of EP0012, the 30-day 
Safety Follow-up will be performed as part of EP0012; otherwise, the Safety Follow-up will be 
performed in SP0982. 
Unscheduled visits may be performed at any time after Visit 1 at the discretion of the 
investigator. 
Schematic diagrams of the study are provided in Section 5.3.
5.1.1
Study duration per subject
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 36 weeks per subject, consisting of the following study periods:
•
4-week Prospective Baseline Period
•
6-week (minimum) to 24-week (maximum) Treatment Period (including a 6-week titration)
•
4-week End of Study Period consisting of either: 
−
4-week blinded transition (required for subjects participating in EP0012)
−
Up to 4-week blinded taper followed by a 30-day Safety Follow-up Period (required for
subjects not participating in EP0012)
−
Subjects can enter EP0012 after the completion of Visit 10 (Week 24) or ET Visit and a 
4-week blinded transition. Subjects who choose not to continue in EP0012 must complete 
an up to 4-week blinded taper followed by a 30-day Safety Follow-up Period (see Section
7.2.4).
Titration Period
In case the 125th event occurs in the study while subjects are still in their 6-week Titration 
Period, these subjects will not have to proceed to Week 6 prior to initiating the Transition/Taper 
Period; these subjects will also be invited for their ET Visit at the next scheduled visit.
Maintenance Period
In case the 125th event occurs in the study while subjects are in their Maintenance Period, these 
subjects will also be invited for their ET Visit at the next scheduled visit and enter the 
Transition/Taper Period.
Transition Period
In case the subject is in the Transition/Taper Period, these subjects will proceed to their 
scheduled completion visit.
REDACTED 
) T
g of ei
g of ei
uired f
uired f
follo
follo
COPY 
Trea
Tre
This document
n ca
n ca
sub
sub
T
cannot 
hes
e
ntena
tena
an
ase
as
be 
e su
e s
se s
se s
used
eve
eve
subj
subj
to support 
inded
nded
any 
2 2
ion.
ion. S
d
marketing 
owed b
wed b
EP0012
P00
2 afte
aft
authorization 
atmen
men
ither:
her:
for su
or su
application 
s.s. The
The
riods:
riods:
and any extensions 
up p
of the
of the
or
y
wil
wi
variations 
ectct
ay
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 22 of 267
Screening Period
In case the 125th event occurs while a subject is in screening, the subject may proceed to the 
scheduled Baseline Visit if they are eligible or are a Baseline failure; these subjects will be able 
to enter EP0012 and will not proceed to randomization in SP0982 but will enter EP0012. For the 
subjects entering EP0012, their next visit will be Visit 1. 
The end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Study completers
The following subjects will be considered study completers:
•
Subjects who meet any of the predetermined exit criteria (Section 6.3)
•
Subjects who experience <2 PGTC seizures within the 24-week Treatment Period
Further information is provided in Section 6.3.
5.1.3
Planned number of subjects and sites 
The number of screened subjects may vary according to the observed screen failure rate. Up to 
250 subjects (100 to 125 per treatment arm) will be randomized to achieve a total of 125 events, 
where an event is defined as the occurrence of the second PGTC seizure.
Subjects will be randomized in the following age categories:
•
(a) ≥4 years of age to <12 years of age
•
(b) ≥12 years of age to <18 years of age
•
(c) ≥18 years of age category
There will be approximately 150 to 180 sites in order to recruit the required subjects; additional 
sites will be added if deemed necessary. A target of at least 40 of the randomized subjects should 
consist of subjects <18 years of age.
5.1.4
Anticipated regions and countries
The study is planned to be conducted in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions.
5.2
Schedule of study assessments
The schedule of study assessments is provided in Table 5‒1, Table 5‒2, and Table 5‒3.
REDACTED 
ge
180
18
COPY 
catego
atego
This document cannot be used 
ch
ch
of stu
of stu
o
hed
hed
support 
e cond
e con
untries 
ntries
any 
regio
egio
marketing 
0 sites
sites
sary
ary. A
ge.
ge.
authorization 
ori
application
ved 
ed
d to ach
to ac
GTC se
GTC s
ies:
es:
and 
d sc
d sc
any extensions 
Perio
Perio
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 23 of 267
Table 5‒1:
Schedule of study assessments for SP0982 (Prospective Baseline, Titration Period, Maintenance 
Period, ET Visit, and Unscheduled Visits)
Assessments
Prospective 
Baseline
4 weeks
Treatment Perioda
Unscheduledb
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period (18 weeks)
Visitc
V1bb
TC
V2d
TCe
V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/ETf
Visit
Study week
-4
-2
1
2
3
4
5
6
8
12
16
20
24
NA
Informed consent/assent
X
Inclusion/Exclusion criteria
X
X
X
Subject ID card dispensing
X
Concomitant medications and 
AED(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical history/Epilepsy history
X
Physical exam (complete)g
X
X
X
Physical exam (brief)h
X
X
X
X
X
X
X
Neurological exam (complete)i
X
X
X
Neurological exam (brief)j
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
Vital signs (BP and pulse) 
including orthostatic assessmentsl
X
X
X
X
X
X
X
X
X
X
Body weight 
X
X
X
X
X
X
X
X
X
X
Height
X
X
EEGm
X
Tanner Stagen
X
X
Laboratory tests:
Chemistry/hematology
X
X
X
X
X
X
X
Endocrinologyaa
X
X
Urinalysiso
X
X
X
X
X
X
X
Pregnancy testp
X
X
X
X
X
X
X
X
X
X
LCM plasma concentrationq
X
X
Contact IRTr
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense subject diarys
X
X
X
X
X
X
X
X
X
X
Subject diary return/reviews
X
X
X
X
X
X
X
X
X
Dispense study drugt
Xu
X
X
X
X
X
X
X
X
Study drug review/return
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
REDACTED 
D
TE
AC
DA
X
RE
R
COPY 
Y
X
PY
CO
This document t
en cannot t
ot
no
an
c
be 
X
e
b
used 
d
se
se
se
se
se
u
to 
o support 
rt
X
rtrtrt
ort
X
po
X
up
s
any y
any marketing 
g
tin
titin
tin
tin
ke
ma
m
authorization 
n
tio
X
atititi
X
iz
ho
th
a
application 
X
on
ca
pli
pli
pli
pli
pl
ap
and 
d
nd
a
any y
a
extensions 
ns
e Peri
Peri
sio
V8
V8
en
xt
e
or 
or variations 
on
Peri
erio
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 24 of 267
Table 5‒1:
Schedule of study assessments for SP0982 (Prospective Baseline, Titration Period, Maintenance 
Period, ET Visit, and Unscheduled Visits)
Assessments
Prospective 
Baseline
4 weeks
Treatment Perioda
Unscheduledb
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period (18 weeks)
Visitc
V1bb
TC
V2d
TCe
V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/ETf
Visit
Study week
-4
-2
1
2
3
4
5
6
8
12
16
20
24
NA
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Achenbach CBCLv
X
X
BRIEF-P/BRIEFw
X
X
EQ-5D-3Lx
X
X
QOLIE-31-P/PedsQLy
X
X
C-SSRSz
X
X
X
X
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
Work/school days lost due to 
epilepsy
X
X
X
X
X
X
X
X
X
Days with help from a caregiver
due to epilepsy
X
X
X
X
X
X
X
X
X
Socio-professional data
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; bid=twice daily; BP=blood pressure; exam=examination; BRIEF=Behavior Rating Inventory of Executive Function; 
BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; EEG=electroencephalogram; EQ-5D-3L=EuroQol-5D; ET=Early Termination; ID=identification; IEC=Independent Ethics 
Committee; IGE=idiopathic generalized epilepsy; IRB=Institutional Review Board; IRT=interactive response technology; LCM=lacosamide; NA=not 
applicable; PEDsQL=Pediatric Quality of Life Inventory; PGTC=primary generalized tonic-clonic; QOLIE-31-P=Patient-Weighted Quality of Life in Epilepsy 
Inventory-Form 31; TC=telephone contact; V=Visit
a
The Treatment Period starts at the time of the Randomization Visit (Visit 2). The Treatment Period continues until 1 of the following occurs (whichever 
occurs first): completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures, or completion of 24 weeks of the Treatment Period 
without occurrence of 2 PGTC seizures. 
b
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or TCs, at the discretion of the investigator. In addition to the required 
assessments indicated above, depending on the type of visit (clinic or telephone), further assessments can be completed as needed and may include ECG, 
vital signs, laboratory tests, etc. The C-SSRS must be performed (for subjects ≥6 years of age) if the unscheduled visit is due to an AE. 
c
A window of ±2 days relative to Visit 1 is applicable for all protocol specified visits and TCs. During the Treatment Period, each visit should occur at the 
end of the week indicated in accordance with this time window.
d
All assessments at Visit 2 should be conducted prior to the first dose of study drug. At the end of the Prospective Baseline, subjects will be randomized at 
Visit 2 to receive LCM or placebo in a 1:1 fashion (active:placebo) and commence the Treatment Period with a 6-week, double-blind, flexible dose titration 
(see Section 7.2.1). 
REDACTED 
D
ACT
DA
DA
DA
DA
blood p
blood 
choo
choo
COPY 
Y
X
Y
X
OPY
This document canno
s
ot 
ac
a
houl
houl
M or pla
or pla
be 
o Vi
Vi
cord
cord
used 
ng o
g o
e C-SS
SS
isit
isit
to 
any
ny
on th
on th
support 
domi
om
atment 
tmen
y tim
y tim
any 
mizat
miza
marketing
pre
l Versi
l Versi
D-3L
3L=E
onal Rev
nal Re
C=prim
C=pr
authorization 
tio
X
atiti
h
ti
ho
uth
essur
ssur
application 
on
io
X
ca
pli
plplplpl
ap
and 
d
nd
a
any 
X
y
a
extensions 
ns
e Peri
Peri
sio
V8
V8
en
xt
e
or 
or variations 
on
Peri
erio
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 25 of 267
e
Subjects and/or caregivers will receive TCs throughout titration (Study Weeks 1, 3, and 5) to discuss titration dosing options. 
f
Once the subject has experienced 2 PGTC seizures, the site may contact the Medical Monitor to confirm whether the subject has met the exit criteria. If the 
exit criteria are met, sites will be advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure (Section 6.3). 
g
The complete physical examination will include cardiac and respiratory function via auscultation, and review of all body systems.
h
The brief physical examination will include review of the following body systems: cardiovascular, pulmonary, abdominal (hepato-gastrointestinal), and 
dermatologic.
i
The complete neurological examination will include selected assessments of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function.
j
The brief neurological examination will include selected assessments of general neurological status, reflexes, muscle strength, and coordination/cerebellar 
function.
k
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample collection and vital sign assessments. Care 
should be taken to assure proper lead placement and quality ECG recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to 
each recording and should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
l
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
m
Subjects are required to have had an EEG showing discharges consistent with IGE prior to Visit 1. A confirmatory EEG may be performed during the
Prospective Baseline, if approved by the Central Reviewer. Investigators will send a copy of the EEG report to the Central Reviewer. The information 
provided will be reviewed and any questions regarding the subject’s eligibility will be discussed with the investigator prior to the subject being randomized.
n
The Tanner Stage will be performed only for subjects who are pubescent at Visit 2 or who enter puberty during the course of the study. 
o
Urinalysis will be required for all subjects.
p
Serum pregnancy tests will be conducted at the following visits: Visit 1, Visit 10/ET Visit. At Visit 2, a urine dipstick pregnancy test should be performed 
prior to IRT contact. The result of the urine dipstick test must be negative prior to administration of the first dose of study drug. All other pregnancy tests (ie, 
Visits 3 through Visit 9) will be urine dipstick. Pregnancy tests will be performed for female subjects of childbearing potential only.
q
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 2 successive bid doses.
r
An IRT will be used to control all drug distribution and inventory for this study.
s
At all visits, subjects and/or caregivers will be reminded to report the occurrence of all seizure types, including days without seizures.
t
During the Maintenance Period, a single dose reduction is allowed as long as the minimum target dose is maintained (see Table 7‒3). Once the dose has been 
reduced, it cannot be increased. Subjects who are not able to tolerate the minimum target dose during the Maintenance Period will be withdrawn from the 
study. All dose reductions should be discussed with the Medical Monitor.
u
At Visit 2, subjects should take the first dose of study drug in the clinic.
v
The Achenbach CBCL/1½-5 is for children <5 years and 11 months of age and the CBCL/6-18 is for children ≥6 years to <18 years of age; the questionnaire 
is to be completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). For each subject, the same version of the scale that was 
completed at Visit 2 (CBCL/1½-5 or CBCL/6-18) should be maintained for the duration of the study and should be completed by the same parent/legal
representative. 
w
The BRIEF-P should be used for subjects who are <5 years of age at Visit 2 and the BRIEF should be used for subjects who are ≥5 years of age at Visit 2. 
The same version of the scale that was completed at Visit 2 (BRIEF-P or BRIEF) should be maintained for each subject for the duration of the study.
REDACTED
s will 
s will
eligibil
eligibil
bescent
bescen
ts: V
ts: V
COPY 
proper 
proper 
h IGE
h IGE
This document
ld be
d be
n of th
of th
cannot 
ent
en
CL/1½
L/1½
be u
e u
be 
for 
or 
nt(s)/
nt(s)/
used 
scu
cu
first do
irst do
chi
chi
to
who
w
usse
usse
support 
an
eminde
minde
e reduct
reduc
ho are
o ar
any
ns w
ns 
nd inv
d inv
marketing 
Visit 1, 
Visit 1,
be nega
be neg
ests wil
sts w
will
wi
authorization
s
E prior
E prior
end a c
end a 
ity wil
ty wil
t at Vis
at Vis
application 
ood
od
ects sho
cts sho
ars of a
ars of a
ized cu
zed cu
and 
d sa
d sa
any 
xes, m
xes, m
extensions
sys
sys
minal (
minal (
mototor fu
r fu
or 
ur
ur
stste
variations 
on
as met 
met 
re (S
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 26 of 267
x
The EQ-5D-3L will be performed in subjects who are ≥12 years of age.
y
The QOLIE-31-P will be performed for subjects who are ≥18 years of age and the PedsQL will be performed for subjects <18 years of age. The version of 
the PedsQL used should be consistent with the subject’s age at Visit 2 and should be maintained for each subject for the duration of the study. 
z
The C-SSRS will be completed for all subjects ≥6 years of age. 
aa
Thyroid function will be required in subjects <18 years of age only.
bb
Participation in the study starts from the time of signing the approved Informed Consent/Assent form. However, sites may conduct prescreening EEGs and 
prior to this, subjects will read and sign a separate Informed Consent form that has been approved by an IRB/IEC and the Sponsor, and which complies with 
regulatory requirements.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions 
tes may
es may
C and 
C and 
or 
tio
tio
variations 
on
yea
ears o
rs o
on o
on o
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 27 of 267
Table 5‒2:
Schedule of study assessments for SP0982 (Transition Period)
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=Early Termination; IRT=interactive response technology; TC=telephone contact
Note: For all transition visits, a window of ±2 days relative to Visit 1 (Baseline Period) is applicable. Each visit 
should occur at the end of the week indicated in accordance with this time window.
a
At the end of Visit 10/ET, subjects who complete the study may be eligible to participate in an open-label 
extension study (EP0012). Subjects who choose to enroll in the open-label extension study will proceed to a 
blinded 4-week Transition Period. 
b
A Transition TC is required. A Transition Clinic Visit is optional, at the discretion of the investigator. Subjects 
requiring a clinic visit will have the same assessments conducted as an Unscheduled Visit.
c
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain 
accurate measurements.
d
The complete physical examination will include cardiac and respiratory function via auscultation, and review of 
all body systems.
Assessment
Transition Period 
(4 weeks)a
Transition TC or 
Visitb
Final Clinic Visit 
(EP0012 Visit 1)
2 weeks after 
Visit 10/ET
Concomitant medications and AED(s)
X
X
Body weight
X
Height
X
Physical exam (complete)d
X
Neurological exam (complete)e
X
12-lead ECGf
X
Vital signs (BP and pulse) including orthostatic assessmentsc
X
Laboratory tests:
Chemistry/hematology
X
Urinalysisi
X
Endocrinologyk
X
Pregnancy testj
X
Contact IRT
X
Subject diary return/reviewg
X
Study drug review/return
X
Withdrawal criteria
X
X
AE reporting
X
X
C-SSRSh
X
Healthcare resource use
X
Work/school days lost due to epilepsy
X
Days with help from a caregiver  due to epilepsy
X
Socio-professional data
X
REDACTED 
ED
CT
DA
R
COPY 
PY
CO
This document
A
cannot 
troc
ro
or all
or all
uld occ
d occ
A
be
event
ven
card
car
us
t;t;
used 
nal da
al da
d
m 
m 
d
us
to
a ca
a ca
o support 
rt 
due to e
ue to e
pp
s
any 
ny marketing 
ng
ke
ma
authorization 
n
on
za
ho
au
application 
ion
ica
pp
a
and 
d
an
any y
a
extensions 
X
ns
sio
te
ex
e
or 
X
r variations 
)
on
tio
v
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 28 of 267
e
The complete neurological examination will include selected assessments of mental status, sensory systems, 
motor functions, cranial nerves, reflexes, and coordination/cerebellar function.
f
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample 
collection and vital sign assessments. Care should be taken to assure proper lead placement and quality ECG 
recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to each recording and 
should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs
(2 interpretable recordings) approximately 20 to 30 minutes apart must be performed.
g
The subject diary will be dispensed at Visit 1. At all subsequent visits, subjects and or caregivers will be 
reminded to report the occurrence of all seizure types, including days without seizures.
h
The C-SSRS will be completed for all subjects ≥6 years of age.
i
Urinalysis will be required for all subjects.
j
Urine pregnancy tests will be performed for female subjects of childbearing potential only.
k
Thyroid function will be required in subjects <18 years of age only.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 29 of 267
Table 5‒3:
Schedule of study assessments for SP0982 (Taper Period and Safety 
Follow-up Period) 
Assessment
Taper Perioda
(up to 4 weeks)
Safety Follow-up Periodc
End of Taper 
Visitb
Safety Follow-up Visit
Safety Follow-up TC
2 weeks (±2 days)
after last dose of 
study drug
30 days (-1/+3 days) 
after last dose of 
study drug
Concomitant medications and AED(s)
X
X
X
Physical exam (complete)k
X
X
Neurological exam (complete)l
X
X
12-lead ECGh
X
Xi
Vital signs (BP and pulse) including 
orthostatic assessmentsj
X
X
Body weight
X
X
Laboratory tests:
Chemistry/hematology
X
Xi
Endocrinologym
Xi
Urinalysisf
X
X
Pregnancy testg
X
X
Contact IRT
X
Subject diary return/reviewd
X
Study drug review/return
X
Withdrawal criteria
X
AE reporting
X
X
X
C-SSRSe
X
X
Healthcare resource use
X
X
Work/school days lost  due to 
epilepsy
X
X
Days with help from a caregiver  due 
to epilepsy
X
X
Socio-professional data
X
X
REDACTED 
D
X
CT
DA
RE
COPY 
Y
CO
CO
CO
CO
CO
This document cannot
profes
rofes
t
nn
be 
lp
b
used 
from
from
se
to
stst d
support t
p
due
su
any y 
a
marketing 
X
X
g 
ket
ma
m
authorization 
n
at
riz
or
X
ut
application 
X
on
ca
pp
and 
d any y
ny
a
extensions 
y d
y
X
ns
sio
te
e
or
o
dru
dru
variations 
n
TC
TC
n
on
days)
days)
ose o
se o
at
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 30 of 267
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=early termination; IRT=interactive response technology; TC=telephone contact
a
Subjects completing Visit 10 (Week 24) or the ET Visit who choose not to continue in EP0012 must complete a 
blinded taper followed by the End of Taper Visit. 
b
An End of Taper Visit will be scheduled at the end of the Taper Period (up to 4 weeks) depending on dose level 
achieved; see Table 7‒5. Of note, for subjects who enter the Taper Period at ≤2mg/kg/day (oral solution) or 
100mg/day (tablets), the End of Taper Visit will take the place of the ET Visit.
c
There will be a 30-day (-1/+3 days) Safety Follow-up Period for subjects who complete the End of Taper Visit. 
The Safety Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks 
later by a TC. After the 125th event occurs, the 30-day Safety Follow up Period will be done as part of EP0012, 
except if the subject refuses to sign the EP0012 informed consent form. If the subject signs the informed 
consent form for a short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as 
part of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
d
The last subject diary will be returned at the End of Taper Visit.
e
The C-SSRS will be completed for all subjects ≥6 years of age.
f
Urinalysis will be required for all subjects.
g
Urine pregnancy tests will be performed for female subjects of childbearing potential only.
h
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample 
collection and vital sign assessments. Care should be taken to assure proper lead placement and quality ECG 
recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to each recording and 
should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs
(2 interpretable recordings) approximately 20 to 30 minutes apart must be performed.
i
The assessment will be required only for subjects with an abnormal value (clinical chemistry, hematology, or 
endocrinology) or reading (ECG) at the previous clinic visit.
j
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain 
accurate measurements. 
k
The complete physical examination will include cardiac and respiratory function via auscultation, and review of 
all body systems.
l
The complete neurological examination will include selected assessments of mental status, sensory systems, 
motor functions, cranial nerves, reflexes, and coordination/cerebellar function.
m
Thyroid function will be required in subjects <18 years of age only.
REDACTED
cardiac
ardia
l includ
nclu
and co
and c
bjects
bjects
COPY 
sit.
it.
proper
prop
This document cannot be used to support any marketing 
 <18 y
<18 
authorization 
r plpl
and re
and re
de sele
e sele
ordina
ordina
application
rs of a
rs of a
t be per
be pe
value (
value 
lacem
acem
and
d pla
d pla
utes p
utes p
any
onl
on
and pr
and p
acem
extensions 
per
nlyly
or
d
rform
rfor
variations 
.
 
P0012,
0012,
d
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 31 of 267
5.3
Schematic diagrams for SP0982
The schematic diagram for the Combined Baseline Period eligibility is provided in Figure 5-1.
A schematic diagram for the Prospective Baseline Period through the Taper Period with 
successive panels for pediatric subjects weighing <30kg, pediatric subjects weighing ≥30kg to 
<50kg, and adult subjects and pediatric subjects weighing ≥50kg is provided in Figure 5‒2. The 
schematic diagram for the Transition Period is provided in Figure 5‒3.
Figure 5-1:
Combined Baseline Period seizure eligibility for SP0982
REDACTED 
D COPY 
This document cannot be used to support any marketing authorizatio
tion application and any 
ns 
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 32 of 267
Figure 5‒2: SP0982 Prospective Baseline Period through the Taper Period schematic diagram
V1
V2
V3-V4 
V5
V6-V10/ET
V10
Taper 
Prospective 
Baseline Period
Titration Period
Maintenance Perioda
Taper Periodb
12mg/kg/day or
placebo
10mg/kg/day or 
placebo
8mg/kg/day or 
placebo
9 or 
8mg/kg/day 
or placebo
Subjects
6mg/kg/day or 
placebo 
6mg/kg/day 
or placebo
<30kg
4mg/kg/day or 
placebo
4mg/kg/day or 
placebo
2mg/kg/day or 
placebo 
2mg/kg/day 
or placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum dose 
achieved during the Maintenance 
Period.
W -4 to 0
W1
W2
W3
W4
W5
W6
W 7 through W 24
W1
W2
W3
W4
V1
V2
V3-V4 
V5
V6 –V10/ET
V10
Taper
Prospective 
Baseline Period
Titration Periodc
Maintenance Perioda
Taper Periodb
8mg/kg/day or
placebo
Subjects
6mg/kg/day or 
placebo
6 mg/kg/day 
or placebo
≥30kg and 
<50kg
4mg/kg/day or 
placebo
4mg/kg/day or 
placebo
2mg/kg/day or 
placebo
2mg/kg/day or 
placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum 
dose achieved during the 
Maintenance Period.
W-4 to 0
W1
W2
W3
W4
W5
W6
W7 through W24
W1
W2
W3
W4
REDACTED 
be adju
e adju
ical jud
ical jud
W
DA
DA
DA
DA
DA
DA
DA
DA
DA
RE
RE
RE
RE
RE
RE
RE
RE
RE
RE
RE
COPY 
Y
PY
PY
PY
PY
PY
PY
PY
PY
PY
P
This document cannot t
ot
ot
ot
ot
ot
ot
o
0
no
no
no
no
no
no
an
an
an
an
an
an o be 
Dur
Dur
used
la
or 
ebo
ebo
ed
ed 
d
ed
ed
ed
e
to
ay
aceb
ceb
t
support 
g/day o
/day 
plac
plac
y or 
or 
up
up
up
up
u
any 
P
g/kg/da
/kg/d
p
mark
Period
erio
rketing 
5
g
tititititin
tin
tin
tinin
rk
authorization 
itititititi
ati
ati
ati
at
at
at
at
a
sted up
sted up
gment
ment
a
ut
ut
ut
ut
ut
ut
ut
ut
a
application
tion 
tio
d
and 
d
y
any 
any
a
extensions
oioioioioioioioioi
e
ns 
0
ns or 
or
or
or
or
or
or variations 
on
am
am
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 33 of 267
Figure 5‒2: SP0982 overall schematic diagram
V1
V2
V3-V4 
V5
V6–V10/ET
V10
Taper
Prospective 
Baseline Period
Titration Periodc
Maintenance Perioda
Taper Periodb
400mg/day or 
placebo
Subjects
300mg/day or 
placebo
300mg/day 
or placebo
≥50kg
200mg/day or
placebo
200mg/day or 
placebo
100mg/day or 
placebo
100mg/day or 
placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum 
dose achieved during the 
Maintenance Period.
W-4 to 0
W1
W2
W3
W4
W5
W6
W7 through W24
W1
W2
W3
W4
ET=Early Termination; LCM=lacosamide; V=Visit; W=Week
Note: Lacosamide dosing is designated as “mg/kg/day” (oral solution) and “mg/day” (tablets) and matching placebo is shown as “placebo.”
a Subjects will be required to achieve and maintain a minimum LCM (or matching placebo) dose for at least the final 3 days of Week 6 to be eligible for entry 
into the Maintenance Period.
b If the subject discontinues from the study at any time and is not eligible or chooses not to enter EP0012, the subject must complete the ET Visit or Visit 10 
(Week 24) and an up to 4-week blinded taper followed by an End of Taper Visit. There will be a 30-day Safety Follow-up Period for subjects who complete the 
End of Taper Visit. After the 125th event occurs, the 30-day Safety Follow up Period will be done as part of EP0012, except if the subject refuses to sign the 
EP0012 informed consent form. If the subject signs the informed consent form for a short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up 
will be performed as part of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
c If the subject is in the Titration Period when the 125th event occurs, the subject will proceed to the Transition/Taper period directly after their ET/V10 Visit.
REDACTED 
“mg/da
“mg/da
or matc
r mat
eligib
eligib
d o
d o
COPY 
Y
PY
PY
PY
PY
W6
PY
PY
PY
PY
PY
PY
PY
PY
PY
CO
CO
CO
CO
CO
CO
CO
COPY
PY
PY
PY
P
This document cannot be used to support any
Fol
Fo
ent oc
nt oc
marketing 
le or 
e or 
of Taper
f Taper
ety Follo
y Fol
med con
med co
ollow
ollo
authorization 
n
ay”
y” (ta
(ta
ching p
hing p
ch
application 
dose red
ose re
Maintena
ainten
minimum
nimum
pp
pp
pp
pp
pp
pp
pp
pp
a
and any y
ensions 
n
exten
exten
e
or r variations 
on
ar
ar
ari
ar
ari
ari
ari
aririririri
v
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 34 of 267
Figure 5‒3: SP0982 Transition Period schematic diagram
Maintenance Period 
(18 weeks)
Transition Perioda
(4 weeks)
Entry into EP0012
(Follow-up study)
12mg/kg/day 
12mg/kg/day
10mg/kg/day 
10mg/kg/day
10mg/kg/day
9mg/kg/day
9mg/kg/day
Subjects
8mg/kg/day
8mg/kg/day
<30kg
6mg/kg/day
4mg/kg/day
2mg/kg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
Maintenance Period 
(18 weeks)
Transition Perioda
(4 weeks)
Entry into EP0012
(Follow-up study)
8mg/kg/day 
8mg/kg/day
8mg/kg/day
7mg/kg/day
7mg/kg/day
Subjects
6mg/kg/day
6mg/kg/day
≥30kg and
4mg/kg/day
<50kg
2mg/kg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
TW
TW2
CT
CT
CT
CT
CT
CT
CT
CT
DA
DA
DA
DA
DA
DA
DA
DA
COPY 
2
C
This document cannot be 
e used 
d
u
to 
t
support 
2mg/k
2mg/
pp
any y
a
market
ma
eting 
et
authorization 
ioioioioio
or
or
or
or
or
or
ut
ut
ut
ut
ut
ut
ut
ut
application
kg/day
kg/da
tio
and 
d
a
any 
any extensions s
12
12
e
or 
o variations 
on thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 35 of 267
Figure 5‒3: SP0982 Transition Period schematic diagram
Maintenance Period 
(18 weeks)
Transition Perioda
(4 weeks)
Entry into EP0012
(Follow-up study)
400mg/day 
400mg/day 
400mg/day
400mg/day
350mg/day
350mg/day
Subjects
300mg/day
300mg/day
≥50kg
200mg/day
100mg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
TW=transition week
Note: Lacosamide dosing is designated as “mg/kg/day” (oral solution) and “mg/day” (tablets) and matching placebo is shown as “placebo.”
a If a subject is in the Titration Period and the next scheduled visit after the 125th event is not until Week 6, the subject will enter the Transition/Taper Period, and 
the escalation will be adapted accordingly.
REDACTED
25
25thth ev
e
COPY 
PY
PY
PY
PY
PY
PY
PY
PY
PY
day” (
ay” (
This document cannot be used to support any marketing authorization
tablets
tablets
entnt is 
is 
application 
TW
TW
at
at
at
at
ati
ati
ati
ati
atitititi
pp
pp
pp
pp
pp
pp
pp
pp
and any extensions 
400mg
00mg
en
or variations 
on
va
va
va
va
va
va
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 36 of 267
5.4
Rationale for study design and selection of dose
Clinical experience has shown that up to 30% of patients with PGTC seizures who are treated 
with currently available AEDs have insufficient seizure control or unacceptable drug tolerability. 
Thus, there is a significant unmet medical need for new treatment options in this patient 
population. 
In 3 primary efficacy studies (SP667, SP754, and SP755), adjunctive LCM treatment has 
demonstrated efficacy and was well tolerated in the treatment of secondary generalized seizures 
in subjects with uncontrolled partial-onset seizures. In these studies, LCM dose titration was
initiated at 100mg/day (in 2 divided doses) and escalated to the randomized dose 
(LCM 200mg/day, LCM 400mg/day, or LCM 600mg/day) in 100mg/day per week increments. 
These 3 primary efficacy studies were the basis of the approval of LCM as adjunctive therapy in 
the treatment of partial-onset seizures in subjects 16 years and older in the EU and 17 years and 
older in the US, with an established therapeutic dose range of 200mg/day to 400mg/day.
Additionally, the safety of LCM in subjects (16 to 65 years of age) with uncontrolled PGTC 
seizures with IGE was assessed in a clinically complete, Phase 2, multicenter, open-label, pilot 
study (SP0961). In this study, LCM dose titration was initiated at 100mg/day (in 2 divided 
doses) and increased to a maximum dose of LCM 400mg/day at weekly increments, as deemed 
clinically appropriate. Although evaluation of changes in PGTC seizure frequency was not 
intended for evaluation of efficacy, an assessment was made for exploratory purposes and a 
reduction in PGTC seizure frequency was observed. In addition, the AE profile was similar to 
that observed with adjunctive LCM for the treatment of subjects with partial-onset seizures, with 
the exception of seizure-related AEs.
5.4.1
Rationale for dose 
For adult subjects, the LCM 100mg/day dose was selected to be the starting dose for this study to 
ensure a safe and well-tolerated up-titration scheme. The LCM 400mg/day maintenance dose 
was well tolerated and demonstrated efficacy in 3 primary efficacy studies as adjunctive therapy 
in subjects with partial-onset seizures. In SP0961 (the Phase 2 pilot study) and SP0962 (the 
open-label extension study) in subjects with uncontrolled PGTC seizures with IGE, the
400mg/day dose was also well tolerated. Generally, the doses of AEDs used for the treatment of 
partial-onset seizures are similar to those used to treat generalized seizures. Thus, the 300mg/day 
to 400mg/day target dose range is considered the optimal maintenance dose for the population 
with uncontrolled PGTC seizures with IGE. 
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, as 
well as on information available in the medical literature, the pediatric dosing recommendations 
for SP0982 are to achieve LCM plasma concentrations similar to the average steady-state LCM 
plasma concentration reached after a LCM 400mg/day dose administration in adult studies.
A population PK model (CL0177) was developed using plasma concentration data and 
demographic information from all pediatric subjects in SP847 and SP1047. The data consisted of 
402 LCM plasma concentration-time records obtained in 79 children, with a balanced 
distribution of 14, 22, 25, and 18 subjects in the age groups 6 months to <2 years, 2 to <6 years, 
6 to <12 years, and 12 to <18 years, respectively. Body weights ranged from 6kg to 76kg. 
REDACTED 
erve
erv
treatm
treatm
COPY
ges in
ges in
t t was
was
ved
ed
This document
lasm
asm
A p
A 
cannot
on in
on in
SP09
P098
sma
ma
be
he
he cu
c
used 
get
get
led P
ed P
to 
es a
et do
t do
support
y) in s
in 
so wel
o we
are s
are s
any 
ate
at
seizur
eizu
marketing 
day
day dos
do
p titrati
itrat
ted e
ed
authorization
ma
ma
 In ad
n ad
ment o
ent o
application 
mul
mu
at 100
at 10
y at we
at w
y
PGTC
PGTC
ade
ade
and
ith u
th u
ultic
ltic
any
to 40
to 4
nc
extensions 
k incre
k incre
unctive
unctiv
U and
U and
0
or 
wa
wa
variations 
zures
ures
as
as
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 37 of 267
Different pediatric dosing adaptation schemes were simulated with the aim of reaching the range 
of average steady-state plasma concentration (CSS,ave) obtained in adults receiving LCM
400mg/day, which is approximately 8μg/mL (90% prediction interval: 5μg/mL to 12μg/mL). 
This was achieved with a dosing scheme of 12mg/kg/day in children weighing <30kg, 
8mg/kg/day in children weighing from 30kg to <50kg, and 400mg/day in children weighing 
≥50kg. The proportional pediatric dose adaptation corresponding to 300mg/day in adults and in 
children weighing ≥50kg, are 8mg/kg/day in children weighing <30kg, and 6mg/kg/day in 
children weighing from 30kg to <50kg.
5.4.2
Rationale for second PGTC seizure
The primary efficacy variable, the time to the second PGTC seizure, has several advantages from 
a clinical and methodological perspective. In traditional adjunctive study designs, the primary 
endpoint is percent reduction in seizure frequency over the entire Treatment Period; which 
requires a higher frequency of seizures at entry. Using the time to second seizure, the frequency 
of Baseline seizures and the duration of the Prospective Baseline can be reduced as the endpoint 
is time to reach an event (second seizure), rather than a percentage decrease in the number of 
events (seizures). This expands the patient population under study and allows for enrollment of 
subjects more representative of the broader PGTC seizure population. Furthermore, subjects are 
treated for up to 24 weeks in a traditional adjunctive design, depending upon the titration 
schedule of the active treatment. Subjects must remain on treatment as they continue to 
experience seizures. In the time to nth seizure design, subjects are required to remain in the study 
for a minimum of 6 weeks. If a subject experiences ≥2 seizures while on treatment, then after 
6 weeks the subject exits the study, rather than continuing to have PGTC seizures, while 
remaining eligible to receive LCM in the open-label extension study (EP0012).
The rationale for time to second seizure was established by using data from an adjunctive study 
in subjects with PGTC seizures, using an 8-week Baseline, 7-week Titration, and 12-week 
Maintenance Period comparing lamotrigine and placebo (French et al, 2007). This posthoc 
analysis using a Cox proportional hazards model revealed that time to third seizure was 
statistically significant with a hazard ratio of 0.533 (lamotrigine 48.2%, placebo 25.4%). 
Lamotrigine requires a long Titration Period, where a minimally effective dose is not reached 
until the fifth week of the Titration Period (100mg/day). Lacosamide, by comparison, reaches a 
minimally effective dose in the second week (200mg/day) for a majority of trial subjects. Since a 
majority of the events in the lamotrigine study occurred before Day 21, it is likely that fewer 
events would occur using LCM as it reaches an effective dose earlier; therefore, time to second 
seizure was chosen as a reasonable endpoint from a clinical and statistical perspective.
5.4.3
Rationale for minimum duration of treatment
The minimum duration of the Treatment Period for each subject will be 6 weeks. There are 
3 reasons for the requirement of a minimum Treatment Period duration:
•
To collect a minimum of placebo-controlled safety data for the entire study population
•
To allow for the analysis of reduction in seizure days for non-PGTC seizures (eg, absence or 
myoclonic seizures)
•
To allow for increased flexible dosing during titration
REDACTED
ence
ence
han co
han co
e open
ope
zure w
zure w
g a
g
COPY
ain on
ain o
ign, su
ign, s
es
This document
rea
rea
•
cannot 
minim
mini
aso
aso
be 
ch
sed
ccur u
ccur 
hose
hose
to
nts i
nts 
support
g Tit
Ti
he Titra
e Titr
ose in
ose in
ini
any
hazar
haza
itra
itr
marketing
was e
as 
an 8
an 8-w
motrigin
otrigi
hazar
haza
d
authorization
ubje
ubje
≥2
≥2 se
se
ontinu
ontinu
n-labe
labe
es
es
application 
an
an
ulation.
lation
depen
depen
n treatm
treat
ects
ects
and
crea
crea
nd a
d a
any 
eiziz
reduc
reduc
se
extensions
vantag
antag
s, the p
 the p
eriod
riod
zure
zur
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 38 of 267
Primary generalized tonic-clonic seizures are sparse but severe clinical events that profoundly 
affect the lives of patients. Should the minimum duration of the study be longer (eg, 12 weeks), 
this would prolong the time subjects randomized to placebo (or subjects randomized to LCM 
who do not respond to the treatment) have to stay on a nonefficacious treatment. By allowing 
subjects to exit the study after completing 6 weeks of the Treatment Period, sufficient 
double-blind safety data can be collected from a high proportion of subjects to be meaningful. 
Moreover, additional safety data will be available from the open-label, long-term, extension 
study (EP0012).
5.4.4
Rationale for selected age range
Idiopathic generalized epilepsies are assumed to have a genetic etiology and onset almost always 
occurs during childhood or adolescence, although there are exceptions; some patients develop 
these kinds of epilepsies after the second decade of life or, rarely, even later.
There are a number of different epilepsy syndromes within the group of IGEs. Patients with the 
most common IGE syndromes (ie, childhood absence epilepsy, juvenile absence epilepsy, 
juvenile myoclonic epilepsy, and epilepsy with grand mal seizures on awakening) may 
experience generalized tonic-clonic seizures. Onset of these syndromes normally occurs during 
childhood and adolescence.
The ≥4-year age cutoff was established based on the difficulty of establishing a clear diagnosis 
of IGE in younger subjects with PGTC seizures. This is further supported by epidemiology data, 
which indicates that the incidence and prevalence of generalized epilepsies is lower in 
preschoolers compared to older children (Olafsson et al, 2005).
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/Assent form is signed and dated by the subject or by the parent(s) or legal 
representative. The Informed Consent form or a specific Assent form, where required, will be 
signed and dated by minors.
2. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, and medication intake according 
to the judgment of the investigator.
3. Male and female subjects ≥4 years of age. 
4. Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset 
prior to 30 years of age, consistent with IGE experiencing PGTC seizures (Type IIE) that are 
classifiable according to the ILAE Classification of Epileptic Seizures (ILAE, 1981).
5. Subject has ≥3 PGTC seizures during the 16-week Combined Baseline (12-week Historical 
Baseline plus 4-week Prospective Baseline) distributed as described below:
−
at least 3 PGTC seizures should have occurred during the 16-week Combined Baseline 
Period, 
REDACTED 
nce 
nce
lafsso
lafsso
WIT
WIT
a
COPY
diff
diff
This is
This 
e of
e o
This document 
p
cannot 
 an
an
Subjec
ubjec
prio
prio
be 
g
nd f
nd f
used
unde
nde
gmen
men
to
epre
pre
support
forme
orm
y mino
mino
esen
ese
any 
rd 
rd
form
form
d
marketing 
study
tudy, a
d (IR
d (IR
authorization
s fu
fu
f gene
gene
on et a
n et a
HDR
HDR
application
drome
drom
cult
ulty o
y o
furth
urth
and 
e a
e a
n aw
n aw
any
GEs.
GEs
absen
abs
extensions
almost
lmos
ients d
ents d
P
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 39 of 267
−
at least 2 PGTC seizures should have occurred during the 12-week Historical Baseline 
Period, 
−
of the above seizures, at least 1 PGTC seizure should have occurred during the first 8 
weeks and at least 1 PGTC seizure should have occurred during the second 8 weeks of 
the 16-week Combined Baseline Period. 
The schematic diagram for the Combined Baseline Period eligibility is provided in 
Figure 5-1. Examples of PGTC seizure frequency and eligibility are provided in the table 
below: 
Number of PGTC seizures
Is subject eligible?
(In terms of 
Inclusion Criterion 5)
Historical Baseline
Weeks -16 to -8 
Historical Baseline
Weeks -8 to -4 
Prospective Baseline
Weeks -4 to 0
(Visit 1 to Visit 2)
2
1
0
Yes
3
0
0
No*
1
1
1
Yes
0
2
1
No
1
2
0
Yes
2
0
1
Yes
1
0
2
No
1
1
0
No*
Screening Visit
*Eligible to roll over to EP0012 if all other inclusion criteria are also met.
PGTC=primary generalized tonic-clonic
6. If a brain magnetic resonance imaging (MRI)/computed tomography (CT) scan has been 
performed, there must be no evidence of any progressive abnormality or any lesion likely to 
be associated with partial-onset seizures.
7a. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs with no benzodiazepine AEDs OR 1 benzodiazepine marketed AED with 1 to 2 
non-benzodiazepine marketed AEDs (see examples in the table below) for at least 28 days 
prior to Visit 1 with or without additional concurrent stable VNS (see Section 7.8).
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline and 
Treatment Period.
TE
1
DA
RE
COPY 
PY
CO
C
This document
V
canno
n
ot
w
-ben
ben
prior 
prior 
be 
ha
with
with
sed
d wit
wi
as be
s be
to
e m
e m
ith
ith
support 
onic
nic-
c reson
reson
must
mus
any 
all oth
all ot
clo
cl
marketing 
g authorization 
io
riz
riz
riz
riz
riz
uth
application 
1
on
1
ca
app
and 
nd any 
ny
a
extensions 
bject e
bject e
(In 
In
Inclu
Inclu
or 
or variations 
e
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 40 of 267
Benzodiazepine AEDs
Non-Benzodiazepine AEDs
Total AEDs
Is subject eligible?
(In terms of 
Inclusion Criterion 7)
0
1
1
Yes
0
2
2
Yes
1
1
2
Yes
1
2
3
Yes
1
0
1
No
0
3
3
No
2
1
3
No
AED=antiepileptic drug
8. Subjects are required to have had an EEG report consistent with IGE (eg, generalized ≥3Hz 
epileptiform discharges and a normal EEG background) confirmed by a Central Reviewer. 
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject has previously been randomized in this study or subject has previously been assigned 
to treatment in a clinical study of LCM.
2. Subject has participated in another study of an investigational medicinal product (IMP) or an 
experimental medical device within the last 30 days or is currently participating in another 
study of an IMP or a medical device. 
3. Subject has a history of partial-onset seizures or EEG findings indicative of partial-onset 
seizures.
4a. Subject has symptomatic generalized epilepsy ([ILAE, 1989] (eg, Lennox-Gastaut Syndrome
typically presenting with seizures including tonic seizures), some other related syndrome like 
Doose’s syndrome (typically presenting with myoclonic-atonic seizures), or evidence of both 
focal and generalized epilepsy.
5. Subject has a history of convulsive status epilepticus 1 year prior to screening.
6. Subject has a current or previous diagnosis of pseudoseizures, conversion disorders, or other 
nonepileptic ictal events which could be confused with seizures.
7. 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.
8. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening.
9. Subject has a known hypersensitivity to any components of the investigational product(s).
REDACTED 
y of a
y of a
the las
he la
ce.
ce.
nse
ns
COPY 
o
s study
s stud
This document
8. S
cannot 
bject
ject
eopar
eopar
S
be
epti
pti
h
used 
s a cu
 a cu
tic i
ic
to
istor
sto
support
ypicall
pical
ed epil
d ep
ry
any
ner
ner
seizur
eizur
marketing 
et seizu
t seizu
raliz
rali
authorization 
dy
an inve
n inve
ast 30 
st 30 
application 
e follow
follo
or su
or su
and 
E
ed b
d by
any 
(eg,
eg
extensions 
N
N
s
si
xt
or 
o
variations 
n
on
at
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 41 of 267
10. Subject has a medical condition that could reasonably be expected to interfere with drug 
absorption, distribution, metabolism, or excretion.
11. Subject has multiple drug allergies or severe drug allergy.
12. Subject has any history of alcohol, opioid, or other drug use disorder, as per Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), within the previous 2 years.
Note: previous sporadic cannabis use is not exclusionary as long as subject is requested and 
agrees not to use cannabis during the study.
13. Subject has an acute or sub-acutely progressive central nervous system disease.
14. Subject with a known history of severe anaphylactic reaction or serious blood dyscrasias.
15. At Visit 1, 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 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. This includes re-screening.
16. Subject has impaired renal function (ie, creatinine clearance [CLcr] is <30mL/min) at 
Screening (see Section 10.2).
17. Subject has a known cardiac channelopathy, such as Brugada syndrome.
18. Subject has sick sinus syndrome without a pacemaker, or second- or third-degree 
atrioventricular (AV) block, or subject has any other clinically significant ECG 
abnormalities.
19. Subject has experienced a myocardial infarction in the last 3 months prior to Visit 1.
REDACTED
at 
ng to e
ng to 
y rele
y rele
r.r.
r AL
r AL
COPY 
a
doe
doe
This document cannot be
has
has
used 
es.s.
as e
s e
to
(AV
(A
support
ardia
ardia
inus sy
nus sy
V)
V
any 
2).).
marketing
LP up 
P up
des re-
des re
nction
ction
authorization
es not 
s not 
ensure
ensure
evant 
evant 
application 
lir
ALT, A
LT, A
meaning
eanin
and
actio
acti
rubin
ubin
any
ndrom
ndro
iona
on
extensions 
dy
dyscra
scra
wing:
wing:
sphat
phat
or variations 
nd 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 42 of 267
20. Subject has New York Heart Association Class III or Class IV heart failure.
New York Heart Association Criteria:
Class I
Patients with cardiac disease, but without resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain.
Class II
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Class III
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased.
The Criteria Committee of the New York Heart Association, 1994
21. Female subject who is pregnant or nursing and/or a woman of childbearing potential who is 
not surgically sterile, 2 years postmenopausal, or does not practice 1 highly effective method 
of contraception (according to International Council for Harmonisation [ICH] guidance,
defined as those that result in a failure rate of <1% per year when used consistently and 
correctly), unless sexually abstinent, for the duration of the study.
Female subject of childbearing potential taking enzyme-inducing antiepileptic drugs 
(EI-AEDs: carbamazepine, phenytoin, barbiturates, primidone, topiramate, oxcarbazepine) 
who is not surgically sterile, 2 years postmenopausal, or does not practice 1 highly effective 
method of contraception according to the World Health Organization recommendation 
(ie, depot medroxyprogesterone acetate, norethisterone enantate, intrauterine devices, 
combined injectables, and progestogen implants) with administration of EI-AEDs or does not 
practice 2 combined methods of contraception (ie, combined hormonal contraception plus 
barrier method with spermicidal agent), unless sexually abstinent, for the duration of the 
study.
22. Subject has been taking 1 or more of the following medications on a regular basis within 
28 days prior to Visit 1: monoamine oxidase A (MAO-A) inhibitors, barbiturates (for 
indications other than epilepsy), or clozapine.
23. 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.
24. Subject has taken vigabatrin in the preceding 6 months. Note: A subject with a history of 
vigabatrin treatment must have had a visual perimetry test at least 6 months following 
conclusion of treatment. The results of the visual perimetry test must have shown either no 
damage or a visual field defect associated with 1 of the following 2 conditions: 1) there was 
no change from a visual field test done at some point while the subject was taking vigabatrin, 
or 2) there was no change from a visual field test done shortly after stopping vigabatrin 
administration.
taking
takin
, barb
barb
s post
pos
ng to 
ng to
COPY
1% pe
% p
duratio
duratio
This document
24. S
cannot
ned
e
r <12 
<12 
and w
and w
be 
ha
d as 
d as
sed
other
ther
as be
s be
to
 Vi
Vi
r th
r th
support 
aking 1
king 
Visit 
isit
any
micida
icida
marketing 
o the 
the 
cetate
etate
estogen
stoge
of co
of co
authorization
on o
on o
g enzy
g enzy
biturat
iturat
tmeno
meno
e W
application 
chi
chi
practic
ractic
Harmo
Harm
er y
r year 
ea
f t
f
and 
ildld
any 
an extensions
yspne
spne
ysical 
sical 
y be p
y be p
ns
or
They
The
variations 
or 
or 
on
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 43 of 267
25. 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.
Subjects may be rescreened with prior consultation and permission of the Medical Monitor. If 
the investigator has any doubts concerning the subject’s eligibility, he/she should consult the 
UCB Study Physician or representative for clarification.
6.3
Exit criteria
Subjects will be required to exit the study if either of the following events occurs:
•
Subject completes the first 6 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTC seizures during that time
•
Subject experiences a second PGTC seizure after the first 6 weeks of the Treatment Period
•
The 125th event occurs in the study
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure, 
with the following exception: if the 2 PGTC seizures occur during the first 6 weeks of the 
Treatment Period (after randomization), the subject should continue the Titration Period visits 
and wait for the end of the first 6 weeks of the Treatment Period to complete the ET Visit.
6.4
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Subjects must be withdrawn from the study if any of the following events occurs:
•
The subject is unable to attain at least the minimum Maintenance Period target dose 
(Table 7‒3).
•
The subject requires a subsequent dose increase after dose reduction during the Maintenance 
Period or the subject requires more than 1 dose reduction during the Maintenance Period.
•
Subject develops a second- or third-degree AV block.
•
The subject becomes pregnant, as evidenced by a positive pregnancy test.
•
The sponsor or a regulatory agency requests withdrawal of the subject.
•
The subject is unwilling or unable to continue and withdraws consent.
•
In the case of liver function test (LFT) results of transaminases (AST and/or ALT) ≥3xULN 
to <5xULN and total bilirubin ≥2xULN or transaminases (AST and/or ALT) ≥5xULN, LCM 
must be immediately discontinued and the subject withdrawn from the study. The LFTs will 
be repeated as soon as possible, and in no case more than 1 week later.
•
Subject ≥6 years of age has actual suicidal ideation as indicated by a positive response 
(“Yes”) to either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. 
The subject should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
REDACTED 
dy
dy at a
at a
y
he stu
he stu
COPY 
hou
o
tment
tmen
This document cannot 
sub
ub
n the 
n the 
to <
to <
be 
bjec
bjec
used 
eco
ec
or or
or or
o
com
om
support
equir
quir
a secon
seco
any 
seque
sequ
res
marketing 
udy
udy i
y f
least th
least 
authorization 
any
ny tim
ti
y
f
application
f the
f the
uring th
ring t
contin
conti
Perio
Perio
and 
tac
ac
iteria 
teria 
any 
ct the
ct the
extensions 
an
eatme
atme
or 
nd d 
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 44 of 267
Subjects may be withdrawn from the study if any of the following events occur:
•
The subject requires a medication that is not permitted.
•
The subject requires a modification to concomitant AED dose(s) during the study (see 
Section 7.8).
•
The subject is unable to manage the completion of the diary, demonstrates a questionable 
diary, or is noncompliant with the study procedures or medications in the opinion of the 
investigator.
•
An episode of status epilepticus, a prolongation of seizure duration, a worsening of seizure 
frequency, or emergence of a new seizure type considered by the investigator to require 
intervention.
•
Subject develops a clinically relevant change in medical condition (or ECG or laboratory 
parameter) as determined by the investigator, and the investigator feels it is in the interest of 
the subject to withdraw.
•
Subject develops an intolerable AE during the course of the study.
•
Discontinuation criteria for potential drug-induced liver injury (PDILI) are described in 
Section 6.4.1.
Investigators should attempt to obtain information on subjects, in the case of withdrawal. For 
subjects considered as lost to follow up, the investigator should make an effort (at least 1 phone 
call and 1 written message to the subject), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The 
electronic Case Report form (eCRF) must document the primary reason for withdrawal.
Investigators should contact the Medical Monitor whenever possible to discuss the withdrawal of 
a subject in advance.
6.4.1
Potential drug-induced liver injury IMP discontinuation criteria
Subjects with PDILI must be assessed to determine if IMP must be immediately and permanently
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: 
•
ALT or AST ≥5xULN
•
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
•
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%).
REDACTED
vest
ves
and do
nd do
age in 
ge in 
tions 
tions 
bject
bject
COPY 
n on s
n on 
stig
stig
This document 
•
S
cannot
T or 
or 
AL
ALT
be 
crit
rit
A
used
sary
ary
iteri
teri
to
ditio
diti
s
support
drug
drug
must be
must b
ion
on
any 
g
marketing
t, mus
t, mu
must d
must 
Medica
Medic
authorization
subj
ubj
gator s
ator s
ocume
cume
the so
the so
and o
nd o
application 
udy
njury
ury (P
(
y
ject
ect
and 
y
any
s it i
s it 
extensions
f s
o requi
o requ
CG or
G or
or
seizu
eiz
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 45 of 267
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).
Evaluation of PDILI must be initiated as described in Section 10.2.1. 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 product
Investigational medicinal product will be provided as LCM oral solution (syrup)
(LCM 10mg/mL), LCM tablets (LCM 50mg), and matching placebos.
The LCM 10mg/mL oral solution and matching placebo oral solution are colorless to pale yellow 
in appearance. Both oral solutions will be packaged in amber polyethylene terephthalate (PET) 
bottles. Oral solution doses will be measured and administered via a dosing syringe.
The LCM 50mg tablets and matching placebo are white, oval tablets debossed with “SP” on one 
side. Tablets will be packaged in high-density polyethylene (HDPE) bottles.
7.2
Treatments to be administered
Study medication will be administered orally bid (at approximately 12-hour intervals in the 
morning and in the evening).
At Visit 2, subjects will be randomized to receive either LCM (oral solution for pediatric subjects
[≥4 to <18 years of age] weighing <50kg or tablets for adult subjects [≥18 years of age] and 
pediatric subjects weighing ≥50kg) or matching placebo. At the end of Visit 2, subjects should 
take the first dose of study drug while in the clinic. Treatment assigned will be determined by the 
subject’s weight at Visit 2.
Tablets are 50mg and must not be broken; instead unequal dosing is allowed – if subjects are
taking an odd number of tablets per day (eg, 7 tablets totaling 350mg), they should take the 
lower dose in the morning (eg, 150mg [3 tablets]) and the higher dose in the evening (eg, 200mg
[4 tablets]).
SP0982 will target Maintenance Period doses of LCM or matching placebo as presented in 
Table 7‒3.
7.2.1
Titration Period
Table 7‒1 provides the recommended LCM (or matching placebo) dosing during the Titration 
Period for subjects to reach the target doses for the Maintenance Period. All subjects should 
REDACTED
p
ckage
ckag
red an
ed an
place
place
gh
gh-de
de
COPY
match
match
place
place
This document
[4 tab
4 ta
S
cannot 
are 
re 
g an od
an o
wer do
er do
b
be 
g
e 50m
e 50m
used
se of
e of
ght at
ht at
to
weig
weig
f
support 
be rand
e ran
ge] wei
we
ghin
gh
any 
stst
marketing
ensit
ensity
e adm
adm
tered
ere
authorization
ebo or
ebo o
ed in a
d in a
nd adm
nd adm
bo are
o ar
application
al pr
al pr
oral so
oral so
ing pla
ng pl
and any extensions
the 
he 
nd d 
drawa
rawa
d
ument
ment
or
tinu
tin
stu
st
variations 
nuat
uat
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 46 of 267
follow this recommended dosing schedule, unless dose adjustments based on tolerability are 
needed. 
Table 7‒1:
Recommended dosing schedule for LCM (or matching placebo) 
during the Titration Period
Body weight 
category 
(formulation)
Target LCM (or matching placebo) doses for the Titration Period
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<30kg (oral 
solution)a
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/day
12mg/kg/day
≥30kg to <50kg 
(oral solution)a
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
8mg/kg/day
8mg/kg/day
≥50kg (tablets)b
100mg/day
200mg/day
300mg/day
400mg/day
400mg/day
400mg/day
LCM=lacosamide
a The oral solution formulation is for pediatric subjects weighing <50 kg.
b The tablet formulation is for adult subjects (≥18 years of age) and pediatric subjects weighing ≥50kg.
Table 7‒2 provides LCM (or matching placebo) dosing with flexibility based on tolerability 
during the Titration Period.
Table 7‒2:
Dosing of LCM (or matching placebo) with flexibility based on 
tolerability during the Titration Period
Body weight category
(formulation)
Target LCM (or 
matching 
placebo) dose 
increase/weeka
(titration)
LCM (or matching placebo) 
dose decrease per
back-titration step
Subsequent LCM (or 
matching placebo) dose 
increase
(dose increase after 
back-titration step)
Min
Max
Min
Max
<30kg (oral solution)
2mg/kg/day
1mg/kg/day
2mg/kg/day
1mg/kg/day
2mg/kg/day
≥30kg to <50kg (oral 
solution)
≥50kg (tablets)
100mg/day
50mg/day
100mg/day
50mg/day
100mg/day
LCM=lacosamide; Max=maximum; Min=minimum
Note: Asymmetrical dosing with no more than 50mg difference between morning and evening doses will be allowed 
for subjects who require back titration in a 50mg increment.
a Titration step to achieve a dose not previously administered.
All subjects are required to complete Week 1 dosing before study drug dosing flexibility based 
on tolerability is allowed. Investigators will assess whether a subject would tolerate a further 
study drug dose increase or whether a subject should hold the dose for a longer duration. There is 
no limit to the number of back-titration steps or dose holds allowed and all are at the 
investigator’s discretion; however, subjects must achieve the minimum LCM (or matching 
placebo) target dose by the end of the Titration Period (Table 7‒3). If it becomes apparent that a 
subject is unable to attain at least the minimum Maintenance Period target dose, then the subject 
must enter the Taper Period and be withdrawn from the study.
REDACTED
g 
g
ratio
ratio
M (or
M (or
g
CT
DA
COPY 
plac
plac
This document
study
tudy
no 
no
cannot 
bjbjects
ects
tolera
olera
be
ho 
ep to 
ep to
used 
Max
ax
cal dos
al dos
requ
requ
to 
o
x=m
x=m
support 
2mg
2m
up
su
any 
g/k
y marketing
se
se
week
eeka
tion)
ion)
LC
LC
tin
authorization
cebo
cebo
n Per
n Pe
C
or
application 
j
flexibi
flexib
and 
ects w
cts w
any 
g
y extensions 
8
ns
si
g/day
/day
te
or
mg/k
mg/
variations 
on
6
io
/kg
/kg
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 47 of 267
Subjects who titrate to a next higher dose level should remain at that dose prior to a dose increase 
for ≥7 days unless a back-titration step is required based on tolerability. Subjects who have their 
study drug back titrated must remain on the lower dose for ≥3 days (in order to reach steady 
state) before a subsequent dose increase. 
As outlined in Table 7‒3, subjects will be required to achieve and maintain a minimum LCM (or 
matching placebo) dose for at least the final 3 days of Week 6 (to achieve steady-state 
concentrations) to be eligible for entry into the Maintenance Period. Subjects may have a 
back-titration step as late as the last day of Week 6 as long as the minimum target dose is 
maintained. 
Table 7‒3:
Required LCM (or matching placebo) dose for at least the final 3 days 
of Week 6
Body weight category
(formulation)
LCM (or matching placebo) dose for at least the final 3 days of Week 6
Min
Max
<30kg (oral solution)
8mg/kg/day
12mg/kg/day
≥30kg to <50kg (oral solution)
6mg/kg/day
8mg/kg/day
≥50kg (tablets)
300mg/day
400mg/day
LCM=lacosamide; Max=maximum; Min=minimum
7.2.2
Maintenance Period
Subjects will enter an 18-week Maintenance Period at the dose they received on the last day of 
the Titration Period in accordance with targeted Maintenance Period dosing (Table 7‒3). 
During the Maintenance Period, a single dose reduction is allowed as long as the minimum target 
dose is maintained. Once the dose has been reduced, it cannot be increased. Subjects who are not 
able to tolerate the minimum target dose during the Maintenance Period (Table 7‒3) will be 
withdrawn from the study and enter an up to 4-week blinded Taper Period. All dose reductions 
should be discussed with the Medical Monitor.
7.2.3
Transition Period (for subjects who enter EP0012)
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period or when the 125th event occurs in the 
study (whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012. Subjects completing Visit 10 (Week 24) or the ET 
Visit must complete a 4-week blinded transition followed by a Final Clinic Visit. Two weeks 
after Visit 10 (Week 24) or the ET Visit, a Transition telephone contact is required; a subsequent 
Clinic Visit is at the discretion of the investigator (Table 5‒2). The background AED may be 
adjusted during the Transition Period at the discretion of the investigator. The Final Clinic Visit 
is the same as Visit 1 of EP0012. 
The following schematic displays the scenario for subject dispensation: 
Visit 10 
or ET Visit
2 weeks
Transition 
TC/Visita
2 weeks 
Final Clinic Visit 
(EP0012 Visit 1)
ET=Early Termination; TC=telephone contact 
a
A Transition TC is required. A Transition Clinic Visit is optional, at the discretion of the investigator.
REDACTED
Perio
Perio
geted 
geted 
gle dos
gle dos
as be
as be
COPY 
d
This document
s the
the
Th
T
cannot 
it 1
t 
Visit
Visit
usted 
sted 
be 
com
10 (
10 (
used
co
c
hoose
oose
mple
mple
to
ome
om
support 
Pe
Pe
eeks an
eks a
eting t
eting 
any 
d
eriod
erio
marketing
een re
en re
ose dur
ose du
r an up
u
ical M
ical
authorization 
d at th
d at th
d Main
Main
se red
e red
d
application 
tio
icicicica
and 
d
a
any 
fif
y
a
extensions 
he fin
e fin
final
ina
xt
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 48 of 267
Subjects will transition in a double-blind fashion to LCM dosing as described Table 7‒4. At the 
completion of the Transition Period, subjects eligible to enter EP0012 will be placed on a 
common dose (see Figure 5‒3).
Table 7‒4:
Transition Period LCM dosing schedule for subjects 
randomized to placebo
Body weight category 
(formulation)
LCM (or matching placebo) doses for the Transition Period 
Week 1
Week 2
Week 3
Week 4
<30kg (oral solution)
LCM 
2mg/kg/day
LCM 
4mg/kg/day
LCM 
6mg/kg/day
LCM 
8mg/kg/day
≥30kg to <50kg 
(oral solution) 
LCM 
2mg/kg/day
LCM 
4mg/kg/day
LCM 
6mg/kg/day
LCM 
8mg/kg/day
≥50kg (tablets)
LCM 
100mg/day
LCM 
200mg/day
LCM 
300mg/day
LCM 
400mg/day
LCM=lacosamide
Note: If a subject is in the Titration Period and the next scheduled visit after the 125th event occurs, dosing will 
be adapted to reach the target dosing at Week 4.
7.2.4
Taper Period
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24) and an up to 4-week 
blinded taper followed by an End of Taper Visit (Table 7‒5). 
A slower taper is permitted if medically necessary. Whenever possible, these cases should be 
discussed with the Medical Monitor prior to withdrawing the subject from the study, especially 
in cases in which exit criteria have been met. In case of an emergency, a faster taper is permitted 
after discussion with the Medical Monitor, whenever possible.
Following the End of Taper Visit, there will be a 30-day Safety Follow-up Period. The Safety 
Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed by a 
Safety Follow-up telephone contact 30 days after the last dose of study drug. In case the 125th
event occurs in the study, the subjects discontinuing treatment will complete the ET Visit or 
Visit 10 (Week 24), and an up to 4-week blinded taper followed by an End of Taper Visit. 
However, the End of Taper Visit will be the same as Visit 1 of EP0012. The 30-day Safety 
Follow-up Period will be done as part of EP0012, except if the subject refuses to sign the 
EP0012 informed consent form. If the subject signs the informed consent form for a short Safety 
Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part of EP0012; 
otherwise, the Safety Follow-up will be performed in SP0982.
REDACTED 
y t
y
Visit o
Visit o
er Vis
er Vis
all
ally ne
y ne
prio
prio
COPY 
time
time
This document canno
w
ot 
nf
nf
-up a
up a
erwis
rwis
be 
Peri
e
form
form
used
4),
4)
End of
nd o
riod
iod
to
, an
, an
support 
of a
of a
hone co
one c
udy
udy, tht
d
any
isit, t
isit, 
cl
marketing 
ece
or to w
or to w
een me
een m
Monit
oni
authorization 
e and 
and
or Vis
r Vis
sitit (Ta
Ta
essa
essa
application 
fter the
ter th
and
mg/d
mg/d
an
any 
day
y extensions 
L
8mg/
8mg/
sio
xt
e
or 
CM
CM
r variations 
on
on
on
k 4
k 4
ria
v
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 49 of 267
The following schematic displays the scenario for subject dispensation:
Visit 10 or 
ET Visit
0-4 week 
taper
End of 
Taper Visit
Final Clinic 
Visit 
Safety 
Follow-up 
TC
2 weeks after 
last dose of 
study drug
(±2 days)
30 days after last 
dose of study 
drug
(-1/+3 days)
After the 125th event 
occurs
ET=Early Termination; TC=telephone contact
Note: An End of Taper Visit will be scheduled at the end of the Taper Period (up to 4 weeks) depending on the dose 
level achieved; see Table 7-5. Of note, for subjects who enter the Taper Period at 2mg/kg/day (oral solution) or 
100mg/day (tablets), the End of Taper Visit will take the place of the ET Visit.
Table 7‒5 summarizes the Taper Period dosing for each treatment dose for subjects not entering 
EP0012.
Table 7‒5:
Taper Period dosing of LCM (or matching placebo)
LCM (or matching 
placebo) dose achieved
LCM (or matching placebo) doses for the Taper Period 
Week 1
Week 2
Week 3
Week 4
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
NA
5 or 6mg/kg/day
4mg/kg/day
2mg/kg/day
NA
NA
3 or 4mg/kg/day
2mg/kg/day
NA
NA
NA
≤2mg/kg/day
NA
NA
NA
NA
350 or 400mg/day
300mg/day
200mg/day
100mg/day
NA
250 or 300mg/day
200mg/day
100mg/day
NA
NA
150 or 200mg/day
100mg/day
NA
NA
NA
100mg/day
NA
NA
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: The oral solution is dosed as “mg/kg/day” and tablets are dosed as “mg/day.”
Note: Dosing for the Taper Period will be adapted depending on the dose subjects reached during the Titration 
Period when the 125th event occurs.
7.3
Packaging
Lacosamide (tablets and oral solution) and matching placebos are manufactured, packaged, and 
labeled according to Good Manufacturing Practice (GMP) guidelines and applicable laws or 
EP0012 
Visit 1
REDACTED 
match
atch
D
CTE
DA
DA
DA
DA
DA
R
COPY 
(or m
(or m
C
This document 
No
Not
Not
P
cannot 
ay
no
M=laco
M=laco
ote: T
te: T
be 
/day
day
be used 
y
se
to 
o
to support 
2mg/
mg
or
up
s
any 
kg/da
kg/d
g/kg
/k
any marketing 
ng
tin
day
ay
ke
ay
m
authorization
matc
matc
hing pl
ing pl
tio
We
We
ori
6
ut
application 
ment d
ment 
ch
ch
and
mg/kg
g/k
any
eeks) 
eeks)
kg/da
kg/d
extensions or variations 
on
on
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 50 of 267
regulations. The IMP is suitably packaged in such a way as to protect the IMP from deterioration 
during transport and storage.
Lacosamide tablets and matching placebos will be packaged in HDPE bottles.
Lacosamide 10mg/mL oral solution and matching placebo 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 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 (eg, room, 
refrigeration unit) or by completion of a temperature log (showing actual and minimum/
maximum temperatures reached over the time interval) in accordance with local requirements on 
a regular basis.
In case an out-of-range temperature is noted, it must be immediately reported as per the 
instructions contained in the IMP Handling Manual.
The investigator (or designee) will instruct the subject 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’s 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 or destroyed.
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 IMP is used only in accordance with the protocol.
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/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 (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol.
REDACTED 
m
Manu
Manu
uct the
uct th
itit
COPY 
l) 
must 
must
This document
The 
he 
Pe
Pe
canno
estig
stig
o an a
o an a
inin
be 
f I
ga
ga
used
or (or 
r (or 
IMP
MP
to 
iew
ew
support 
e tot
the sp
he sp
macy d
acy d
w.
w
any
as so
as s
o bre
o bre
marketing 
ty 
be used
e us
sou
sou
authorization 
be im
be im
ualal.
he subj
subj
application 
ling t
ing 
wing 
ing ac
a
ccorda
ccord
and 
abel
bel.
thth
any
in a s
in a 
extensions 
e
of IM
f IM
or
eces
ces
variations 
ood 
od 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 51 of 267
7.7
Procedures for monitoring subject compliance
At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP kits. 
Drug accountability must be completed in the subject’s presence 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 less than 75% or more than 
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.
Timely completion of the subject diary is essential for evaluation of safety and efficacy. Subject 
diary completion, including AED usage, will be evaluated at each clinic visit and telephone 
contact. Sites are encouraged to call subjects to inquire about their diary completion.
Investigators should advise subjects and/or caregivers about the importance of reporting 
non-PGTC seizures. Subjects should be reminded that diaries must include daily entries even if 
no seizures have occurred.
7.8
Concomitant medication/treatment
7.8.1
Permitted concomitant treatments (medications and therapies)
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 2 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to 
Visit 1 and during the Prospective Baseline and Treatment Period with or without additional 
concurrent stable VNS. 
•
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the 
course of the study.
•
The chronic (daily dose) use of a benzodiazepine is allowed regardless of indication and will 
be counted as 1 of the 3 allowed AEDs.
•
Intermittent use of benzodiazepines (limited to 2 doses per 28 days) is allowed only for 
epilepsy indications if established at least 28 days prior to Visit 1. Intermittent use of 
benzodiazepines for any other indication is prohibited during the study.
Contraceptive treatment is allowed as described in in Section 6.2 (Exclusion Criterion 21).
Recommended contraception methods for subjects on enzyme-inducing antiepileptic drugs 
(EI-AEDs) or not on EI-AEDs are detailed in Section 17.9.
Stable use of amphetamines and sedative antihistamines is allowed during the study. 
Neuroleptics (except for clozapine) are allowed during the study but the investigator should 
make every effort to keep the dose stable.
7.8.2
Prohibited concomitant treatments (medications and therapies)
The following medications/therapies are prohibited during the course of this study:
•
Clozapine.
•
Any MAO inhibitors.
REDACTED 
d T
d T
been 
been 
day
days pr
s pr
COPY
en of 
en of
s a ben
s a be
Trea
Tre
This document
make
make
7.
7
cannot
use o
se o
urolep
rolep
be
or n
r n
f
used 
atm
atm
d cont
cont
not
not
to
men
men
support
zodi
odi
f estab
f esta
for an
or any
any 
we
we
diaze
iaz
marketing
rior
ior
f a a ben
ben
ed A
ed A
authorization
nzo
nzo
atmen
atmen
in pla
n pla
or to
r to
application 
dicatio
icatio
1 to 2 n
to 2 
odia
odia
and any
e dai
e da
extensions
cy
cy. S
. 
teleph
eleph
etion.
etion.
of rep
f rep
ilil
or 
Su
Su
variations 
will
will
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 52 of 267
•
Barbiturates (except as antiepileptic medications).
•
Patients taking non-benzodiazepine anxiolytics or once-daily hypnotics must remain on 
stable doses of these medications throughout the study.
•
Herbal medicines for epilepsy
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.
7.9
Blinding
UCB Global Clinical Trial Supply will create a packaging list using a validated application. The 
packaging list will be provided to the interactive response technology (IRT) vendor and to the 
packaging vendor who will prepare the kits accordingly.
The treatment randomization schedule will be generated by UCB (or designee) in a manner that 
will ensure that the study team remains blinded, in accordance with current standard operating 
procedures (SOPs). The randomization schedule will be maintained in a secure location until the 
study is unblinded for the final statistical analysis. 
All sponsor, investigator sites, and contract research organization (CRO) staff involved with the 
study will be blinded to the treatment code with the following exceptions:
•
Sponsor personnel and its subcontractors directly involved in the packaging of the IMP or in 
the management of the IRT.
•
Sponsor Patient Safety (PS) staff will receive separate access to the IRT in order to meet their 
requirements for serious adverse event (SAE) reporting to regulatory authorities.
•
Central laboratory staff assaying study drug. However, no randomization list will be 
provided.
An interim futility assessment is planned to allow UCB to consider terminating the study should 
the likelihood of a positive outcome be unacceptably low based on an unblinded assessment of 
interim data by an independent data monitoring committee (IDMC). Such an interim assessment 
will be conducted in a manner that ensures that blinding is not compromised for individuals 
involved with operational aspects of the study or individuals involved with the planning and 
conduct of the final statistical analyses. The 3 planned interim safety assessments will be 
conducted similarly to assure that blinding is maintained.
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 IRT system.
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 which treatment arm and dose 
the subject has been allocated by contacting the IRT. All sites will be provided with details of 
REDACTED
ith th
ith th
ctors d
tors d
f w
f w
COPY 
arch o
rch o
This document 
7.9.
7.9.
A
cannot
ted s
d s
.1
be
the 
the 
i
used
ed in
d in
oper
oper
to
inde
nde
support 
sment i
ment
sitive o
itive o
epe
ep
any 
yinin
marketing 
will rece
ill rece
e event
even
ng
ng st
authorization
organ
organ
e follo
e foll
directl
irectl
application 
(or 
or 
with cu
with c
ntained
ntaine
i
and 
r de
de
any
T) ve
) v
extensions 
ted ap
ed ap
or 
r a
r a
variations 
bility
bility
and
an
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 53 of 267
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 CPM will be informed immediately via the IRT 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 eCRF page.
7.10
Randomization and numbering of subjects 
An IRT will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by UCB. The 
randomization schedule will be produced by the IRT Vendor who is otherwise not involved in
this study. The IRT will generate individual assignments for subject kits of IMP, as appropriate, 
according to the visit schedule.
To enroll a subject (Visit 1), the investigator (or designee) will contact the IRT and provide brief 
details about the subject to be enrolled. Each subject will receive a 5-digit number assigned 
during screening at Visit 1 that serves as the subject identifier throughout the study. The subject 
number will be required in all communication between the investigator (or designee) and the IRT
regarding a particular subject. Subject numbers and kit numbers will be tracked via the IRT. 
To randomize a subject (Visit 2), the investigator (or designee) will contact the IRT and provide 
brief details about the subject to be randomized. The IRT will automatically inform the 
investigator (or designee) of the subject’s randomization number. The IRT will allocate kit 
numbers to the subject based on the subject number during the course of the study. The 
randomization number must be incorporated into the eCRF.
8
STUDY PROCEDURES BY VISIT 
All visits occur at the end of the respective week in the study and a window of ±2 days relative to 
Visit 1 is applicable for all visits and telephone contacts.
A detailed schedule of study assessments is provided in Table 5‒1, Table 5‒2, and Table 5‒3.
8.1
Prospective Baseline Period
8.1.1
Visit 1 (Week -4)
At Visit 1 (Week -4), subjects will be evaluated for their suitability for enrollment. The Visit 1
assessments will be conducted up to 4 weeks (±2 days) prior to the first administration of study 
drug.
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 and the subject’s 
parent/legal guardian (for subjects <18 years of age) by the investigator (or designee). The 
IRB/IEC-approved Informed Consent/Assent form must be signed and dated by the subject, or 
his/her legal representative, and by the person who conducted the informed consent/assent 
discussion (investigator or designee). Participation in the study starts from the time of signing the 
IRB/IEC-approved Informed Consent/Assent form. 
Sites may conduct prescreening EEGs and prior to this, subjects will read and sign a separate 
Informed Consent form that has been approved by an IRB/IEC and the Sponsor, and which 
complies with regulatory requirements.
REDACTED
numb
umb
ed 
ed int
int
URE
UR
ec
ec
COPY 
des
e
he
he IR
IRT
mizati
mizat
This document
RB/
B/
his
his
cannot 
he 
he
n) of t
n) of t
ent/le
nt/le
/I/I
be 
e con
e con
used
l be 
be 
to
4)
4), s
, s
co
support
ve 
ve 
(Week
Wee
subj
su
any 
es
e Ba
B
marketing 
ctive w
tive w
d telep
d telep
ssme
sm
authorization
ion n
ion n
er duri
er dur
o the
the
ES B
S B
application 
gato
at
s will b
will
nee) wi
ee) w
will a
will 
and
hout 
out 
tor 
or
any 
R
t num
t num
th
extensions
volv
olv
as appr
s appr
RT a
or 
The
h
ved
ve
variations 
he
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 54 of 267
The subject’s eligibility for the study will be determined on the basis of the inclusion/exclusion 
criteria, signature of an informed consent/assent prior to any study-related procedures or 
evaluations, and the results of the following assessments:
•
Subject ID card dispensed
•
Medical history and/epilepsy history
•
EEG report
•
Body weight and height
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a serum pregnancy test [for women of childbearing potential])
•
Dispense subject diary
•
AE reporting
•
Concomitant medications and AEDs
•
Contact IRT
8.1.2
Telephone contact (Week -2)
The investigator (or designee) should contact the subject by telephone 2 weeks following Visit 1
to assess continued eligibility and will remind the subject of the importance of accurate seizure 
diary completion. During the telephone contact, the following assessments will be performed:
•
Inclusion/exclusion criteria
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
8.2
Treatment Period
The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
•
The 125th event occurs in the study
REDACTED 
t (W
(W
COPY 
This document 
•
cannot 
e Trea
Trea
be 
wa
w
used
me
me
al cr
al cr
to 
edid
support 
riteria
iteria
any 
d
eleph
elep
marketing 
Week 
Week
uld con
d co
will
wil
authorization application 
(inclu
(incl
omen o
men 
and any 
static 
static
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 55 of 267
8.2.1
Visit 2 (Day 0) Randomization
All assessments at Visit 2 (Day 0) should be conducted prior to the first dose of study drug. 
During Visit 2 (Day 0), the following assessments will be performed:
•
Inclusion/exclusion criteria
•
Randomization
•
Body weight
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments)
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, and a urine pregnancy test [for women of childbearing 
potential])
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Achenbach CBCL
•
BRIEF-P/BRIEF
•
EQ-5D-3L
•
QOLIE-31-P/PedsQL
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
Tanner Stage (will be performed only for subjects who are pubescent at Visit 2 or who enter 
puberty during the course of the study)
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
The subject will take the first dose of study drug in the clinic.
COPY 
This document 
•
cannot 
er 
er 
uberty
berty
AE 
AE
be 
Sta
Sta
used 
p p 
fessio
fessio
o
from
fro
support 
e
lost
lost du
d
any marketing authorization application 
ncl
y test [f
test [
y
and 
lude
ud
any 
ic
extensions 
c ass
c as
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 56 of 267
8.2.2
Titration Period
8.2.2.1
Week 1 to Week 6
Both clinic visits and telephone contacts will be conducted during the Titration Period, beginning 
with a telephone contact at the end of Week 1 and continuing through clinic Visit 5 at the end of 
Week 6. 
At each clinic visit and telephone contact, the investigator, in conjunction with the subject and/or 
parent(s)/legal representative(s), will decide how to proceed with study drug dosing based on 
tolerability (including vital signs, body weight, 12-lead ECG, and AE reporting, as applicable to 
the type of visit contact). If the withdrawal of study drug is required during the Titration Period, 
the subject will enter the blinded Taper Period (Table 7‒5).
8.2.2.1.1
Telephone contact (Week 1, Week 3, Week 5, and unscheduled)
The following assessments will be performed during telephone contacts (both scheduled 
[Week 1, Week 3, and Week 5] and unscheduled) during the Titration Period:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
8.2.2.1.2
Visit 3 (end of Week 2)
During Visit 3 (end of Week 2), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
REDACTED
ng ass
ng ass
COPY 
This document
•
S
•
cannot
pens
ens
Dispe
Dispe
be 
di
se s
se
used
rinal
na
ary
ary r
y
to 
sa
alaly
support 
y
(for su
(for s
ampl
amp
any 
tolic 
tolic
marketing 
Sectio
Sect
authorization 
essme
essme
application and 
Pe
P
any
oth 
oth
riod
riod
extensions
ion 
on 
ched
ched
h sc
h sc
or 
cab
ca
Pe
P
variations 
d/or 
/or 
on
able
ble
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 57 of 267
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.2.1.3
Visit 4 (end of Week 4)
During Visit 4 (end of Week 4), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Urine pregnancy test (for women of childbearing potential)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3
Maintenance Period 
8.2.3.1
Visit 5 (end of Week 6)
During Visit 5 (end of Week 6), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
REDACTED COPY 
This document
.2.3
2.3
Du
Du
cannot 
c
3
be 
t IR
IR
used 
m
al crit
l cri
to
edic
edi
support 
a
any
give
give
marketing 
pilepsy
ileps
erer d
authorization application 
al)
al)
and
thost
hos
any 
tat
t
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 58 of 267
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, a urine pregnancy test [for women of childbearing potential], and LCM 
plasma concentration)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3.2
Visit 6 (end of Week 8)
During Visit 6 (end of Week 8), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Urine pregnancy test (for women of childbearing potential)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
REDACTED COPY 
This document 
•
D
cannot
ne pr
e pr
Subje
Subje
be 
as
used
puls
puls
sses
sses
to 
se
support 
n (brief
(brie
minati
minat
any marketing 
k 8)
8)
he foll
he fol
authorization application and any extensions or variations 
M
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 59 of 267
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3.3
Visit 7 (end of Week 12)
During Visit 7 (end of Week 12), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3.4
Visit 8 (end of Week 16)
During Visit 8 (end of Week 16), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
REDACTED 
ator
ator
ancy
ancy tet
y
COPY 
ge)
ge)
ry
ry a
y
This document 
•
cannot 
ncom
ncom
Wit
Wit
be
ortin
ortin
used
ession
ssion
to
from
fro
support 
ostst due
du
om a
m
any marketing authorization 
assess
ssess
est [fo
est [fo
application 
uding 
uding
and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 60 of 267
•
Neurological examination (brief)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Urine pregnancy test (for women of childbearing potential)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3.5
Visit 9 (end of Week 20)
During Visit 9 (end of Week 20), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
REDACTED 
k 20)
k 20)
e fo
e fo
COPY 
This document 
•
cannot 
d a
emistr
emistr
Sub
Sub
be 
and 
and 
used 
uls
ul
ssessm
sess
to
se r
se r
support
tion (
on (
sment
smen
t
any 
f)f)
(br
(b
marketing 
ollowin
llowin
authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 61 of 267
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.2.3.6
Visit 10/ET Visit (end of Week 24) 
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure. 
Once the 125th event occurs subjects will return to the site at the next scheduled visit and the 
ET/Visit 10 will be performed (see Section 6.3).
During the Visit 10/ET Visit (end of Week 24), the following assessments will be performed:
•
Body weight
•
Height
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, a serum pregnancy test [for women of childbearing 
potential], and LCM plasma concentration)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Achenbach CBCL (same version used at Visit 2)
•
BRIEF/ BRIEF-P (same version used at Visit 2)
•
EQ-5D-3L (for subjects ≥12 years of age)
•
QOLIE-31-P/PedsQL (same version used at Visit 2)
•
Healthcare resource use
•
Work/school days lost due to epilepsy
n 10.
10.
BP
BP, an
, an
COPY 
This document
B
•
cannot 
y d
Achen
chen
BR
BR
be 
drug
drug
used 
ec
ec
study
study
o
ct di
ct d
support
lasma
asm
n/revi
n/rev
any 
clc
urina
urin
ma
marketing
nd di
nd d
s ≥6
≥6 ye
y
linica
linic
authorization 
3.1.1)
i
application 
ssm
and 
men
men
any
dule
dule
extensions 
dical M
ical 
met, sit
et, sit
ct’s se
t’s se
ed
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 62 of 267
•
Days with help from a caregiver due to epilepsy
•
Tanner Stage (will be performed only for subjects who are pubescent at Visit 2 or who enter 
puberty during the course of the study)
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.3
End of Study Period
8.3.1
Transition Period
8.3.1.1
Transition Clinic Visit/telephone contact
A Transition telephone contact is required. The following assessments will be performed during 
the Transition telephone contact:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
A Transition Clinic Visit is optional, at the discretion of the investigator. Subjects requiring a 
clinic visit will have the same assessments conducted as an Unscheduled Visit (see Section 8.4).
8.3.1.2
Final Clinic Visit
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment
Period or after completing the 24-week Treatment Period or the 125th event occurs in the study 
(whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012. Subjects completing Visit 10 (Week 24) or the ET 
Visit must complete a 4-week blinded transition followed by a Final Clinic Visit. The Final 
Clinic Visit is the same as Visit 1 of EP0012. Subjects choosing to enter EP0012 must sign and 
date the EP0012 extension IRB/IEC-approved informed consent prior to receiving EP0012 study 
drug. 
During the Final Clinic Visit, the following assessments will be performed:
•
Body weight
•
Height
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
REDACTED 
he disc
he dis
ments c
ments c
COPY 
This document 
•
cannot
dy we
y we
Heig
Heig
be
Fin
Fin
used 
x
al
to
xtens
ten
suppor
ntinu
tinu
week 
week
me as V
e as 
i
any
ble su
ble su
ue i
ue
marketing 
perienc
erienc
week
wee
b
authorization 
cretion
cretion
condu
ondu
application 
ent
and 
nts w
ts w
any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 63 of 267
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, and a urine pregnancy test [for women of childbearing 
potential])
•
Subject diary return/review
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Study drug return/review
•
Withdrawal criteria
•
Contact IRT
8.3.2
Taper and Safety Follow-up Period
8.3.2.1
End of Taper Visit
Subjects completing Visit 10 (Week 24) or the ET Visit who choose not to continue in EP0012 
must complete an up to 4-week blinded taper followed by the End of Taper Visit. At the End of 
Taper Visit, the following assessments will be performed:
•
Body weight 
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Subject diary return/review
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
REDACTED
e ET
ET
per fol
per fol
will be
will b
COPY 
od
T V
T V
This document 
•
H
cannot
ject 
ect 
Study
Study
be 
ry, 
y,
d
used
urine 
urine 
, uri
uri
to 
men
men
support 
t (
ate, s
e, sys
ntnt (f
any 
om
om
see
see S
marketing 
)
mple
mple
authorization 
Visit 
Visit 
llowe
lowe
e perf
e perf
application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 64 of 267
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
8.3.2.2
Safety Follow-up Visit
Following the End of Taper Visit, the subject will return 2 weeks (±2 days) after the last dose of 
study drug for a Safety Follow-up Visit. In case the 125th event occurs in the study, the subjects 
discontinuing treatment will complete a 30-day Safety Follow-up Period in the EP0012 study.
The 30-day Safety Follow up Period will be done as part of EP0012, except if the subject refuses 
to sign the EP0012 informed consent form. If the subject signs the informed consent form for a 
short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part 
of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
During the Safety Follow-up Visit, the following assessments will be performed:
•
Body weight 
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG 12-lead assessment (see Section 10.3.1) (required only for subjects with an abnormal 
reading at the previous clinic visit)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology [required only for subjects with an abnormal value at the previous 
clinic visit], urinalysis, and a urine pregnancy test [for women of childbearing potential]).
•
Healthcare resource use
•
Work/school days lost due to epilepsy
•
Days with help from a caregiver due to epilepsy
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
8.3.2.3
Safety Follow-up telephone contact
Thirty days (-1/+3 days) after the last dose of study drug, the subject will receive a Safety 
Follow-up telephone contact. In case the 125th event occurs in the study, the subjects 
discontinuing treatment will complete a 30-day Safety Follow-up Period in the EP0012 study.
The 30-day Safety Follow up Period will be done as part of EP0012, except if the subject refuses 
to sign the EP0012 informed consent form. If the subject signs the informed consent form for a 
short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part 
of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
REDACTED 
diasto
diasto
6 ye
yearar
nical 
nical 
COPY 
requir
requir
This document
Thirt
hirt
Fol
Fol
d
cannot 
om
om
2.3
tyt
be 
mita
mita
used 
ion
o
ing
ng
to
onal 
nal
support
due 
due 
om a ca
m a c
d
any 
to
marketing
labor
labo
ed 
ed only
onl
rine
ne pr
p
authorization 
olic BP
lic B
rs of a
s of a
application 
ed d onl
on
and any
orme
orm
extensions
ec
nt form
form
perf
erform
orm
f
med
or
ct re
t re
variations 
f f 
ects
cts
udy
udy
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 65 of 267
During the Safety Follow-up telephone contact, the following assessments will be performed:
•
AE reporting
•
Concomitant medications and AEDs 
8.4
Unscheduled Visit
Unscheduled Visits may be performed at any time after Visit 1, as clinic visits or telephone 
contacts, at the discretion of the investigator. During an Unscheduled Visit, the following
assessments are required:
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IRT
If an Unscheduled Visit is due to an AE, then the C-SSRS (for subjects ≥6 years of age) is 
required.
In addition to the required assessments listed above, depending on the type of visit (clinic or 
telephone), further assessments can be completed as needed and may include ECG, vital signs, 
laboratory tests, dispense study drug, diary review, etc.
9
ASSESSMENT OF EFFICACY
9.1
Primary efficacy variable
The primary efficacy variable is the time to the second PGTC seizure during the 24-week 
Treatment Period.
9.2
Secondary efficacy variables
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures during the 24-week Treatment Period, estimated using 
Kaplan-Meier analysis
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline) 
•
The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline 
•
Time to the first PGTC seizure during the Treatment Period
9.3
Other efficacy variables
Other efficacy variables are:
•
Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline
REDACTED
FICA
FICA
able
ble
time t
time t
COPY
need
nee
w, etc.
w, etc
A
This document 
•
cannot 
ric
ri
The pe
he pe
rela
rela
be 
nt
cal a
cal a
used
nt chan
chan
Per
Per
to
y efef
y
support 
GTC 
GTC
ysisis
effic
ffi
any
iabl
iab
se
marketing 
to th
o t
cacy
acy v
y
lel
authorization 
ACY
CY
e
the 
he
application 
ng on t
ng on 
ed and 
d and
and 
cts
cts ≥6
≥6
any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 66 of 267
•
Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline
•
Percent change in days with absence seizures per 28 days during the Treatment Period
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline
•
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the Treatment Period
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period Percentage 
of subjects with at least a 50% reduction in PGTC seizure frequency during the first 12 
weeks of the Treatment Period compared to Combined Baseline
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Treatment Period compared to Combined Baseline
•
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the
Treatment Period 
•
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period 
•
Change from Baseline in QOLIE-31-P subscale (Seizure Worry, Daily Activities/Social 
Functioning, Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, 
Overall Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age
or change from Baseline in the PedsQL subscale (Physical Functioning, Emotional 
Functioning, Social Functioning, and School Functioning) and total scores in subjects 
<18 years of age
•
Change from Baseline to end of treatment or ET in the EQ-5D-3L VAS score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age)
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject due to epilepsy
•
Number of days with help from a caregiver due to epilepsy
REDACTED
to C
to C
50% re
0% r
mbined
mbined
all g
all g
COPY
for th
for th
GTC s
GTC 
Com
Com
This document
•
H
cannot
ange 
ange 
utility
utility
be
ars o
ars o
used
om B
m B
ng, So
g, So
of
of
to 
of 
of 
Ba
Ba
support
e in Q
in Q
gy/Fati
y/Fat
f Life
f Li
any 
O
marketing
genera
enera
or all g
r all
authorization
seiz
seiz
mbine
mbine
reduct
reduct
d Bas
d Bas
application 
st 12 w
st 12 w
e 24
24-w
zure
zure
and
c seiz
seiz
any extensions 
eeks o
eeks 
reatm
reatm
or variations 
ive to
ve to
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 67 of 267
9.3.1
Seizure variables 
Subjects will keep a diary to record daily seizure activity from Visit 1 until the end of study 
participation. Efficacy and safety variables will be assessed using the seizure count information 
recorded on the subject diaries. Subjects should be reminded that diaries must include daily 
entries even if no seizures have occurred. The subject should be reminded to bring the diary to 
each clinic visit. 
9.3.1.1
PGTC seizures
The following information will be recorded on a daily basis as applicable:
•
Seizure type
•
Number of PGTC seizures
If more than 1 PGTC seizure occurs on a single day, each seizure should be counted separately, 
provided there is a complete recovery of consciousness between seizures. 
9.3.1.2
Absence and myoclonic seizures
In the subject diary, the following information will be recorded on a daily basis:
•
Seizure type
•
Number of seizures to be recorded although for the purpose of data analysis, only the number 
of days with seizure will be analyzed.
Investigators should advise subjects and/or caregivers about the importance of reporting absence 
and myoclonic seizures. 
9.3.2
Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P)
The QOLIE-31-P Version 2 will be used to evaluate the health-related quality of life (HRQoL)
of study subjects ≥18 years of age (Cramer and Van Hammée, 2003). 
The QOLIE-31-P is an adaptation of the original QOLIE 31 instrument (Cramer et al, 1998) that 
includes 30 items grouped into 7 multi-item subscales (Seizure Worry [5 items], Overall Quality 
of Life [2 items], Emotional Well-being [5 items], Energy/Fatigue [4 items], Cognitive 
Functioning [6 items], Medication Effects [3 items], and Daily Activities/Social Functioning 
[5 items]) and 1 health status item.
In addition to the 31 items, the QOLIE-31-P contains 7 items assessing the degree of “distress” 
associated with the topic of each subscale (ie, distress items) and 1 item asking about the relative 
importance of each subscale topic (ie, prioritization item).
9.3.3
Pediatric Quality of Life Inventory 
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 version of the PedsQL used at Visit 2 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 ≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to 
REDACTED 
careg
careg
Qual
Qual
COPY 
r the p
r the p
This document 
3.
3
The
Th
cannot 
ed w
d w
rtance
tance
.3
be
to th
o t
wit
wit
used
 heal
hea
the
the
to
ms], 
ms],
lt
support
ptat
tat
d into
d int
otional
tional
M
any
ge 
ge 
tion
tion
marketing
lity
ty
e used 
use
 (Cr
(C
authorization 
pu
p
givers 
ivers 
of
o
application
on a d
on a d
urpos
urpos
and any extensions 
coun
oun
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 68 of 267
<18 years of age. Self-report is measured for pediatric subjects ≥5 years to <18 years of age, and 
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 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
9.3.4
EQ-5D-3L Quality of Life Assessment 
The EQ-5D-3L (EuroQol Group, 2011) is a self-administered questionnaire designed to measure 
health status in subjects ≥12 years of age. The EQ-5D-3L defines health in terms of 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is 
divided into 3 levels:
•
No problem=1
•
Some or moderate problems=2
•
Extreme problems=3
The EQ-5D-3L also captures a self-rating of health status on a 20cm vertical visual analog scale, 
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at 
the bottom.
9.3.5
Healthcare resource use
Healthcare resource use will include concomitant medical procedures, hospitalizations, and 
healthcare provider visits.
9.3.6
Number of working or school days lost due to epilepsy
The number of working or school days lost due to epilepsy by the subject will be recorded, as 
applicable.
9.3.7
Number of days with help from a caregiver due to epilepsy
The number of days with help from a caregiver due to epilepsy will be recorded, as applicable.
9.3.8
Socio-professional data
Socio-professional data, such as highest level of education, current professional status, housing 
status, and regular assistance will be collected throughout the study, as applicable.
10
ASSESSMENT OF SAFETY
10.1
Adverse events
10.1.1
Definitions
10.1.1.1
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 
REDACTED
) at th
) at t
e use
e use
con
con
COPY 
lth sta
th st
h
This document 
0
10
10
cannot 
ofe
ofe
, and r
and 
be 
fessi
fessi
used 
ays s
Soc
Soc
to 
s w
s w
support 
ch
ber of 
er of 
any 
hool d
hool d
marketing 
ncomi
ncomi
king o
ing 
authorization
atus o
atus 
he top 
e top 
application 
on
and any
on). 
on)
extensions 
signed
gned
rms o
rms o
E
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 69 of 267
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 an IMP, 
whether or not related to the IMP.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the Informed Consent/Assent form), including any pretreatment and posttreatment 
periods required by the protocol, must be reported in the eCRF even if no IMP was taken but 
specific study procedures were conducted. This includes all AEs not present prior to the initial 
visit and all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
investigator from the subject’s history or the Baseline Period.
10.1.1.2
Serious adverse event
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
•
Death
•
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)
•
Significant or persistent disability/incapacity
•
Congenital anomaly/birth defect (including that occurring in a fetus)
•
Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious
(Important medical events may include potential Hy’s Law [see Section 10.1.1.3], 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.)
•
Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if 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 
REDACTED 
capacit
apaci
(inclu
(inclu
COPY 
that m
that m
This document 
tht
cannot
al in
l in
hospita
ospita
em
em
be
ent a
ent 
np
np
used
tient h
ient h
d
to
drug
dru
support 
nts 
ts
ing int
ng in
not res
not re
ug ab
ug
any 
io
may
may
marketing 
udin
di
ed upon
d upo
uire me
re m
on of
on o
authorization
migh
migh
ity
ing t
ng 
application 
a:
t h
and
ss of
s of
any 
f th
f t
extensions 
b
nsit
sity y
own t
own t
or 
e
variations 
al
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 70 of 267
since there is no AE upon which to assess the serious criterion. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.)
10.1.1.2.1
Anticipated serious adverse events
Table 10‒1 provides a list of anticipated SAEs which have been identified as events that are 
anticipated to occur in the population studied in this protocol at some frequency that is 
independent of drug exposure. This original list will remain in effect for the duration of the 
protocol. 
This list does not change the investigator’s obligation to report all serious AEs (including 
anticipated SAEs) as detailed in Section 10.1.2.
Table 10‒1: Anticipated SAEs for the epilepsy population
System Organ Class
Preferred Term
Congenital, Familial and Genetic Disorders
Teratogenicity
General disorders and Administration Site Conditions
Sudden unexplained death in epilepsy
Nervous System Disorders
Convulsion
Incontinence
Status epilepticus
Pregnancy, Puerperium and Perinatal Disorders
Abortion spontaneous
Psychiatric Disorders
Psychotic behavior
Abnormal behavior
Anxiety
Sleep disorder
Reproductive System and Breast Disorders
Menstrual disorder
Impotence
SAE=serious adverse event
10.1.1.3
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 AEs of special interest: 
•
The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (second degree, Type I and II, and third degree), and marked bradycardia 
(<45 bpm)
•
Syncope or loss of consciousness (other than seizure related)
•
Serious suspected multiorgan hypersensitivity reactions
REDACTED 
orders
orders
CT
ED
COPY
Co
C
OP
OP
OP
OP
This document
The 
The 
cannot
f s
f s
ited ba
ed ba
ministr
inistr
be 
spec
spec
used 
e e
Ad
Adv
to
even
eve
o support 
Breast
Brea
t
s
any 
a
marketing authorization
Inco
Inco
at
at
ati
at
or
au
application 
city
ity
n unexp
n unex
tio
nvulsio
vuls
lic
a
and 
m
an
any 
an extensions 
cludin
ludin
or variations 
e
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 71 of 267
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the Food and Drug 
Administration:
An AE or laboratory value (as defined below) 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 ≥2xULN
−
AST ≥2xULN
•
Emergence of non-preexisting or worsening of any existing epileptic seizure types
•
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.
10.1.2
Procedures for reporting and recording adverse events
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study.
10.1.2.1
Description of adverse events
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation.
Details for completion of the AE eCRF (including judgment of relationship to study drug) are 
described in the eCRF Completion Guidelines.
REDACTED 
LT
LT
P, with
P, wit
orted
rted t
c inve
c inv
rted i
rted i
COPY 
an
any ex
y e
T or
T o
This document
and s
nd s
on h
on 
cannot
recor
ecor
ndard m
dard 
so
so
be used
ve
v
e stud
e stud
D
to
estig
esti
support 
y visi
visi
y
ing un
ng un
any 
oppor
oppo
it t
it
marketing
if an 
if an 
he
he subj
sub
repor
repo
authorization 
r AST
AST
th no a
h no a
to UC
o UC
stigat
stiga
application 
xisting
istin
and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 72 of 267
10.1.2.2
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:
•
The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
•
The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one
10.1.2.3
Additional 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 
investigational product), up to 30 days from the end of the study for each subject, and to also 
inform participating subjects of the need to inform the investigator of any SAE within this 
period. Serious AEs that the investigator thinks may be associated with the IMP must be reported 
to UCB regardless of the time between the event and the end of the study.
Upon receipt of the SAE Report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure.
10.1.3
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. 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 10.2.1.4.
REDACTED
CB to
CB t
res rep
res rep
or la
or la
COPY
g the 
g the
he SAE
e SAE
This document
10.1
10.1
A
cannot 
eip
ei
ed SA
d SA
chure
chure
be 
ipt o
ipt o
used
AEs 
AEs
dless 
dless 
to
g su
g su
s tht
support 
ally
ll
gator i
gator 
ct), up t
), up
ubje
ubj
y
any 
A
req
req
y
marketing
abora
bora
ents in 
nts in
ant info
nt inf
AE R
AE R
authorization
AE an
AE an
consi
consi
portin
ortin
at
application 
tigator
gator
SAE re
AE 
d
and 
fo
fo
any
ore 
ore
rm w
rm w
extensions
mati
at
vent R
vent R
ts rep
s rep
AE R
AE R
e d
or 
tion
tion
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 73 of 267
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 subjects have discontinued their IMP. 
Information on SAEs obtained after clinical database lock will be captured through the PS 
database without limitation of time.
10.1.4
Pregnancy
If an investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol). The subject should be withdrawn from the study 
as soon as pregnancy is known (by positive pregnancy test), and the following should be 
completed:
•
The subject should return for an ET Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the ET Visit.
•
A Safety Follow-up Visit (Final Clinic Visit) should be scheduled 2 weeks after the subject 
has discontinued her IMP.
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the investigator site file. In case of questions about the consent process, the 
investigator may contact the UCB/CRO contract monitor for the study. The investigator will 
complete the Pregnancy Report and Outcome form and send it to UCB’s PS department (for 
contact details see Serious Adverse Event reporting information at the beginning of this protocol) 
only after the partner has agreed that additional information can be captured and has provided the 
signed Partner Pregnancy Consent form. UCB’s PS department is also the primary contact for 
any questions related to the data collection for the partner pregnancy, eventual birth, and follow 
up.
REDACTED 
f info
f info
es.s.
on th
on th
COPY 
should
hou
This document 
e av
 av
inve
inve
c
cannot
gator
ator
ner Pr
er Pr
avai
vai
be
here 
here
used 
me
me
, even
even
to
he
ent 
ent
support
reque
equ
low up
ow u
e subj
e sub
any 
r r 
for 30
for 3
es
marketing
he Pre
he Pr
regnan
regna
Report a
port
and 
and
authorization 
d b
ormati
mati
application 
or be 
or be
be sc
e sc
and any
wing
wing
extensions
of an
f an
omple
ompl
Event r
vent 
wn fr
wn fr
g s
or 
ny
ny
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 74 of 267
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form.
10.1.5
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.
10.1.6
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 serious 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).
10.1.7
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 PS 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.
10.2
Laboratory measurements
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis parameters will be collected according to the schedule of study assessments in
Table 5‒1, Table 5‒2, and Table 5‒3. A central laboratory will perform the routine analysis of 
blood and urine specimens. Pregnancy testing will also be performed (see Section 10.2.2). The 
procedures for handling and shipping these specimens will be provided to the sites.
The laboratory tests to be performed are presented in Table 10‒2.
REDACTED 
ed per
ed pe
at inv
at inv
ormed
ormed
ualif
ualif
COPY 
This document
The 
The 
cannot
, ,
and u
nd u
cedur
edur
be 
is
Tab
Tab
used
e spec
e spe
par
par
to
bor
bor
support 
resul
esul
rato
rat
any
at 
at UC
U
lts)
lt
marketing
fied de
fied d
reconci
econc
velop
velop
authorization 
riodic
iodic
vestiga
vestiga
d appr
appr
application 
ex
re onl
e only
act of ta
ct of t
and
ng ov
g ov
xces
xces
any 
ver
extensions
co
or inf
or inf
), path
, path
or
rde
rde
variations 
icina
cina
d
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 75 of 267
Table 10‒2: Laboratory measurements
Hematology
Clinical chemistry
Endocrinologya
Urinalysisb
Hematocrit
Hemoglobin
Platelet count
RBC count
WBC count
Differential count
Calcium
Phosphorus
Serum electrolytes 
(sodium, potassium, 
chloride, bicarbonate)
Creatinine
BUN
AST
ALT
Total bilirubin
Alkaline phosphatase
GGT
Glucose
Albumin
Total serum protein
Uric acid
TSH
T3 (total and serum-free)
T4 (total and serum-free)
pH
Ketones
Glucose
Albumin
Specific gravity
Microscopic exam for 
blood cells or casts/hpf
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; GGT=gamma 
glutamyl transferase; hpf=high power field; RBC=red blood cell; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid-stimulating hormone; WBC=white blood cell
a    Thyroid function will be required in subjects <18 years of age only.
b    Urinalysis will be required for all subjects.
10.2.1
Evaluation of PDILI
The PDILI IMP discontinuation criteria for this study are provided in Section 6.4.1, 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 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.1.2). 
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in
Table 10-3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1). 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 10.2.1.4). 
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.
REDACTED
ransf
rans
red blo
red blo
e bloo
e bloo
<18 y
<18 y
s.s.
COPY 
fer
f
C
This document
gastr
gastr
on 
on
cannot 
ion
o
ologist
logist
nagem
agem
be 
(sp
n w
n w
used
PDILI
DILI
peci
peci
to 
0.1.1
support 
and
nd
PDILI
PDIL
special 
pecia
1.1.2
1
any
up i
up 
d rep
d re
marketing 
riteria 
iteri
inv
in
authorization 
rase; B
ase; B
ood cel
od ce
d cell
d cell
years o
ears o
ion application and any 
a
extensions 
c ex
ls or c
ls or c
or 
xam
xam
variations 
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 76 of 267
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 6.4.1), IMP must be permanently 
discontinued. 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.
COPY 
This document cannot be used to support any marketing authorization application and any extensions 
 perm
perm
liver i
iver 
or variations 
nging
ging
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 77 of 267
Table 10-3: Required investigations and follow up for PDILI
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptomsa 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 10.2.1.3); 
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
≥8xULN
NA
NA
≥3xULN
NA
Yes
≥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 10.2.1.2).
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator).
≥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
10.2.1.3).
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, 
stabilize, or return to within 
Baseline valuesd
REDACTED 
T
r 
e
llo
ll
F
TE
CT
COPY 
This document t cannot 
c
be used to 
o support 
dical
ica
require
equir
s
any 
sion w
sion w
al M
l M
y marketing 
ows 
ws 
nuation
uatio
g 
m
authorization 
Furthe
Furthe
– im
im
d
riz
a
application 
a
tes
te
io
and
hemis
emi
and a
nd
any 
l: M
l: 
repeat
repea
t
extensions 
on
Mu
Mu
xt
o
Follo
oll
o variations 
on
ow
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 78 of 267
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 10.2.1.1. 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.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions
Medidica
ca
r assess
asses
nation o
ation 
or 
l
variations 
on
care pr
are p
malal
nclude
clude
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 79 of 267
10.2.1.1
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 10.2.1.3) and SAE report (if applicable).
10.2.1.2
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 6.4.1 and Table 10-3 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.
10.2.1.3
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 10‒4 (laboratory measurements) and Table 10‒5 (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.
REDACTED
n req
n req
may
may ha
ha
y
and 
and Ta
T
ation c
ation 
hist
hist
COPY 
ox
o
on of
on o
qui
This document cannot be used to support 
so be
o be
any
tored
tored
e s
e
marketing 
co
tory
tory o
y
se addi
e add
authorization 
of a
ired fo
red f
ave be
ve be
able
ble 1
ollec
ollec
application 
r sho
sho
d consi
cons
to a sui
o a su
alter
alte
and
supple
uppl
ou
ou
any
0-3
-3 fo
f
extensions 
hepati
hepat
te in
e in
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 80 of 267
The following measurements are to be assessed:
Table 10‒4: 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
Eosinophil count
Urinalysis
Toxicology screen
Chemistry
Amylase
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation
Additional
Prothrombin time/INR
a
Serum pregnancy test
PK sample
ALT=alanine aminotransferase; CPK=creatine phosphokinase; 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; RNA=ribonucleic acid; 
ULN=upper limit of normal
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).
REDACTED 
N, obta
, obta
TE
to eva
to eva
AC
R
a
RE
COPY 
PY
CO
This document cannot be used
su
s
y. Hep
Hep
yperse
yperse
to
no
ubje
ubje
support 
CP
CP
e antige
antig
potentia
otent
ormal
rmal
an
PK=c
PK=
any 
an marketing 
g
estst
ke
ma
authorization 
on
ain fra
ain fra
iza
uate 
uate
th
application 
ualitati
ualitat
n
ca
pp
and 
ive)
ve)
d any y extensions 
ns
tain he
ain h
ns
or r variations 
ns
ns
ns
ns
ia
v
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 81 of 267
The following additional information is to be collected:
Table 10‒5: 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:
•
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)
•
Adverse reactions to drugs
•
Allergies
•
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
•
Recent travel 
•
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
Alcohol and illicit drug use
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
10.2.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up monitoring as described in Table 10-3.
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.
10.2.2
Pregnancy testing
Females of childbearing potential (who have not been surgically sterilized or who are not at least 
2 years postmenopausal) will have serum and urine dipstick pregnancy testing performed 
according to the schedule of study assessments in Table 5‒1, Table 5‒2, and Table 5‒3.
10.3
Other safety measurements
10.3.1
12-lead ECG
Standard 12-lead ECGs will be performed according to the schedule of study assessments in
Table 5‒1, Table 5‒2, and Table 5‒3.
REDACTED 
poxem
poxem
D
CTE
y, if do
y, if do
DA
R
COPY 
pati
pat
reased
reased
C
This document 
ye
yea
acco
acc
cannot 
males o
ales 
arsr
be 
t (a(
used
d 
of sta
of sta
as ap
as a
to
con
con
support
p eva
eva
d liver 
liver
ti
any
T=asp
T=as
alu
marketing 
one
ne
con
consult,
sul
ng
rk
m
authorization 
mia wit
ia wit
tio
ori
ut
application
ic dis
c di
nd/or AL
d/or A
or hyp
or hyp
appeti
appet
ca
and 
ise
ise
any extensions 
lpha
pha
or
faf
variations 
ns
fatty
fatty
tio
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 82 of 267
The ECG recordings should be performed at the same time of day (when possible) and prior to 
blood sample collection and vital sign assessments. Care should be taken to assure proper lead 
placement and quality ECG recordings. If possible, subjects should rest in a supine position at least 
5 minutes prior to each recording and should be motionless during the recording. In pediatric 
subjects (<18 years of age), 12-lead ECGs (2 interpretable recordings) approximately 20 to 
30 minutes apart must be performed.
10.3.1.1
Overall ECG interpretation
Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified 
designated reader. If the reading identifies a second- or third-degree AV block 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 6.4). The investigator may 
consult with a cardiologist 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. 
10.3.2
Vital signs, body weight, and height
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits in a supine 
position after at least 3 minutes at rest, according to the schedule of study assessments in Table 5‒1,
Table 5‒2, and Table 5‒3. Assessment of orthostatic changes will be as follows: after the 3-minute 
measurement in a supine position, the subject is asked to stand and BP and pulse rate are taken 
approximately 1 minute and approximately 3 minutes after the subject stands up, as feasible. Blood 
pressure measurements should be taken with the proper placement and proper sized cuff to obtain 
accurate measurements.
Body weight will be determined without shoes and wearing light clothing and height will be 
measured without shoes. Body weight and height will be measured using equipment that is age 
appropriate and assessed according to the tabular schedule of study assessments (Table 5‒1, 
Table 5‒2, and Table 5‒3).
10.3.3
New seizure types 
Incidence of new seizure types, and increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period will be assessed using the seizure count 
information recorded on the subject diaries (see Section 9.3.1).
10.3.4
Physical examination
Physical examinations will be performed by a medically qualified clinician licensed to perform the 
examination, according to the schedule of study assessments in Table 5‒1, Table 5‒2, and 
Table 5‒3. Clinically significant physical examination findings are to be reported as AEs.
10.3.4.1
Complete physical examination
The complete physical examination will include cardiac and respiratory function via auscultation 
and review of all body systems.
REDACTED 
osta
osta
ct is a
ct is a
elyly 3 m
3 m
en with
en wi
COPY
tete wi
w
to the
to th
tatic
ati
This document 
xam
am
Tabl
Tabl
1
annot 
ical ex
cal ex
mina
min
be used
28 d
28 d
ecord
cord
to
eizu
eizu
da
d
support 
eizure 
izure
ure
ure
any
ding
ding
marketing 
hout sh
out 
eight a
ight 
to
authorization
e sch
sc
c chan
chan
asked 
sked 
minut
minut
h the 
the 
application 
l be m
be m
ched
ched
and
r this 
this
any 
t E
findin
findin
fif
extensions
he
e ECG
ECG
d b
d by t
y t
he inv
e inv
ECG
EC
or
r ab
r ab
variations 
ied 
ed 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 83 of 267
10.3.4.2
Brief physical examination
The brief physical examination will include review of the following body systems:
•
Cardiovascular
•
Pulmonary
•
Abdominal (hepato-gastrointestinal)
•
Dermatologic
10.3.5
Tanner Stage
At Visit 2 and Visit 10/ET Visit, the investigator or qualified designee will evaluate the subject’s 
sexual development using the 3-item Tanner scale, according to the tabular schedules of study 
procedures (Section 5.2). The investigator should use clinical judgment in deciding which subjects 
are selected for evaluation of Tanner Stage (ie, those subjects who are pubescent at Visit 2 or who 
will enter puberty during the course of the study).
10.3.6
Neurological examination
Neurological examinations will be performed by a medically qualified clinician with documented 
training in the conduct of neurological examinations, according to the schedule of study 
assessments in Table 5‒1, Table 5‒2, and Table 5‒3. 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 IGE with PGTC seizures.
10.3.6.1
Complete neurological examination
The complete neurological examination will include selected assessments of mental status, cranial 
nerves, sensory systems, motor functions, reflexes, and coordination/cerebellar function.
10.3.6.2
Brief neurological examination
The brief neurological examination will include selected assessments of general neurological 
status, reflexes, muscle strength, and coordination/cerebellar function.
10.3.7
Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2012). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed according to the 
schedule of study assessments in Table 5‒1, Table 5‒2, and Table 5‒3.
All subjects who are ≥6 years of age will complete the “Baseline/Screening” version of the 
C-SSRS at Visit 1 and will complete the “Since Last Visit” version at subsequent visits. If a 
subject becomes 6 years of age during the study, the "Already Enrolled" version of the C-SSRS 
should be used at the first visit at which the subject is 6 years of age, and the “Since Last Visit” 
version should be used at subsequent visits.
The C-SSRS is not validated for subjects <6 years of age and will not be used for this population. 
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 younger than 
REDACTED
the d
the d
l exam
exam
on wi
on wi
tion
tion
COPY
ac
. . If p
If p
ct dur
ct dur
dia
di
This document 
ubje
bj
shou
shou
v
cannot
jects
ects
SRS a
RS a
ject
ect
be 
stu
stu
used 
201
0
hat m
at m
ud
udy
to
ss
12)
12)
support 
g
ment o
ment
sessed
essed
any
ion
io
th, an
th, an
marketing
ill
ns, refl
s, ref
l ex
exam
a
on wi
n w
authorization
ring t
ring 
agnos
agnos
mina
mina
l incl
inc
application 
qualifie
ualifi
ding to 
ing to
ossible
ossib
the
th
and any
esce
esc
extensions 
e the 
e the 
edules
dules
eciding
ciding
cen
en
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 84 of 267
6 years old, reference should be made to the current version of the Diagnostic and Statistical 
Manual of Mental Disorders published by the American Psychiatric Association. 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.
10.3.8
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). 
The Achenbach CBCL/1½ -5 is for children <5 years and 11 months of age, and the CBCL/6-18 is 
for children ≥6 years to <18 years of age; the questionnaire is to be completed by the 
parent(s)/legal representative(s). For each subject, the same version of the scale that is completed 
at Visit 2 should be maintained for the duration of the study in accordance with the tabular 
schedules of study procedures (Table 5‒1) and should be completed by the same parent/legal 
representative. The completion of the Achenbach CBCL will require approximately 45 minutes. 
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
Eight syndrome scores will be calculated from these questionnaires, which will in turn be 
summarized by 2 composite scores. Additionally, for each score on the questionnaire, syndrome, 
and total level, categorizations based on a normative sample will be used to evaluate normal, 
borderline, or clinically relevant behavior.
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, activities 
in leisure time, and special interests.
10.3.9
BRIEF
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of subjects 
≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P and BRIEF will be 
used only in countries where a translated scale is available. For each subject, the same version 
(BRIEF-P or BRIEF) that is used at Visit 2 should be maintained for the duration of the study in 
accordance with the tabular schedules of study procedures (Table 5‒1).
The BRIEF-P and BRIEF include 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. 
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).
ed fro
ed fro
Addit
Addit
o
COPY 
This document
unct
nct
for 
for t
cannot
nce 
ce 
BRIE
BRIE
ctio
ctio
be
or B
r B
e wi
e w
used 
ars
ars
ountri
untri
BR
BR
to 
e
rs of
s of
support 
n
 BRI
BRI
any 
CL
CL/
erest
erest
marketing
tiona
ion
on a no
n a no
havior.
avior
/6/6-1
authorization 
om the
m the
nal
nal
application
behavi
ehav
and
y thth
y
e appr
appr
any
wit
wi
he sa
he sa
extensions 
e CB
CB
by the
the
y
ale tha
le tha
thth
or variations 
encies
ncies
egal
egal
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 85 of 267
The BRIEF rating form contains items in nonoverlapping clinical scales. These theoretically and 
statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score.
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and inconsistency 
of responses. 
11
ASSESSMENT OF PHARMACOKINETICS
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 
2 successive bid doses, according to the schedule of study assessments in Table 5‒1. The time the 
subject took the most recent dose of IMP and the time of blood sampling must be recorded. Actual 
dosing and sampling times will be recorded in the eCRF to the minute.
The central laboratory will store the plasma samples at -20°C until analysis. Blood draws for these 
assessments will coincide with the blood collection times for assessment of the hematology and 
clinical chemistry parameters. Time and date of each blood draw will be documented on the eCRF. 
Instructions on blood sample collection, processing, storage, and labeling/shipping are provided in 
the laboratory manual for this study.
12
STUDY MANAGEMENT AND ADMINISTRATION 
12.1
Adherence to protocol
The investigator should not deviate from the protocol. In medical emergencies, the investigator 
may use his/her medical judgment and may remove a study participant from immediate hazard 
before notifying UCB (or its representative) and the IRB/IEC in writing regarding the type of 
emergency and the course of action taken.
12.2
Monitoring
UCB (or designee) will monitor the study to meet the sponsor’s monitoring 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 CRO or a contract 
monitor.
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any missing 
information. The investigator(s)/institution(s) will permit direct access to source data/documents 
for study-related monitoring, audits, IRB/IEC review, and regulatory inspection(s).
The investigator will allow UCB (or designee) to periodically review all eCRFs and corresponding 
source documents (eg, hospital and laboratory records for each study participant). Monitoring 
visits will provide UCB (or designee) with the opportunity to evaluate the progress of the study, 
verify the accuracy and completeness of eCRFs, ensure that all protocol requirements, applicable 
authorities regulations and investigator’s obligations are being fulfilled, and resolve any 
inconsistencies in the study records.
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, 
REDACTED
roto
roto
y remo
remo
ive) an
ve) an
ken.
ken.
COPY 
oco
oc
This document
verif
verif
au
au
cannot
estig
stig
e docu
 docu
ts wi
s wi
be 
at
igat
igat
used
he inv
 inv
ted m
ed m
to
e mo
e m
support 
his/her
his/her
on
any
tory
tor
ing o
ing o
marketing 
he study
e stud
ry
ry rer
y
authorization 
ol. I
ol. In
ove a s
ve a 
nd the
nd the
application 
MINIS
INIS
and 
eling
eling
any 
thth
docum
docu
extensions
corde
orde
lood 
ood 
he h
he h
or 
 tim
ti
ed
variations 
tween
ween
ime
im
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 86 of 267
optical disc). They should not be obscured by correction fluid or have temporary attachments (such 
as removable self-stick notes). Printouts of eCRF screens 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.
If the source documents are maintained by the investigator in a computerized system, the monitor 
should ensure that electronic records are ALCOA (attributable, legible, contemporaneous, original, 
and accurate) compliant and that there is proper access control, validation, and audit trail available 
upon request. If the monitor has no direct access to the original electronic medical records, the 
certified copies should be generated by the investigator and used for the study purposes. Accuracy 
and completeness of data on the certified copies should be verified by the monitor to maintain 
ongoing compliance.
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
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports.
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change.
Corrections made after the investigator’s review and approval (by means of a password/electronic 
signature) will be reapproved by the investigator.
The investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF 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. This study is performed using electronic data capture (EDC); the data are entered into the 
eCRFs once and are subsequently verified.
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.
REDACTED 
omple
omple
rom
rom
COPY
auto
aut
eCRF 
eCRF
This document
will b
will b
the
the
cannot 
Repor
Repo
abase
base
be used 
h
uction
ction
to
ould
oul
support 
he inve
e inve
pproved
prove
d
any 
C
marketing 
mpt rep
pt rep
CRF 
CRF
authorization
 sho
sho
etion
tion
application 
data o
data o
ate, com
ate, co
mated 
mated
hould
oul
and any 
mon
mo
extensions
ou
t trail 
trail
al reco
l reco
y purp
purp
y
onito
nit
or
us, o
s, o
variations 
.
monit
moni
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 87 of 267
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/assent 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 IMP 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/Assent 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 IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (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.
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 Informed Consent/Assent 
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 
REDACTED 
wit
wit
etenti
tenti
te reco
te reco
t/Ass
Ass
COPY
nvest
nves
arrang
arran
th U
This document 
The 
The 
inin
cannot 
file.
le.
6
be
mov
mov
used
izatio
zati
ction 
tion 
to
B 
B (
on
support 
plic
li
f clinic
clini
owever
weve
(CP
(C
any
ation
atio
catio
cat
marketing 
ent 
ent d
particip
partic
retaine
etain
n in
n
authorization 
gem
gem
UCB
CB p
ion
on
ords f
rds f
d
application 
rm
applic
applic
rovided
rovide
gator/i
gator/
emen
men
nd
esent
sen
minat
minat
any 
ntat
nta
extensions 
dy eith
eith
y
ot limi
limi
r unsat
unsat
or variations 
dical
dical
pation
ation
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 88 of 267
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 follows and will be described in more detail in the Statistical 
Analysis Plan (SAP).
13.1
Definition of analysis sets
13.1.1
Screened Set
The Screened Set consists of all subjects who have entered screening at Visit 1, have a signed 
Informed Consent/Assent form, and have at least basic demographic data available.
13.1.2
Randomized Set
The Randomized Set (RS) is a subset of the Screened Set and consists of all subjects who were 
randomized at the Randomization Visit (Visit 2).
13.1.3
Safety Set
The Safety Set (SS) is a subset of the RS and consists of all subjects who have been treated with at 
least 1 dose of study drug, either LCM or placebo. This population will serve as the primary 
population for assessing safety endpoints.
13.1.4
Full Analysis Set
The Full Analysis Set (FAS) is a subset of the SS consisting of all subjects with at least 1 seizure 
diary assessment during the Treatment Period. This population will serve as the primary 
population for assessing efficacy endpoints.
13.1.5
Per Protocol Set
The Per Protocol Set (PPS) is a subset of the FAS excluding subjects who completed fewer than 
6 weeks of treatment or subjects with important protocol violations affecting the interpretation of 
the primary efficacy analysis. Important protocol violations will be determined prior to unblinding.
13.2
General statistical considerations
Descriptive statistics will be used to provide an overview of the primary, secondary, and other 
variable results. For categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based on the number of 
subjects appropriate for the purpose of analysis. For continuous parameters, descriptive statistics 
will include number of subjects, mean, standard deviation, median, minimum, and maximum.
REDACTED 
the Sc
he Sc
t t (Vis
(Vis
COPY
entere
enter
basic 
basic
This document
he p
e p
13
13
cannot
r Pro
Pro
eks o
eks o
prim
prim
be used
assess
sses
P
to
urin
urin
support
ysis 
sis 
(FAS
(FAS
g
any
y endp
y end
S
marketing 
he RS a
e RS 
LCM 
CM
authorization
dem
dem
creene
reene
sit 2).
it 2).
application 
d scree
scre
emog
mo
and any 
deta
det
extensions 
e’s s 
i
or 
B 
B t
variations 
tigato
igato
toto
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 89 of 267
13.3
Planned efficacy analyses
13.3.1
Analysis of the primary efficacy variable
The primary efficacy variable, time to second PGTC seizure during the 24-week Treatment Period,
will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect 
for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs 
>2 per 28 days in the 16 weeks prior to randomization) and age at informed consent (≥4 to 
<12 years of age, ≥12 to <18 years of age vs ≥18 years of age). Pooling strategies for strata with a
low number of events will be defined in the SAP prior to unblinding. Subjects who prematurely
discontinue from the study will be censored on the date of last dose of study drug during the 
Treatment Period.
Additionally, a Kaplan-Meier (KM) plot for time to second PGTC seizure as well as the KM 
estimate for the median time to second PGTC seizure will be provided. This analysis will be 
performed using the FAS population.
Testing for the primary endpoint will be done at the 5% level (2-sided). A gatekeeping strategy 
(Marcus et al, 1996) will be used to test the key secondary efficacy variable provided that the 
primary endpoint is statistically significant (See Section 13.3.2 for additional details). No 
additional adjustments for multiplicity are required as all additional inferences will be hypothesis-
generating only.
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in 
order to assess the effect of dropouts, protocol deviations, and operational bias on the primary 
endpoint: 
•
Repeat the primary analysis using the PPS.
•
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue 
due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment 
failures (ie, events at the time of discontinuation).
•
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue 
due to lack of efficacy or AEs only will be analyzed as treatment failures.
•
Repeat the primary analysis using the FAS, comparing the event rates at each interim analysis 
to examine possible operational bias due to unblinding.
13.3.2
Secondary efficacy analyses
13.3.2.1
Key secondary efficacy variable 
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 
24-week Treatment Period, will be analyzed in the same manner as the primary endpoint using the 
FAS. The percentage of seizure-free subjects at 24 weeks will be estimated from the KM estimates 
of time to first seizure using 2-sided 95% confidence intervals. A gatekeeping strategy will be 
employed to control the Type I error (Marcus et al, 1976). If the primary endpoint is statistically
significant at the 5% level, then the key secondary efficacy endpoint will also be assessed at the 
5% significance level. If the primary endpoint fails to reach statistical significance, then the key 
secondary efficacy endpoint will be exploratory only.
REDACTED
ol dev
ol dev
the PP
the P
g th
g th
COPY 
the pr
the p
i
This document
FAS
AS
of t
of t
cannot 
sis of 
is of 
week 
week
be used 
Seco
Seco
K
to
sible
sibl
support
y
y or A
or A
y
y anal
anal
y
e o
e
any 
is usi
is us
AE
marketing 
the FA
he FA
withdra
withd
of dis
of di
authorization
prima
rima
iation
iation
PS.
S.
application 
y va
v
y
for add
for ad
ditiona
dition
and
d). 
). A
varia
ari
any 
A g
A
extensions 
ng
ell as 
ell as 
analy
analy
or
g the
th
variations 
with
with a
turely
urely
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 90 of 267
13.3.2.2
Other secondary efficacy variables 
All safety analyses will be described in the SAP. Analyses of the other secondary efficacy 
variables will be performed using the FAS and will be descriptive in manner only. Any p-values or 
confidence limits provided other than those for the primary analysis of the primary variable (as 
described in Section 13.3.1) and the analysis of the key secondary efficacy variable (as described 
in Section 13.3.2.1) will be exploratory only. 
Time to the first PGTC seizure for the Treatment Period will be analyzed in the same manner as 
the primary endpoint using the FAS.
Further approaches for the analysis of the secondary variable will be described in a detailed SAP.
13.3.3
Other efficacy analysis
Analysis of the other efficacy endpoints listed in Section 4.1.3 of the protocol will be presented 
descriptively. Additional details will be provided in the SAP.
13.4
Planned safety and other analyses
Analyses of other variables, eg, safety or plasma concentration data, will be descriptive in manner 
only. Lacosamide plasma concentrations will be summarized and evaluated by population PK; 
details will be provided in a separate analysis plan.
The incidence and frequency of TEAEs will be summarized for each treatment group and study 
period. The incidence of SAEs and TEAEs leading to premature discontinuation from study drug
will also be summarized for each treatment group and study period. Additional summaries will be
provided by maximum intensity and relationship to study drug. All tables for AEs will be 
displayed by MedDRA® primary System Organ Class and Preferred Term. Further details on the 
analysis of AE data will be given in the SAP.
Observed values and changes from Baseline in vital signs, body weight, continuous laboratory 
parameters, and 12-lead ECG measurements will be summarized using continuous descriptive 
statistics. The number and percentage of subjects in each category will be summarized for the 
categorical outcomes. Shift tables summarizing the number and percentage of subjects having a 
different status (eg, abnormal laboratory result) post-Baseline compared to Baseline will be 
provided.
Incidence of new seizure types, and increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period will be summarized for each treatment 
group.
13.5
Handling of protocol deviations
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on 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 (DCP). To the extent feasible, 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.
REDACTED
din
group 
group
ionshi
ionshi
em Or
em Or
the S
the S
COPY 
mmar
mma
ng to
ng to
This document
mean
ean
prot
pro
t
cannot 
portan
ortan
nin
ni
be used
se
er 28 d
r 28 d
to
eizu
eizu
support 
tab
a
rmal la
mal l
e
any
enta
enta
bles 
bles 
marketing 
SAP.
AP.
Baselin
aselin
asurem
surem
age
ag
authorization 
iz
o prem
o prem
and s
and s
ip to s
ip to s
rgan C
gan C
application
ata, w
ta, w
and eva
nd ev
zed fo
ed fo
and 
wi
wi
any extensions 
etail
ai
l will 
will
or 
iled
le
variations 
r as 
as
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 91 of 267
Important protocol deviations will be reviewed in a blinded manner a part of the ongoing data 
cleaning process prior to database lock to confirm exclusion from analysis sets.
13.6
Handling of dropouts or missing data
All data will be used to the maximum possible extent, but without any imputations for missing data 
for any parameter, unless otherwise specified in the SAP. Sections 13.3.1 and 13.3.2 provide 
additional sensitivity analyses for the primary efficacy and key secondary efficacy endpoints, 
respectively.
13.7
Planned interim analysis and data monitoring
Some AEDs with sodium channel blocking properties can exacerbate some generalized seizure 
types, such as absence and myoclonic seizures. To enhance safety monitoring, 3 interim analyses 
are planned when 25%, 50%, and 75% of subjects experience an event (31, 62, and 93 events, 
respectively) or 24 weeks after 50, 100, and 150 subjects have been randomized, respectively, 
whichever comes first. An event is defined as the occurrence of the second PGTC seizure during 
the Treatment Period. 
Three interim analyses for safety will be performed by the IDMC with a single futility assessment 
planned at the second interim analysis. The IDMC will oversee the safety of the study by 
reviewing safety data periodically. Details will be provided in an IDMC charter. Both safety and 
futility will be assessed in a manner that ensures that blinding is not compromised for individuals 
involved with operational aspects of the study, or individuals involved with the planning and 
conduct of the final statistical analyses. Analysis of the primary endpoint (time to second PGTC 
seizure) will only be examined at the planned futility assessment; an unblinded, descriptive review 
of safety, PGTC seizure frequency, and changes in days with absence and/or myoclonic seizures 
will be provided for all IDMC meetings. 
Additional details, including the methods used for assessing futility, will be provided in the interim 
SAP. Neither futility or the IDMC safety assessments are expected to have any impact on the Type 
1 error as there will be no stopping rule for success in place; however, the significance level will 
be set using a Haybittle-Peto boundary at alpha=0.0001 so as not to require any adjustment to the 
overall alpha level for the final analysis.
The IDMC will consist of 3 voting members, none of whom will be involved with the conduct of 
the study, either by management or participation. In addition, there will be an independent 
reporting team, consisting of an independent statistician and statistical programmers, who will be 
completely independent from the blinded reporting team. The blinded reporting team will be 
responsible for all operational aspects of the study, including routine monitoring and cleaning of 
the data, programming, and quality control (QC) of all analyses defined in the interim SAP on 
blinded data. 
The blinded study team will actively monitor the number of events in the study. Once the required 
number of events (or subjects) has been met and the blinded reporting team has completed the QC 
of the IDMC tables, figures, and listings (TFLs), the programs will be passed to the independent 
reporting team. The independent statistician will request unblinded treatment codes from the IRT 
randomization coordinator and the TFLs will be re-run and QC’d using the actual treatment codes. 
Additional TFLs or ad hoc analyses can be requested by the IDMC based on their data review.
REDACTED
ysis o
sis 
ned fu
ned fu
d chan
d chan
ings.
ings.
COPY 
vid
vi
hat blin
at bli
r indi
r ind
This document
The b
The 
nu
nu
cannot
a, pro
a, pro
ded da
ed d
b
be
e for
e for
used
cons
ons
depe
depe
to
ma
ma
i
support
final 
final
st of 3 
t of 3
ana
any 
ng
ng
bound
boun
marketing 
hods us
hods u
safety
safet
g rul
g ru
authorization
ividu
ividu
of the p
of the 
utility
tility
nges in
ges in
application
C with
C wit
e the s
the 
d in an 
in an
ding i
ding 
l
and 
h
any 
miziz
nd PG
nd PG
extensions
ized s
zed s
interim
nterim
2, and 
and
zed,
zed
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 92 of 267
Any changes to predefined TFLs or new requests will be handled by the independent reporting 
team.
The actual randomization codes and the unblinded outputs will be stored in a secure location which 
will be accessible only to the independent reporting team. A secure, restricted-access directory will 
hold electronic copies of documents such as meeting minutes, interim reports, emails, and periodic 
data deliveries. Only the independent reporting team will have access to this secure location.
13.8
Determination of sample size
Observing 125 events (subjects who had a second PGTC seizure during the 24-week Treatment
Period) will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, assuming 
a dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate for placebo 
and 48.2% for lamotrigine from a previous study comparing lamotrigine and placebo (French et al, 
2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in order to account 
for the possibility of an increased placebo response, as has been documented in recent clinical 
studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample size for this 
study. The rationale for the increase in the hazard ratio included the following considerations: 
different active compounds (LCM and lamotrigine) and a choice of time to second seizure as the 
primary efficacy endpoint (in the lamotrigine study, percent change in PGTC seizure frequency 
was the primary endpoint) (see rationale for second PGTC seizure in Section 5.4.2). 
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring or a 
maximum of 250 subjects randomized, whichever comes first.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Informed consent/assent
Subject’s Informed Consent/Assent 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/Assent, information should be given in a language and at a 
level of complexity understandable to the subject in both oral and written form by the investigator 
(or designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator.
Prior to participation in the study (and prior to prescreening EEG, if applicable), the written 
Informed Consent/Assent form should be signed and personally dated by the subject, or his/her 
legal representative, and by the person who conducted the Informed Consent/Assent discussion 
(investigator or designee). The subject or his/her legal representative must receive a copy of the 
signed and dated Informed Consent/Assent form. As part of the consent/assent process, each 
subject must consent/assent to direct access to his/her medical records for study-related 
monitoring, auditing, IRB/IEC review, and regulatory inspection.
If the Informed Consent/Assent 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/Assent form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form.
REDACTED
ever
ver
LA
LAT
/asse
ass
mu
m
COPY 
GT
G
study
tudy w
y
r co
r c
This document
ubje
ubje
mon
mo
cannot
gato
gato
ned an
ed an
ect
ec
be
senta
sent
used
pation
tion
nsent/
sent/
to support
rstand
stand
bject w
ect 
any 
onsen
onse
marketing 
e
ust be o
st be o
s, and t
, and 
elsink
elsin
authorization
will
will
omes 
omes 
TOR
ORY
R
ent
nt
application
of tim
of ti
hange 
hange
seizur
seizu
l co
l co
and 
mat
mat
follow
follow
any
ted in
ed i
ating
tin
extensions
evel,
vel
ate fo
ate fo
acebo
acebo
er,r, in 
in 
or 
atm
at
l
variations 
me
me
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 93 of 267
Subjects may withdraw their consent to participate in the study at any time. A subject is considered 
as enrolled in the study when he/she has signed the Informed Consent/Assent form. An eCRF must 
not be started, nor may any study specific procedure be performed for a given subject, without 
having obtained his/her written consent/assent to participate in the study.
14.2
Subject identification cards
Prior to study participation at Visit 2, upon signing the Informed Consent/Assent form (as 
applicable), the subject or legal representative will be provided with a subject identification card in 
the language of the subject. The investigator will fill in the subject identifying information and 
medical emergency contact information. The investigator will instruct the subject to keep the card 
with them 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/Assent form (including Informed Consent/Assent form for prescreening EEG, if 
applicable), 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 the 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 
REDACTED
gator’
gator
d docu
d docu
gator
gator
COPY 
app
ap
orward
orward
nt/A
nt/A
This document 
equ
qu
per 
per
c
cannot
of th
of th
be res
be res
uire
uire
be 
h
used 
a p
a 
ay be 
be 
y
to
er
pre
pre
support
ds to
s to
ot mak
t mak
re n
e ne
any
ing r
ng r
o su
o s
marketing
r will
r will
ly repo
rep
y
isi
authorization
Assent
ssent
s curri
s curr
cumen
cumen
application
ed I
d IR
ountry
untry
val of t
al of
copie
copi
f
and 
RB
RB
any 
n l
n 
rigin i
rigin 
extensions 
eep
cs 
s C
loc
loc
r
p th
p th
variations 
card i
ard i
n and 
and
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 94 of 267
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.
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.
16
REFERENCES
Bartolomei F, Roger J, Bureau M, Genton P, Dravet C, Viallat D, et al. Prognostic factors for 
childhood and juvenile absence epilepsies. Eur Neurol. 1997;37:169-75.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale, 
http://www.cssrs.columbia.edu/. Accessed on 10 Apr 2012.
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 1972;34(2):187-220.
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. Development 
and cross-cultural translation of a 31-item quality of life in epilepsy inventory. Epilepsia. 
1998;39:81-8.
Cramer JA, Van Hammée G, N132 Study Group. Maintenance of improvement in health-related 
quality of life during long-term treatment with levetiracetam. Epilepsy Behav. 2003;4:118-23.
EuroQol Group. EQ-5D-3L User Guide. Basic information on how to use the EQ-5D-3L 
instrument. Version 4.0. Apr 2011.
REDACTED
E,
E, A
rding 
rding 
rights
rights
COPY
autho
auth
A
This document 
d
1998
1998
C
cannot 
Re
R
mer JA
er JA
cro
cro
be 
Regr
Regr
used
ersity
rsity
ssrs.c
srs.c
to 
y
support
ence
nce
MH. 
MH. Pr
P
any
M, G
M, 
ce ep
e e
marketing 
are
are
G
authorization 
ND P
ND P
to loc
to loc
re ad
e ad
application
udy
udy fu
fu
y
amendm
mend
rities (
ities 
and 
and m
and m
l
any extensions
t lim
lim
spital 
pital 
occur
occur
or
on 
on
mit
mit
variations 
evant 
evant 
n of
n of
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 95 of 267
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.
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of 
lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. 
Epilepsia. 2007;48(S6):77-78.
Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev. 2000;22:75-80.
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-68.
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4.
ILAE. 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.
ILAE. Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:489-501.
Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 
2005;46(Suppl 9):S10–4. 
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered 
analysis of variance. Biometrika. 1976;63:655-60.
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of 
epilepsy: a systematic review and meta-analysis. Neurology. 2011;77(10):1005-12.
Olafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. Incidence 
of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome 
classification: a prospective study. Lancet Neurol. 2005;4:627-34.
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5:693-722.
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 
Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39:800-12.
Verotti A, Greco R, Giannuzzi R, Chiarelli F, Latini G. Old and new antiepileptic drugs for the 
treatment of idiopathic generalized epilepsies. Curr Clin Pharmacol. 2007;2:249-59.
REDACTED
testing
testin
:655
655
C, Klei
, Kle
eta
eta
COPY
ralize
raliz
This document 
reatm
eat
cannot 
800
800
otti A,
tti A,
atme
tme
be
versi
rs
00
00-1
-
used 
d M, K
M, K
sion
sion
to
2009
009
support
ntiepil
iepil
DF. Me
F. Me
9;4
9 4
any
udy
udy. L
. 
marketing 
in
anal
analy
ndsson 
dsson
psy
sy inin
y
L
authorization 
g proc
g proc
60.
60.
nschm
sch
application
na
phic cl
hic c
ed d epil
epi
and 
ation
ation
any
drom
dro
extensions 
;280:6
280:6
ague A
ague A
om
om
or 
n
variations thereof. 


Thefollowinginformation(eg,ƋƵĞƐƚŝŽŶŶĂŝƌĞ)iscopyrightedandUCBdoesnothavepermissionto
disclosethecontents.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 108 of 267
17.3
Protocol Amendment 1
Rationale for the amendment
The primary purpose of this substantial amendment is to identify significant changes to the study 
design including inclusion and exclusion criteria, as well as the addition of an IDMC. In addition, 
study secondary variables were changed to more accurately represent the study design.
The protocol has been updated to include randomization stratified by age at informed consent (≥12 
to <18 years of age vs ≥18 years of age). This is in order to maintain balance within each treatment 
arm and within the existing baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days 
for the 16-week Combined Baseline Period prior to randomization) as well as provide greater 
control for variability when analyzing the primary efficacy variable (time to second seizure).
An inclusion criterion was added to include subjects of normal intelligence for age in the judgment 
of the investigator. Exclusion criteria were added or modified to further exclude subjects who have 
a diagnosis of developmental delay or mental retardation or a history of status epilepticus. The 
rationale for adding the inclusion/exclusion criteria is that subjects with developmental delay or 
mental retardation are more likely to have symptomatic rather than idiopathic seizures.
The inclusion criterion regarding the lower limit body weight for male and female subjects 
≥12 years of age was changed from ≥30kg to ≥50kg. This was based on the observations collected 
to date from pediatric PK/tolerability studies. 
The text regarding the use of benzodiazepines was revised to clarify that up to 3 marketed AEDs 
are allowed for study inclusion provided at least 1 of the 3 AEDs is a benzodiazepine regardless of 
indication. The intermittent use of a benzodiazepine is permitted for epilepsy indications only and 
limited to 2 doses per 28 days; intermittent use for non-epilepsy indications is prohibited. The 
rationale for this change was based on data from SP0961 in which approximately 20% of PGTC 
seizure subjects with IGE used benzodiazepines. Subjects should not be excluded from the study 
due to benzodiazepine use unless they are using benzodiazepines intermittently for indications 
other than epilepsy. This change is consistent with other PGTC seizure studies in regards to 
benzodiazepine use.
The secondary efficacy endpoint time to first PGTC seizure during the 24-week Treatment Period
was added as a key secondary endpoint as UCB considers that LCM will improve the rate of 
seizure freedom in this difficult to treat population. A gatekeeping strategy will be used to control 
Type I error (Section 13.3.2).
For the assessment of the effect of LCM on quality of life in pediatric subjects, the SP0982 
protocol has been updated to include the PedsQL. The PedsQL is widely used in epilepsy and other 
therapeutic areas, and may allow for comparison with other diseases. In addition, the PedsQL also 
allows for consistency across age groups and development programs, and is available in many 
languages for global clinical studies.
For the assessment of neurobehavior and cognition in pediatric subjects, the SP0982 protocol has 
been updated to include the Achenbach CBCL and the BRIEF, respectively. The addition of these 
assessments also allows for consistency across age groups and development programs.
To ensure subject safety, interim assessments for safety and futility will be performed using an 
IDMC due to the novel study design and primary endpoint in this patient population. Furthermore, 
REDACTED 
was
wa
least 1
least 1
zodiaz
odiaz
ittent 
ittent
on da
on da
COPY 
Th
Th
as re
as r
This document
langu
angu
F
cannot
has
has
peutic
eutic
ws fo
ws f
be
essm
ssm
as b
as b
used
ction
ction
me
me
to
this
this
support 
endpoi
ndpo
econda
conda
s did
any
e is 
is
marketing
ata fro
ata fr
odiazep
diazep
they
hey ara
y
s con
s co
authorization 
revised
evised
1 of th
of th
zepine
epine
use fo
se fo
application
n idid
for ma
for m
was ba
as b
and
ith d
th d
diop
diop
any 
lulu
status 
tatus
ev
extensions
e gre
gr
nd seiz
d seiz
r age 
age 
ude 
ude
or
28 
28 
ea
variations 
(≥12 
≥12
reatme
eatme
da
d
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 109 of 267
a minority of subjects (~10%) in SP0961 showed an increase in absence seizures that, in this 
uncontrolled study, could not be distinguished between the drug vs the natural course of the 
disease and required additional examination in the current study.
SP0982 is an event-driven study where the statistical properties are based upon the number of 
events, not the number of subjects as is typical in most epilepsy studies (the primary efficacy 
variable is time to second PGTC seizure). As a result, the protocol was amended to reflect this 
focus. Furthermore, a maximum sample size of 250 subjects was introduced if 125 events were not 
observed on or before the 200th subject randomized. This is standard for event-driven studies and 
represents an approximate 25% increase from the projected sample size, in case the event rate is 
lower than anticipated.
Other changes made in this amendment are to provide clarification or administrative in nature.
Modifications and changes
Global changes
The following global changes were made within the protocol:
•
Study contact information was updated.
•
Additional sites and countries were added.
•
PedsQL, BRIEF, and Achenbach CBCL assessments were added.
•
Vital signs were updated to include orthostatic assessments.
•
Subject age range for the QOLIE-31-P (subjects ≥18 years of age) and the PedsQL (for 
subjects <18 years of age) was added.
•
The maximum study duration and the maximum duration of study drug administration were 
increased by 1 week as a result of the change to the End of Study Period.
•
Baseline failures and study completers were defined.
•
Section renumbering was done as needed when sections were added or removed.
•
Minor editorial/administrative/organizational changes were made throughout the protocol.
•
Assessments by visit were updated throughout text and the Schedule study of assessments
(Table 5‒1).
Specific changes
Change #1
Title page:
The title was updated from “Protocol SP0982” to “Protocol SP0982 Amendment 1.”
The information below was revised to include Protocol Amendment 1 and the type of protocol 
amendment:
Protocol/Amendment Number
Date
Type of Amendment
Final Protocol
05 Aug 2011
N/A
REDACTED
static
static
P (sub
P (sub
ded.
ded.
d th
d th
COPY 
smen
men
This document 
The 
The 
T
cannot
ge #
ge #
e pag
e pag
be
cha
ha
#1
#1
used 
han
an
to
y v
y visi
support 
as d
s d
ministr
nistr
sit w
sit
any 
om
om
done
don
marketing 
he max
he ma
of the c
f the
mple
mpl
authorization 
ts w
asses
asses
bjects
bjects
application 
wer
wer
and any extensions 
tive in
ve in
or
nt ra
nt r
variations 
re not 
re not
es and
s and
rate
rat
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 110 of 267
Has been changed to:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
05 Aug 2011
Not applicable
Protocol Amendment 1
25 Sep 2012
Substantial
Change #2
Section 1 Summary
First paragraph
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multi-center study 
designed to assess the efficacy of adjunctive lacosamide (LCM, VIMPAT®; SPM 927; previously 
referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, ADD 234037) 
400mg/day (200mg, twice daily [bid]) compared to placebo for uncontrolled primary generalized 
tonic-clonic (PGTC) seizures in subjects with idiopathic generalized epilepsy (IGE) in prolonging 
the time to second PGTC) seizure, despite treatment with 1 to 2 concomitant antiepileptic drugs 
(AEDs).
Has been changed to:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy and safety of oral lacosamide (LCM) (VIMPAT®; SPM 927; 
previously referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, 
ADD 234037) 400mg/day (200mg, twice daily [bid]) vs placebo as adjunctive therapy for 
uncontrolled primary generalized tonic-clonic (PGTC) seizures in subjects ≥12 years of age with 
idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant antiepileptic drugs 
(AEDs) independent of the number of prior failed AEDs (see Section 7.8)
Seventh through ninth paragraphs
The primary efficacy variable is the time to the second PGTC seizure during the 24 week 
Evaluation Period. 
Secondary efficacy variables include the percent change in PGTC seizure frequency per 28 days 
from Baseline (combined historical and prospective) to the first 5 weeks of the Evaluation Period 
and to the 24-week Evaluation Period. 
Other efficacy variables include percent change in days with absence seizures, percent change in 
days with myoclonic seizures, seizure free status for PGTC seizures and for all seizure types, 50% 
response for PGTC seizures, 50% response for days with absence seizures, and 50% response for 
days with myoclonic seizures, change from Baseline in Patient Weighted Quality of Life in 
Epilepsy Inventory-Form 31 (QOLIE-31-P), EuroQol 5Dimension (EQ 5D) Quality of Life 
Assessment items, healthcare resource use, number of working or school days lost by subject 
and/or caregiver, and socio-professional data. 
Have been changed to:
The primary efficacy variable is the time to the second PGTC seizure during the 24-week 
Treatment Period. The key secondary efficacy variable is the time to the first PGTC seizure during 
the 24-week Treatment Period, which will use a gatekeeping strategy to assess statistical 
REDACTED
cetam
ceta
dail
daily y
cloni
cloni
E)
E) curr
curr
of p
of
COPY 
ntrolle
ntroll
laco
laco
This document 
pil
pil
Asse
Asse
an
an
cannot
e for
for
with 
with 
leps
eps
be
my
myoc
o
P
used 
k k
y vari
vari
y
l
to
Eva
Ev
support 
iables i
ables
ned h
ned h
l
any
s the
s th
marketing
rent
ent
prior fa
prior f
e t
authorization
osami
sami
mido
ido-N
[bid])
[bid])
ic (PG
c (PG
ntly
tly
application 
d, par
d, par
d
and
pile
ile
comit
omit
any
led p
ed p
epsy
eps
extensions 
center 
enter
PM 92
92
de, A
de, A
or variations s thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 111 of 267
significance (see Section 13.3.2). Other secondary efficacy variables include 1) the percent change 
in PGTC seizure frequency per 28 days from the Combined Baseline (Combined 12-week 
Historical and 4-week Prospective Baseline) to the first 5 weeks of the Treatment Period, 2) from 
the Combined Baseline to the full Treatment Period and 3) seizure-free status for PGTC seizures 
during the 24-week Treatment Period.
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); withdrawal 
due to AEs; changes in hematology, chemistry, and urinalysis parameters; changes in 12-lead 
electrocardiograms (ECGs); changes in vital sign measurements; changes in neurological 
examination findings. In addition for pediatric subjects <18 years of age, safety will be evaluated 
using behavioral assessments (Achenbach Child Behavior Checklist [CBCL]), cognitive function 
assessments (Behavior Rating Inventory of Executive Function® [BRIEF®]), and quality of life 
assessments (Pediatric Quality of Life Inventory [PedsQL]).
Change #3
Sections 3.1 Primary objective
The primary study objective is to demonstrate the efficacy of adjunctive LCM at the dose of 
400mg/day (200mg bid) compared to placebo in subjects with IGE with uncontrolled PGTC 
seizures despite treatment with 1 to 2 concomitant AEDs.
Has been changed to:
The primary study objective is to demonstrate the efficacy of oral LCM (400mg/day [200mg bid]) 
vs placebo as adjunctive therapy for uncontrolled PGTC seizures in subjects with IGE currently 
taking 1 to 3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
Change #4
Sections 4.1 Efficacy variables
The following sections have been updated.
Sections 4.1.2 Secondary efficacy variables
Secondary efficacy variables include:
•
Percent change in PGTC seizure frequency per 28 days from Baseline (combined historical and 
prospective) to the first 5 weeks of the Evaluation Period.
•
Percent change in PGTC seizure frequency per 28 days from Baseline (combined historical and 
prospective) to the 24-week Evaluation Period.
Have been changed to:
The key secondary variable is:
•
Time to the first PGTC seizure during the 24-week Treatment Period 
The other secondary efficacy variables are:
REDACTED 
ate the
ate the
ontrol
ontrol
pende
pende
COPY
AEDs
AED
This document 
The 
The
cannot
spect
pect
ve b
ve b
be
t cha
t cha
i
used 
ge i
e 
e) to t
e) to t
to
in P
in P
support
ndar
dar
ariable
iable
any
en up
en u
ry
marketing 
bles
bles
d
authorization 
e effic
effic
lled P
led P
nt of 
t of 
application 
djuncti
djunct
th IGE
h IGE
and any extensions
be ev
e e
gnitive
nitiv
nd qua
nd qua
or 
l
va
variations 
h
rawal
rawal
ad d 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 112 of 267
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 5 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period
Sections 4.1.3 Other efficacy variables
Other efficacy variables include:
•
Percent change in days with absence seizures and days with myoclonic seizures, respectively, 
per 28 days from prospective Baseline to the first 5 weeks of the Evaluation Period and to the 
24-week Evaluation Period.
•
Seizure free status (yes, no) for PGTC seizures for the first 12 weeks of the Evaluation Period 
and for the 24-week Evaluation Period. 
•
Seizure free status (yes, no) for all seizure types for the first 12 weeks of the Evaluation and for 
the 24-week Evaluation Period.
•
50% response for PGTC seizures during the first 5 weeks of the Evaluation Period, the first 
12 weeks of the Evaluation Period, and the 24-week Evaluation Period; a responder is a subject 
experiencing ≥50% reduction in PGTC seizure frequency per 28 days from Baseline 
(combined historical and prospective) to the respective period.
•
50% response for days with absence seizures and days with myoclonic seizures, respectively, 
during the first 12 weeks of the Evaluation Period and the 24-week Evaluation Period; a 
responder is a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from prospective Baseline to the first 12 weeks of the Evaluation Period.
•
Change from Baseline in patient weighted QOLIE-31-P subscale (Seizure Worry, Daily 
Activities/Social Functioning, Energy/Fatigue, Emotional Well-being, Mental 
Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total 
scores.
•
EQ-5D Quality of Life Assessment items.
•
Healthcare resource use: medical procedures, hospitalizations and healthcare provider visits.
•
Number of working or school days lost by subject and/or caregiver.
•
Socio-professional data.
Has been changed to:
Other efficacy variables are:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 5 weeks of the Treatment Period
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
24-week Treatment Period
REDACTED
izure
zur
o the r
o the r
e seiz
e seiz
Evalua
Evalua
ng
ng
COPY
t 5 w
t 5 w
4-
4 week
wee
re f
re f
This document
Has
as
Ot
Ot
cannot 
be
ocio
cio-
s b
s b
be
er of 
er of
used 
y
e reso
reso
to
of L
of 
support
on
unction
nctio
Li
L
any
atien
atie
ing, E
ing, 
marketing
uation
tio
g ≥50%
≥50%
e first 1
first 
ent w
ent
authorization
ek Ev
k E
freque
requ
respec
espec
zures a
ures a
on
on
application
12 we
12 w
eeks of
eks o
Eval
Eval
and any 
of th
of th
extensions 
es, res
s, res
n Perio
n Perio
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 113 of 267
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 5 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the 24-week Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period 
among subjects who completed the first 12 weeks of the Treatment Period. 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the first 12 weeks of the Treatment Period 
among subjects who completed the first 12 weeks of the Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
50% response for PGTC seizures during the first 5 weeks of the Treatment Period; a responder 
is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the first 5 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 12 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 12 weeks of the Treatment Period
•
50% response for PGTC seizures during the 24-week Treatment Period; a responder is a 
subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the 24-week Treatment Period
•
50% response for days with absence seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from the Combined Baseline to the 24-week Treatment Period
•
50% response for days with myoclonic seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with myoclonic seizures per 
28 days from the Combined Baseline to the 24-week Treatment Period
•
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 
31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change
from Baseline in the PedsQL subscale (Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning) and total scores in subjects <18 years of age
•
EuroQol-5 Dimension (EQ-5D-3L) items
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject
•
Number of days with help from a caregiver
REDACTED 
w
g the 2
g the 2
n in PG
in P
k k Tre
Tre
nc
nc
COPY
12 w
12
uction 
ction 
weeks
eeks
This document
•
E
cannot
ty
m Ba
m Ba
Funct
Funct
be
Fa
y of L
of 
y
sed
-31
31-P
atigu
tigu
to
asel
ase
support
wit
exper
expe
ombin
ombi
ini
any 
th my
h my
i
marketing 
a
e seizu
e seizu
cing
ng ≥5
≥
to the 
o the
authorization
in
s of th
of th
24
24-we
-we
GTC 
GTC 
atmen
tme
application
que
que
riod
iod
eeks of
eks o
n PGT
n PG
and
Treatm
reat
enc
enc
any extensions 
eatme
eatme
ent Pe
nt P
or variations 
ng g 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 114 of 267
Change #5
Section 4.2 Safety variables
Safety variables include
•
AEs as reported spontaneously by the subject and/or caregiver or observed by the investigator.
•
Subject withdrawal due to AE.
•
Changes in hematology, chemistry, and urinalysis parameters.
•
Changes in 12-lead ECGs.
•
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight) and neurological examination findings.
Has been changed to:
Section 4.2 Safety variables
The safety variables are:
•
AEs as reported spontaneously by the subject and/or caregiver or observed by the investigator.
•
Subject withdrawal due to AE
•
Changes in hematology, chemistry, and urinalysis parameters
•
Changes in 12-lead ECGs
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings.
The following section was added.
Section 4.2.1 Other safety variables
Other safety variables are:
•
Achenbach CBCL
•
Cognitive function assessment BRIEF
Change #6
Section 5.1 Study description
Paragraph 1
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multi-center study 
designed to assess the efficacy of adjunctive LCM 400mg/day (200mg bid) compared to placebo 
for uncontrolled PGTC seizures in subjects with IGE in prolonging the time to second PGTC 
seizure, despite treatment with 1 to 2 concomitant AEDs.
Has been changed to:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy of oral LCM (400mg/day [200mg bid]) vs placebo as adjunctive 
therapy for uncontrolled PGTC seizures in subjects ≥12 years of age with IGE currently taking 1 to 
REDACTED 
, blood
, bloo
neuro
neuro
COPY 
alys
ysisis
This document
desig
esig
for 
for 
canno
aph 1
ph 
982 is
82 i
gn
gn
be 
.1 
1
sed 
 St
St
to support 
n asse
n ass
any marketing 
olog
lo
varia
ari
authorization
s para
s para
d pres
d pres
ogic
gic
application 
giver or
iver o
and any extensions 
ncludi
ncludi
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 115 of 267
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8). This study 
will also assess the safety, tolerability, and PK of LCM use in this population.
Paragraph 11
At the end of the Prospective Baseline, eligible subjects will be randomized at Visit 2 to LCM 
400mg/day (200mg bid) or placebo in a 1:1 (active/placebo) fashion and begin the Evaluation 
Period with a double-blind 3-week titration. 
Has been changed to:
At the end of the Prospective Baseline (Visit 2), eligible subjects will be randomized to receive 
LCM (400mg/day [200mg bid]) or placebo in a 1:1 fashion (active:placebo) and stratified by 
Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined 
Baseline Period prior to randomization) and by age at informed consent (≥12 to <18 years of age 
vs ≥18 years of age). The Treatment Period starts at the time of the Randomization Visit (Visit 2).
Change #7
Section 6.1 Inclusion criteria
Inclusion criterion 4 was added and subsequent criteria were renumbered:
4. Subject is of normal intelligence for age in the judgment of the investigator. 
Inclusion criterion 3, 4, 7, and 8:
3. Male and female subjects 12 years of age and older with a body weight≥30kg. 
4. Subject with a confirmed diagnosis of at least 1 year prior to Visit 1 and a disease onset at 4 to 
25 years, consistent with IGE experiencing PGTC seizures (type IIE) that are classifiable 
according to the International League Against Epilepsy Classification of Epileptic Seizures 
(Epilepsia, 1981) 
7. Subject has been maintained on a stable dose regimen of 1 to 2 marketed AEDs for at least 
28 days prior to Visit 1 and during the Prospective Baseline with or without additional 
concurrent stable VNS. Vagus Nerve stimulation must have been in place for at least 6 months 
prior to Visit 1 with constant settings for at least 28 days prior to Visit 1 and during the 
Prospective Baseline. Stable daily doses of benzodiazepines will be counted as AEDs.
8. Subjects are required to have had an EEG report showing discharges consistent with IGE 
confirmed by an Independent Central Reviewer.
Has been changed to:
3. Male and female subjects 12 years of age and older with a body weight ≥50kg. 
5. Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset at 5 to 
30 years of age, consistent with IGE experiencing PGTC seizures (Type IIE) that are 
classifiable according to the ILAE Classification of Epileptic Seizures (ILAE, 1981).
8. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with at least 1 AED identified as a benzodiazepine) for at least 28 days 
prior to Visit 1 with or without additional concurrent stable VNS. (see Section 7.8).
REDACTED
e and 
e and
of at le
f at l
perienc
erien
eagu
eagu
COPY
udgm
dgm
This document
. S
cannot 
en
Male an
ale an
Sub
Sub
be
n ch
n c
used
requ
equ
by a
y a
to 
quir
quir
suppor
. Vag
Va
consta
cons
ine
ne. S
. S
any
d duri
d dur
agu
agu
marketing
ci
ue Aga
ue Ag
on a st
n a 
authorization 
older 
older 
east 1
east 1
ing P
ng P
application 
renum
renum
ent of th
nt of 
and any 
miziz
extensions
o
atified
tifie
week C
ek C
to <18
o <18
zatio
zatio
or
rece
rec
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 116 of 267
•
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline 
and Treatment Period. 
9. Subjects are required to have had an EEG tracing and report showing discharges consistent 
with IGE (generalized >3Hz epileptiform discharges and a normal EEG background) 
confirmed by a Central Reviewer.
Change #8
Section 6.2 Exclusion criteria
Added exclusion criterion 4 and subsequent criteria were renumbered:
4. Subject has a diagnosis of developmental delay or mental retardation including mild forms.
Exclusion criteria 5 and 16:
5. Subject has a history of status epilepticus within the 12-month period prior to Visit 1 or 
experiences status epilepticus during the Prospective Baseline.
16. Subject has impaired renal function, ie, creatinine clearance (CLcr) is lower than 30mL/minute, 
at Visit 1. Creatinine clearance will be estimated as follows:
•
Adult males: CLcr = (140-age) x weight in kg/(72 x serum creatinine in mg/dL)
•
Adult females: CLcr = [(140-age) x weight in kg/(72 x serum creatinine in mg/dL)] x 0.85
Have been changed to:
6. Subject has a history of status epilepticus.
17. Subject has impaired renal function, ie, creatinine clearance (CLcr) is lower than 50mL/min.
Change #9
7.9 Concomitant treatments medications/therapies
Subject must have been maintained on a stable dose regimen of 1 to 2 marketed AEDs for at least 
28 days prior to Visit 1 and must remain stable during the course of the study. Vagus nerve 
stimulation must have been in place for at least 6 months prior to Visit 1 with constant settings for 
at least 28 days prior to Visit 1 and must remain unchanged during the course of the study.
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics
•
MAO inhibitors
•
Barbiturates (except as anti-epileptic medications)
•
Narcotic analgesics
•
Only stable use of amphetamines and sedative antihistamines is allowed during the study.
•
Only stable, low doses of anxiolytics or once-daily hypnotics are allowed for non-epilepsy 
indications.
REDACTED 
igh
igh
epticu
epticu
ion,
ion,
COPY
kg/(72
kg/(7
ht in
ht in
This document
B
•
cannot 
ole
MAO i
AO i
Ba
Ba
be
eptic
epti
used 
rio
g medi
med
to
or to
or to
suppor
ainta
inta
and mu
and m
e been
been
V
any
nts
nt
ain
ain
marketing
, ie, cr
ie, cr
s m
authorization 
n kg/(
kg/(
s.s.
application
(CLcr
(CLc
ws:
ws:
2 x ser
x se
and 
od
od
any 
d prio
prio
extensions 
ding m
ding m
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 117 of 267
•
The chronic use of benzodiazepines is allowed for treatment of epilepsy. Benzodiazepines will 
be counted as one of the AEDs and the dose regimen must be stable for at least 28 days prior to 
Visit 1. Intermittent use of benzodiazepines as rescue, are not allowed during the study.
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.
Has been changed to:
Section 7.8 Concomitant medication/treatment
7.8.1 Prohibited concomitant treatments (medications and therapies)
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with at least 1 AED identified as a benzodiazepine) for at least 28 days 
prior to Visit 1 and during the Prospective Baseline and Treatment Period with or without 
additional concurrent stable VNS. 
•
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the 
course of the study.
•
The chronic (daily dose) use of benzodiazepines is allowed regardless of indication and will be 
counted as 1 of the 3 allowed AEDs.
•
Intermittent use of benzodiazepines (limited to 2 doses per 28 days) is allowed only for 
epilepsy indications if established at least 28 days prior to Visit 1. Intermittent use of 
benzodiazepines for any other indication is prohibited during the study.
7.8.2 Prohibited concomitant treatments (medications and therapies)
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics.
•
MAO inhibitors.
•
Barbiturates (except as antiepileptic medications).
•
Narcotic analgesics.
•
Only stable use of amphetamines and sedative antihistamines is allowed during the study. 
•
Only stable, low doses of non-benzodiazepine anxiolytics or once-daily hypnotics are allowed 
for nonepilepsy indications.
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.
REDACTED 
p
(limite
limit
d at lea
at lea
ndica
ndica
COPY 
nes i
nes i
This document 
Ther
The
n
cannot 
nly
nly stst
y
for n
for n
be
table
table
used 
nalge
nalge
to
xcep
xcep
support 
pt a
t
any
apie
api
marketing
as
ation i
ion 
nt trea
t tre
ies a
ies
authorization
is allo
is allo
ed to
ed to
st 28
t 28
application 
st 6 mo
t 6 m
must r
must 
and
riod
od
any
ne) fo
ne) f
d wi
d w
extensions 
rapies
apies
azepin
zepin
f
or variations 
t’s s 
r.
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 118 of 267
Change #10
Section 7.10 Blinding
Subjects, investigators, and all site personnel are blinded to study medication. 
Lacosamide and matching placebo are tablets identical in shape, size, and color. The blind is 
maintained as the accompanying packaging is identical in appearance so that neither the 
investigator (or designee) nor the subject is able to tell whether the subject is receiving LCM 
placebo.
An interactive voice/web response system (IXRS) will be used to assign a treatment to subjects 
who meet eligibility criteria at Visit 1, based on a predetermined randomization schedule. The 
IXRS is used to control all drug distribution and inventory for this study.
Has been changed to:
Section 7.9 Blinding
UCB Global Clinical Trial Supply will create a packaging list using a validated application. The 
packaging list will be provided to the interactive voice/web response system (IVRS/IWRS) vendor 
and to the packaging vendor who will prepare the kits accordingly.
The treatment randomization schedule will be generated by UCB (or designee) in a manner that 
will ensure that the study team remains blinded, in accordance with current standard operating 
procedures (SOPs). The randomization schedule will be maintained in a secure location until the 
study is unblinded for the final statistical analysis. 
All sponsor, investigator sites, and contract research organization (CRO) staff involved with the 
study will be blinded to the treatment code with the following exceptions:
•
Sponsor personnel and its subcontractors directly involved in the packaging of the IMP or in 
the management of the IVRS/IWRS.
•
Sponsor pharmacovigilance staff will receive separate access to the IVRS/IWRS in order to 
meet their requirements for serious adverse event (SAE) reporting to regulatory authorities.
•
Central laboratory staff assaying study drug. However, no randomization list will be provided.
An interim futility assessment is planned to allow UCB to consider terminating the study should 
the likelihood of a positive outcome be unacceptably low based on an unblinded assessment of 
interim data by an independent data monitoring committee (IDMC). Such an interim assessment 
will be conducted in a manner that ensures that blinding is not compromised for individuals 
involved with operational aspects of the study nor individuals involved with the planning and 
conduct of the final statistical analyses. The 3 planned interim safety assessments will be 
conducted similarly to assure that blinding is maintained.
REDACTED 
le w
le w
alalys
ysisis
ract re
ract re
nt code
nt code
COPY
ated 
ated
n acco
n acc
wil
wi
This document 
ond
n
cannot
ed wi
d wi
uct o
uct o
duc
duc
be
nduct
nduc
thth
used
f a p
a p
y an 
 an 
y
to
ass
asse
os
support 
for
for
staff as
taff a
essm
es
any
e staf
e sta
or ser
r s
marketing 
e w
tractors
tracto
WRS.
WRS.
fff
authorization
orda
rda
ll be m
l be m
. 
esearc
searc
with
with
application
onse s
onse 
ngl
ngly.y.
y UC
y UCB
danc
anc
and 
a val
a val
any extensions
 s
edule
edule
or
ubj
ubj
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 119 of 267
Change #11
The following section and text was added and subsequent sections were renumbered.
Section 9.2 Secondary efficacy variables
The key secondary efficacy variable is:
•
Time to the first PGTC seizure during the 24-week Treatment Period 
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 5 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period
Change #12
Section 9.2 Other efficacy variables
Other efficacy variables include:
•
Percent change in days with absence seizures and days with myoclonic seizures, respectively, 
per 28 days from prospective Baseline to the first 5 weeks of the Evaluation Period and to the 
24-week Evaluation Period.
•
Seizure free status (yes, no) for PGTC seizures for the first 12 weeks of the Evaluation Period 
and for the 24-week Evaluation Period. 
•
Seizure free status (yes, no) for all seizure types for the first 12 weeks of the Evaluation and for 
the 24-week Evaluation Period.
•
50% response for PGTC seizures during the first 5 weeks of the Evaluation Period, the first 
12 weeks of the Evaluation Period, and the 24-week Evaluation Period; a responder is a subject 
experiencing ≥50% reduction in PGTC seizure frequency per 28 days from Baseline 
(combined Historical and Prospective) to the respective period.
•
50% response for days with absence seizures and days with myoclonic seizures, respectively, 
during the first 12 weeks of the Evaluation Period and the 24-week Evaluation Period; a 
responder is a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from prospective Baseline to the first 12 weeks of the Evaluation Period.
•
Change from Baseline in patient weighted QOLIE-31-P subscale (Seizure Worry, Daily 
Activities/Social Functioning, Energy/Fatigue, Emotional Well-being, Mental 
Activity/Cognitive Functioning, Overall Quality of Life and Medication Effects) and total 
scores.
•
EQ-5D Quality of Life Assessment items.
•
Healthcare resource use: medical procedures, hospitalizations and healthcare provider visits.
REDACTED 
res 
res 
o the f
o the f
PGTC 
PGTC
Per
Per
COPY 
s and
an
This document 
C
A
cannot 
ond
nd
om pr
om pr
Cha
Cha
be
the f
he 
der
der
used 
nse fo
nse fo
fir
fir
to
oric
oric
support 
C se
se
uation
uatio
% redu
redu
cal
ca
any 
od
eizu
eiz
marketing 
 sei
se
iod. 
od. 
r all sei
all se
d
authorization 
d day
d day
first 5
first 5
eizu
izu
application and
reatm
eatm
any 
me
extensions
s
weeks 
eeks 
ned B
ed B
or
elin
elin
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 120 of 267
•
Number of working or school days lost by subject and/or caregiver.
•
Socio-professional data
Has been changed to:
Section 9.3 Other efficacy variables
Other efficacy variables are:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 5 weeks of the Treatment Period
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
24-week Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 5 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the 24-week Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period 
among subjects who completed the first 12 weeks of the Treatment Period. 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the 12-week Treatment Period among 
subjects who completed the first 12 weeks of the Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
50% response for PGTC seizures during the first 5 weeks of the Treatment Period; a responder 
is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the first 5 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 12 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 12 weeks of the Treatment Period
•
50% response for PGTC seizures during the 24-week Treatment Period; a responder is a 
subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the 24-week Treatment Period
•
50% response for days with absence seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from the Combined Baseline to the 24-week Treatment Period
•
50% response for days with myoclonic seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with myoclonic seizures per 
28 days from the Combined Baseline to the 24-week Treatment Period
tmen
tme
zure t
zure t
2 week
week
all se
all se
COPY 
 of 
o
es for 
es for
ent
ent
This document
r
cannot
mbin
mbin
50%
50%
be
po
exp
exp
used 
mbin
bi
onse 
nse
to 
ubj
ined
ined
support 
he f
he 
PGTC s
GTC
ject e
ect e
any
50% 
50%
firs
fir
marketing
eizure
eizure
eek Tr
eek T
ures du
res d
authorization
the 
he
Perio
Perio
ypes f
ypes f
ks of t
s of t
application 
st 12 w
t 12 w
e Trea
Trea
e 24
e 24
and
the 
the 
any 
C
extensions
aselin
selin
mbin
mbin
or variations 
to the
o the
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 121 of 267
•
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 
31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or change 
from Baseline in the PedsQL subscale (Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning) and total scores in subjects <18 years of age
•
EQ-5D-3L items
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject
•
Number of days with help from a caregiver
Change #13
The following section number and text was added:
Section 9.3.3 Pediatric Quality of Life Inventory
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 Measurement Model consists of developmentally appropriate forms for pediatric 
subjects 12 years of age and ≥13 years to <18 years of age. Self-report is measured for pediatric 
subjects ≥5 years to <18 years of age, and parent proxy report of child HRQoL is measured for 
pediatric subjects ≥2 years to ≤18 years of age. 
The multidimensional 23-item PedsQL generic core scales encompass the essential core domains 
for pediatric HRQoL measurement: Physical Functioning (8 items), Emotional Functioning 
(5 items), Social Functioning (5 items), and School Functioning (5 items). 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 always). A total health summary score ranging between 
0 and 100 is calculated from the sum of the raw scores of the 23 items, with higher scores 
indicating higher HRQoL.
Change #14
Section 10 Assessments of safety
The following section was updated.
Section 10.7.1 Vital signs and body weight
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured at clinic visits 
in a sitting position after at least 3 minutes at rest, according to the schedule of study assessments 
in Table 5.1. Body weight will be determined without shoes and wearing light clothing, according 
to the schedule of study assessments in Table 5.1. Weight and height will be recorded according to 
the schedule of study assessments in Table 5.1.
REDACTED
rent p
rent 
f age.
age.
L gene
 gen
Phy
Phy
COPY 
lopme
lopme
ars of
ars o
This document 
n a s
a 
inin T
tot
cannot
n 1
n 1
invasi
nvasi
sitt
sitt
be 
g
10.
10.
used 
sse
se
sect
sect
to
ess
es
support any 
, o
, o
he sum
he su
marketing
sical F
sical 
s), and 
s), and
ks, and 
s, and
often
ofte
authorization
f age
f age
proxy
proxy r
y
eric c
ric c
F
application 
ore sca
ore sc
health 
health
ntally
ntally
and any extensions or variations 
visi
visi
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 122 of 267
Has been changed to:
Section 10.7.2 Vital signs and body weight
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits in a supine 
position after at least 3 minutes at rest, according to the schedule of study assessments in Table 5‒1. 
Assessment of orthostatic changes will be as follows: after the 3-minute measurement in a supine 
position, the subject is asked to stand and BP and pulse rate are taken 1 minute and 3 minutes after 
standing up as feasible, Blood pressure measurements should be taken with the proper placement 
and proper sized cuff to obtain accurate measurements.
Body weight will be determined without shoes and wearing light clothing and height will be 
measured without shoes. Body weight and height will be measured using equipment that is age 
appropriate and assessed according to the tabular schedule of study assessments (Table 5‒1).
The following sections were added.
Section 10.7.4 Tanner stage
At Visit 1 and Visit 9/ET Visit, the investigator or qualified designee will evaluate the subject’s 
sexual development using a 3-item scale. The Tanner Stage will be performed for subjects who are 
<18 years of age at Visit 1. At Visit 9/ET Visit, if subject is >18years of age, a repeat assessment is 
not necessary. 
Section 10.7.7 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). For subjects ≥12 years to <18 years of age, the CBCL/6 to 18 version will be 
used.
The same scale will be completed at Visit 2, Visit 4, and Visit 9/ET Visit by the parent(s)/legal 
representative(s). The completion of the Achenbach CBCL will require approximately 45 minutes. 
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
Eight syndrome scores will be calculated from these questionnaires, which will in turn be 
summarized by 2 composite scores. Additionally, for each score on the questionnaire, syndrome, 
and total level, categorizations based on a normative sample will be used to evaluate normal, 
borderline, or clinically relevant behavior.
In addition, the Achenbach CBCL/6 to 18 includes ratings related to performance in school, 
activities in leisure time, and special interests.
Section 10.7.8 BRIEF
The BRIEF is a validated tool that will be used for the evaluation of subjects ≥5 years of age. The 
BRIEF will be administered at the Visit 2, Visit 4, and Visit 9/ET Visit.
REDACTED 
idated
idated
aviora
aviora
ars to 
ars to
COPY 
This document
bord
bord
In
In
cannot 
ndr
dr
arized
arized
total
total
be 
rom
rom
used 
or
or
ue or 
e or 
to
r som
som
support
g scal
sca
as kno
as kno
any 
curren
curre
lel
marketing 
t Visit
Visit 2
of the
of th
authorization 
d ques
ques
al prob
al pro
<18
<18
application 
nee
ee
l be pe
be p
>18yea
>18ye
and 
e wi
w
any extensions
will
wil
ent tha
nt tha
s (
s (Tab
Tab
or 
l b
l b
variations 
after 
fter 
ement 
ment 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 123 of 267
The BRIEF includes rating forms used by parents to assess subjects’ executive functioning and 
include validity scales to measure negativity and inconsistency of responses.
The BRIEF Rating form contains items in nonoverlapping clinical scales and validity scales. These 
theoretically and statistically derived scales form 2 broader Indexes: Behavioral Regulation 
(3 scales) and Metacognition (5 scales), as well as a Global Executive Composite score. Factor 
analytic studies and structural equation modeling provide support for the 2 factor model of 
executive functioning as encompassed by the 2 Indexes.
Change #15
Section 13.1.5 Per Protocol Set
The Per Protocol Set (PPS) is a subset of the FAS excluding subjects with important protocol 
violations affecting the interpretation of the primary efficacy analysis, to be determined during the 
Data Review Meeting.
Has been changed to:
The Per Protocol Set (PPS) is a subset of the FAS excluding subjects who completed fewer than 
5 weeks of treatment or subjects with important protocol violations affecting the interpretation of 
the primary efficacy analysis. Important protocol violations will be determined during the Data 
Review Meeting prior to unblinding.
Change #16
Section 13.3 Planned efficacy analyses
The following sections were updated.
Section 13.3.1 Analysis of the primary efficacy variable
The primary analysis of the primary variable is performed using a cox regression on the dependent 
variable day of the occurrence of the second PGTC seizure during the Evaluation Period (after first 
intake of study medication) adjusted for the subject’s Baseline PGTC seizure frequency per 28 
days as covariate. Subjects who prematurely discontinue from the study during the Evaluation 
Period for reasons unrelated to occurrence of the 2nd PGTC seizure will be censored on the date of 
last dose of study medication during the Evaluation Period.
The treatment effect will be estimated and a confirmatory 1-sided 0.025-level test for superiority of 
LCM over placebo will be performed by reporting 2-sided p-values for the treatment effect and 
comparing to the level of 0.05. If and only if the p-value is below or equal to 0.05 and the point 
estimator for the treatment effect favors LCM, the hypothesis that “LCM does not positively 
influence the time until day of second PGTC seizure” will be declined and the alternative 
hypothesis of “LCM is superior compared to the treatment with placebo with respect to the 
duration until second PGTC seizure happens” will be accepted.
Additionally, Kaplan-Meier (KM) plot for time to second PGTC seizure as well as the KM 
estimate for the median time to second PGTC will be provided.
The above mentioned analyses will be performed using the FAS.
Sensitivity analyses will be conducted by repeating the same analysis using the PPS. Any p-values 
generated herein are of exploratory nature only.
REDACTED 
ly
lyse
se
he pr
he p
COPY 
This document
p
durat
durat
A
cannot 
r fo
fo
nce th
nce th
othes
othe
i
be
to th
o t
for t
for t
used 
fect
ec
cebo w
ebo w
the
the
to
ct w
t w
support
who
wh
ted to 
ed to
dicatio
icatio
any
uste
uste
ho pr
ho p
marketing
prima
rima
variab
varia
the sec
he se
d
authorization 
s
application 
cts 
ts
ions af
ons a
will be
will b
and 
s wh
wh
any extensions 
tant p
ant p
eterm
term
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 124 of 267
Has been changed to:
The primary efficacy variable, time to second PGTC seizure during the Treatment Period, will be 
evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for 
treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 
28 days in the 16 weeks prior to randomization) and age at informed consent (≥12 to <18 years of 
age vs ≥18 years of age). Pooling strategies for strata with no events (ie, no subjects who had a 
second PGTC seizure) will be defined in the SAP prior to unblinding. Subjects who prematurely 
discontinue from the study will be censored on the date of last dose of study drug during the 
Treatment Period.
Additionally, a Kaplan-Meier (KM) plot for time to second PGTC seizure as well as the KM 
estimate for the median time to second PGTC seizure will be provided. This analysis will be 
performed using the FAS population.
Testing for the primary endpoint will be done at the 5% level (2-sided). A gatekeeping strategy 
(Marcus et al, 1996) will be used to test the key secondary efficacy variable provided that the 
primary endpoint is statistically significant (See Section 13.3.2 for additional details). No 
additional adjustments for multiplicity are required as all additional inferences will be hypothesis-
generating only.
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted in 
order to assess the effect of dropouts and protocol deviations on the primary endpoint: 
•
Repeat the primary analysis using the PPS.
•
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue 
due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment 
failures (ie, events at the time of discontinuation).
Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue due to 
lack of efficacy or AEs only will be analyzed as treatment failures.
Section 13.3.2 Secondary analysis and other efficacy analysis
Analyses on secondary efficacy variables will be performed on the FAS and will be descriptive in 
manner only. Any p-values or confidence limits provided other than those for the primary analysis 
of the primary variable as described in Section 13.3.1 will be exploratory only.
Any subject who is seizure-free with regard to PGTC seizure after the 12- the 24-week Treatment 
Period is regarded as a remitter. In one approach, Fisher’s exact test will be used to evaluate any 
differences between the 2 treatment groups, ie, LCM and placebo. For seizure types other than 
PGTC seizures (ie, myoclonic absence, tonic, clonic, and atonic seizures), frequency counts per 
28 days and changes as well as percent changes from Prospective Baseline will be provided for the 
Evaluation Period as well as for the first 12 weeks of treatment. An analysis of covariance of the 
changes from Prospective Baseline and log-transformed percent changes from Baseline will be 
applied as described for PGTC seizure evaluation, respectively. Further approaches of analyzing 
secondary variables will be described in a detailed SAP.
REDACTED 
S.
S.
e FAS
 FAS
ithdraw
ithdra
f disc
f disc
COPY
prim
prim
l devi
l dev
This document
Eval
val
cha
ch
cannot 
ces 
es 
C seizu
seiz
day
days
be
gard
ar
s bet
s bet
used 
ho is s
o is s
rded
rded
to
able
able
support 
efficacy
fficac
values o
alues 
e as
e a
any 
ry
ry an
a
y
marketing
contin
contin
he FAS
e FA
be ana
be an
authorization
iatio
tio
S, exce
, exce
wn, o
wn, o
application
nal in
nal in
ary
ry effi
ef
y
ons
ons
and 
riab
ab
dditio
dditio
any
gate
gat
ble p
ble
extensions
s the K
s the 
lysis w
sis w
k
or variations 
relely y 
he
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 125 of 267
Has been changed to:
Analysis of the key secondary efficacy variable, time to first PGTC seizure during the Treatment 
Period, will be analyzed in the same manner as the primary endpoint using the FAS. A gatekeeping 
strategy will be employed to control the Type I error (Marcus et al, 1976). If the primary endpoint 
is statistically significant at the 5% level, then the key secondary efficacy endpoint will also be 
assessed at the 5% significance level. If the primary endpoint fails to reach statistical significance, 
then the key secondary efficacy endpoint will be exploratory only.
The percent of subjects seizure-free at the end of the 24-week Treatment Period will be estimated 
from the Kaplan-Meier estimates of time to first seizure using 2-sided 95% confidence intervals. 
Analyses of the other secondary efficacy variable will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described above), will be exploratory only. 
The percent change in log-transformed PGTC seizure frequency during the first 5 weeks of the 
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure 
frequency. The percent change in log-transformed PGTC seizure frequency during the 24-week 
Treatment Period will be analyzed in a similar manner. Further approaches for the analysis of the 
secondary variable will be described in a detailed SAP.
Change #17
Section 13.7 Planned interim analysis and data monitoring
No interim analysis is planned for this study. 
Has been changed to:
Some AEDs with sodium channel blocking properties can exacerbate some generalized seizure 
types, such as absence and myoclonic seizures. To enhance safety monitoring, 3 interim analyses 
are planned when 25%, 50%, and 75% of subjects experience an event (31, 62, and 93 events, 
respectively) or 24 weeks after 50, 100, and 150 subjects have been randomized, respectively, 
whichever comes first. An event is defined as the occurrence of the second PGTC seizure during 
the Treatment Period. 
Three interim analyses for safety will be performed by the IDMC with a single futility assessment 
planned at the second interim analysis. Both safety and futility will be assessed in a manner that 
ensures that blinding is not compromised for individuals involved with operational aspects of the 
study, nor individuals involved with the planning and conduct of the final statistical analyses. 
Analysis of the primary endpoint (time to second PGTC seizure) will only be examined at the 
planned futility assessment; an unblinded, descriptive review of safety and seizure frequency data 
will be provided for all IDMC meetings. 
Additional details, including the methods used for assessing futility, will be provided in the interim 
SAP. Neither futility nor the IDMC safety assessments are expected to have any impact on the 
Type 1 error as there will be no stopping rule for success in place; however, the significance level 
will be set using a Haybittle-Peto boundary at alpha=0.0001 so as not to require any adjustment to 
the overall alpha level for the final analysis.
REDACTED 
ysis a
ysis 
study
study
COPY 
AP
AP.
This document
will b
will b
A
cannot
or in
r in
ysis of
sis of
nned 
ned
b
be
t bli
bl
indi
indi
used 
lys
y
secon
secon
lind
ind
to
ys
yses
es
support
fter
fter
An even
n eve
any
nd 7
nd 7
r 50
r 5
marketing 
locking
ockin
onic se
nic s
75
75
authorization 
and 
and 
application 
ontr
nt
re frequ
e freq
her app
her ap
and
ng th
ng th
troll
rol
any
only
only
he
h
extensions 
i
S and 
and 
han th
han th
the a
the a
or
nter
nte
variations 
ce,e,
timat
imat
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 126 of 267
The IDMC will consist of 3 voting members, none of whom will be involved with the conduct of 
the study, either by management or participation. In addition, there will be an independent 
reporting team, consisting of an independent statistician and statistical programmers, who will be 
completely independent from the blinded reporting team. The blinded reporting team will be 
responsible for all operational aspects of the study, including routine monitoring and cleaning of 
the data, programming, and quality control (QC) of all analyses defined in the interim SAP on 
blinded data. 
The blinded study team will actively monitor the number of events in the study. Once the required 
number of events (or subjects) has been met and the blinded reporting team has completed the QC 
of the IDMC tables, figures, and listings (TFLs), the programs will be passed to the independent 
reporting team. The independent statistician will request unblinded treatment codes from the IVRS 
randomization coordinator and the TFLs will be re-run and QC’d using the actual treatment codes. 
Additional TFLs or ad hoc analyses can be requested by the IDMC based on their data review. 
Any changes to predefined TFLs or new requests will be handled by the independent reporting 
team.
The actual randomization codes and the unblinded outputs will be stored in a secure location which 
will be accessible only to the independent reporting team. A secure, restricted-access directory will 
hold electronic copies of documents such as meeting minutes, interim reports, emails, and periodic 
data deliveries. Only the independent reporting team will have access to this secure location.
Change #18
Section 13.8 Determination of sample size
When the sample size in both groups is 90, the log-rank test for equality of survival curves with a 
0.025 one-sided significance level will have 90% power to detect the difference between the 
survival curves, when the assumed survival rate (based on time to second PGTC seizure) for 
placebo is 25.4% and for LCM is 48.2% (a constant hazard ratio of 0.533). This assumes no drop 
out during the study before the second PGTC seizure. These assumptions are derived from a 
lamotrigine (LTG) study, where after 3 months 30/58 subjects have encountered a third PGTC 
seizure under LTG and 44/59 subjects under placebo. 
To adjust for a dropout rate of approximately 10% during the Evaluation Period for any other 
reason than the second PGTC seizure, sample sizes will be 100 per group.
Has been changed to:
Observing 125 events (subjects who had a second PGTC seizure during the 24-week Treatment 
Period) will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, assuming 
a nominal dropout rate of <10%. The observed hazard ratio was based on a 25.4% survival rate for 
placebo and 48.2% for lamotrigine from a previous study comparing lamotrigine and placebo
(French et al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, to 
provide a conservative margin, the hazard ratio was increased to 0.56 for estimating a sample size 
for the study. The rationale for the increase in the hazard ratio was 2-fold: different active 
compounds (LCM and lamotrigine) and a choice of time to second seizure as the primary efficacy 
endpoint (in the lamotrigine study, percent change in seizure frequency was the primary endpoint). 
This is an event driven study. The study will be closed to enrollment once 125 events have been 
observed. If 125 events are observed prior to 200 subjects randomized, then enrollment will stop 
REDACTED 
mple s
mple s
s 90, th
90, th
will hav
will ha
urv
ur
COPY
m will
m wil
This document
(Fren
(Fren
pr
pr
cannot
will
will
minal d
inal d
cebo 
ebo 
be
125 
25
l pr
l p
used
hang
ang
5 ev
5 e
to 
ond
support
59 s
9 s
t rate o
rate 
d PG
d PG
any
e aft
e af
sub
sub
marketing
ave 9
e 9
vival r
vival r
8.2% (a
.2% 
cond P
cond
authorization 
size
size
he log
he log
90
90
application
sto
sto
cure, re
ure, 
s, inter
s, inte
have a
have 
and 
ored
ore
any
ndep
ndep
extensions
ndep
ndep
es from
s fro
ual tre
ual tre
their
their
or
ed t
ed 
pe
variations 
require
equire
the
th
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 127 of 267
and fewer than 200 subjects will be randomized. However, if 125 events are not observed after
200 subjects are randomized, then the study will continue to enroll up to a maximum of 
250 subjects randomized or 125 events, whichever occurs first.
Change #19
Section 16 References
The following references were added.
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered 
analysis of variance. Biometrika. 1976;63:655-60.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39:800-12.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions 
Quali
Quali
ed Car
d Ca
or variations 
ered 
ered 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 128 of 267
17.4
Protocol Amendment 2
Rationale for the amendment
The primary purpose of this substantial amendment is to identify significant changes to the study 
design and the inclusion of pediatric subjects (≥4 to 12 years of age). 
In addition, the key study secondary efficacy variable was changed to more accurately represent 
the study design.
The protocol has been updated to include randomization stratified by age at informed consent for 
subjects ≥4 to <12 years of age. This is in order to maintain balance within each treatment arm and 
within the existing baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days for the 
16-week Combined Baseline Period prior to randomization) as well as provide greater control for 
variability when analyzing the primary efficacy variable (time to second seizure).
An inclusion criterion was modified to include subjects ≥4 years of age. Exclusion criteria were 
modified in regards to subjects who have a diagnosis of developmental delay or mental retardation 
or a history of status epilepticus. The rationale for modifying the exclusion criteria is that subjects 
with developmental delay or mental retardation are more likely to have symptomatic rather than 
idiopathic seizures. The rationale for modifying the exclusion criteria for subjects with a history of 
status epilepticus is to align with the withdrawal criteria (ie, a subject may be withdrawn from the 
study due to an episode of status epilepticus, a prolongation of seizure duration, a worsening of 
seizure frequency, or emergence of a new seizure type considered by the investigator to require
intervention).
Other changes made in this amendment are to provide clarification or are administrative in nature.
Modifications and changes
Specific changes
Change #1
Title page:
The title was updated from “Protocol SP0982 Amendment 1” to “Protocol SP0982 Amendment 2.”
IND 73809 was added.
The information below was revised to include Protocol Amendment 2 and the type of protocol 
amendment:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
REDACTED 
are to 
re to 
COPY 
ria 
ria
longat
longat
e ty
e type
p
y
This document
Pro
Pro
en cannot 
ol/A
l/
al Pro
al Pro
o
ot
ca
be 
Am
Am
be used
belo
el
to 
e
low
ow
support 
om “Pr
m “P
d.d.
any marketing authorization
e con
e con
provi
provi
application
o hav
o hav
criteri
criter
e, a sub
a su
on of
on of
and 
l de
de
clusio
lusio
any
xclu
xclu
elay
ela
extensions
e
day
ays f
s f
reater
eater
ure).
re).
us
or
nt a
nt a
variations 
ent 
ent f
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 129 of 267
Has been changed to:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Change #2
SPONSOR DECLARATION
Clinical Project Manager
_____________________________
Date/Signature
Clinical Study Biostatistician
, MS
_____________________________
Date/Signature
Study Physician
 MD, PhD
_____________________________
Date/Signature
Associate Clinical Program Director 
, PhD
_____________________________
Date/Signature
Has been changed to:
Clinical Project Manager
, MBA, MS
_____________________________
Date/Signature
Clinical Trial Biostatistician
, MA
_____________________________
Date/Signature
Study Physician
, MD, PhD
_____________________________
Date/Signature
Clinical Program Director 
, MSc
_____________________________
Date/Signature
PPD
PPD
PPD
PPD
PPD
PPD
COPY 
__
__
D
This document
C
ent cannot
linic
linic
ot be 
ysi
y
be used 
icia
icia
to 
MA
MA
support 
tistici
istic
A
any marketing authorization
__
Date/
Date/
application 
__
ture
ure
___
__
Si
and 
__
__
any extensions 
____
___
or variations s
ati ns thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 130 of 267
Change #3
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World (except Japan): +32 2 386 2421
USA: +1 800 880 6949
Canada: +1 877 582 8842
Japan: +81 3 5283 1869
Email
Global (except Japan): DS_ICT@ucb.com
Japan: JDSO@ucb.com
Has been changed to:
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 2421
USA: +1 770 970 8858
or +1 800 880 6949
or +1 866 890 3175
Canada: +1 877 582 8842
Email
Global: DSICT.-@ucb.com
Change #4
List of abbreviations
The following abbreviations have been added:
BRIEF®-P
Behavior Rating Inventory of Executive Function®-Preschool Version
EI-AED
Enzyme-inducing antiepileptic drug
GMP
Good Manufacturing Practice
HDPE
High-density polyethylene
PET
polyethylene terephthalate
Change #5
Section 1 Summary
Paragraph 1 through 7:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy and safety of oral lacosamide (LCM) (VIMPAT®; SPM 927; 
previously referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, 
ADD 234037) 400mg/day (200mg, twice daily [bid]) vs placebo as adjunctive therapy for 
REDACTED 
.com
com
AC
RE
COPY 
This document
Sec
Sec
P
cannot 
ange
nge
ct
be used to support 
Behav
Behav
E
any
ave b
ave b
marketing 
g authorization 
tho
a
application 
n and any extensions 
ns
or r variations s
v
thereof. 
t


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 131 of 267
uncontrolled primary generalized tonic-clonic (PGTC) seizures in subjects ≥12 years of age with 
idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant antiepileptic drugs 
(AEDs) independent of the number of prior failed AEDs (see Section 7.8). 
Approximately 200 subjects across approximately 150 sites in the US, Canada, Europe, Asia, and 
Australia with possible extension to other countries and regions, will be randomized in this study. 
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 32 weeks per subject. The study consists of a 4-week Prospective Baseline Period, a 5-week 
(minimum) to 24-week (maximum) Treatment Period (including a 3-week titration), and a 3- to 
4-week End of Study Period.
Eligible subjects who choose to enter the open-label extension study (EP0012) after the completion 
of Visit 9 (Week 24) or the Early Termination (ET) Visit will complete a 4-week blinded 
transition. Subjects who choose not to continue in EP0012 must complete a 1-week blinded taper 
followed by a 2-week Safety Follow-up Period. 
The primary study objective is to demonstrate the efficacy of oral LCM (400mg/day [200mg bid]) 
vs placebo as adjunctive therapy for uncontrolled PGTC seizures in subjects with IGE taking 1 to 
3 concomitant AEDs (See Section 7.8).
The primary efficacy variable is the time to the second PGTC seizure during the 24-week 
Treatment Period. The key secondary efficacy variable is the time to the first PGTC seizure during 
the 24-week Treatment Period, which will use a gatekeeping strategy to assess statistical 
significance (see Section 13.3.2). Other secondary efficacy variables include 1) the percent change 
in PGTC seizure frequency per 28 days from the Combined Baseline (Combined 12-week 
Historical and 4-week Prospective Baseline) to the first 5 weeks of the Treatment Period, 2) from 
the Combined Baseline to the full Treatment Period, and 3) seizure-free status for PGTC seizures 
during the 24-week Treatment Period. 
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); withdrawal 
due to AEs; changes in hematology, chemistry, and urinalysis parameters; changes in 12-lead 
electrocardiograms (ECGs); changes in vital sign measurements; changes in neurological 
examination findings. In addition for pediatric subjects <18 years of age, safety will be evaluated 
using behavioral assessments (Achenbach Child Behavior Checklist [CBCL]), cognitive function 
assessments (Behavior Rating Inventory of Executive Function® [BRIEF®]), and quality of life 
assessments (Pediatric Quality of Life Inventory [PedsQL]).
Have been changed to:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study
designed to assess the efficacy and safety of oral lacosamide (LCM) (VIMPAT®; SPM 927; 
previously referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, 
ADD 234037) twice daily [bid]) vs placebo as adjunctive therapy for uncontrolled primary
generalized tonic-clonic (PGTC) seizures in subjects ≥4 years of age with idiopathic generalized 
epilepsy (IGE) currently taking 1 to 3 concomitant antiepileptic drugs (AEDs) independent of the 
number of prior failed AEDs (see Section 7.8). 
REDACTED
ndary
ndary
om the
om the
eline) 
eline) 
reatme
reatme
d
COPY
d P
able is
able i
gatek
gatek
This document
prev
previ
AD
AD
cannot 
2 is a
2 is 
igned
gned
i
be
en c
en c
used 
hav
av
Pediatr
ediat
to
es
vior
vior
support
s); ch
); ch
n addi
n add
ssmen
sme
any 
e
ology
ology
han
h
marketing 
ent 
nt 
ss the s
s the 
ety va
y v
authorization
keepi
keepi
effica
effica
e Com
Com
to the
o the
t Pe
Pe
application 
n s
TC seiz
C sei
the ti
the t
and
M (4
M (4
subj
sub
any 
400
40
extensions 
er the 
r the 
k blin
k blin
-wee
wee
or variations 
m
ek k 
3- toto
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 132 of 267
Approximately 200 subjects across approximately 150 sites in the US, Canada, Europe, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized in 
this study. 
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 36 weeks per subject. 
The study is comprised of the following: a 4-week Prospective Baseline Period and a 6-week 
(minimum) to 24-week (maximum) Treatment Period, which includes a 6-week Titration Period 
and an 18-week (maximum) Maintenance Period. Eligible subjects who choose to enter the 
open-label extension study (EP0012) after the completion of Visit 10 (Week 24) or the Early 
Termination (ET) Visit will complete a 4-week blinded transition. Subjects who choose not to 
continue in EP0012 must complete an up to 4-week blinded taper followed by a 30-day Safety 
Follow-up Period. 
The primary study objective is to demonstrate the efficacy of oral LCM vs placebo as adjunctive 
therapy for uncontrolled PGTC seizures in subjects with IGE taking 1 to 3 concomitant AEDs (See 
Section 7.8).
The primary efficacy variable is the time to the second PGTC seizure during the 24-week 
Treatment Period. The key secondary efficacy variable is seizure freedom for PGTC seizures for 
the 24-week Treatment Period, which will use a gatekeeping strategy to assess statistical 
significance (see Section 13.3.2). Other secondary efficacy variables include 1) the percent change 
in PGTC seizure frequency per 28 days from the Combined Baseline (Combined 12-week 
Historical and 4-week Prospective Baseline) to the first 6 weeks of the Treatment Period, 2) the 
percent change in PGTC seizure frequency per 28 days from the Combined Baseline to the full 
Treatment Period, and 3) time to the first PGTC seizure during the 24-week Treatment Period.
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); withdrawal 
due to AEs; changes in hematology, chemistry, endocrinology, and urinalysis parameters; changes 
in 12-lead electrocardiograms (ECGs); changes in vital sign measurements; and changes in 
physical and neurological examination findings. In addition, for pediatric subjects <18 years of 
age, safety will be evaluated using a behavioral assessment (Achenbach Child Behavior Checklist 
[CBCL]) and a cognitive function assessment (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/Behavior Rating Inventory of Executive Function-Preschool Version [BRIEF-P]).
Change #6
Section 2 Introduction
Paragraph 1:
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). The most 
common seizure type in patients with epilepsy is partial seizures (57%), followed by tonic-clonic 
seizures (23%), absence seizures (6%), and myoclonic seizures (3%); the latter 3 seizure types 
comprise the majority of generalized seizures (convulsive and nonconvulsive) (Hauser et al, 1993). 
REDACTED 
he 
he 
) to th
) to th
cy
cy per
per
y
first PG
first P
the
the
COPY
ekeep
ekee
y effic
effi
y
Co
Co
This document 
pile
pile
peop
peop
c
cannot 
graph 
raph
leps
eps
be
2 In
2 In
used to
r Ra
r Ra
support
xam
xam
ated us
ated u
tive fun
ive fu
atin
t
any
(ECG
EC
min
min
marketing 
e safet
safet
variab
varia
gy, che
, ch
Gs
G
authorization
cacy
acy
mbin
mbin
he firs
e firs
r 28
r 28 d
GTC 
GTC 
application 
eizure 
izure
zure fr
zure f
ing stra
ng str
cy va
v
y
and 
to 3
o 
any
 pla
 pla
3 co
3 c
extensions
e E
oose n
ose n
30-da
da
ac
or
Earl
Earl
variations 
riod 
iod 
e
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 133 of 267
Has been changed to:
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). Epileptic seizures 
occur in the context of a wide range of epilepsy syndromes that may be of genetic, 
structural/metabolic, or of unknown origin. The most common seizure type in patients with 
epilepsy is partial seizures (57%), followed by tonic-clonic (23%), absence (6%), and myoclonic 
(3%); the latter 3 seizure types comprise the majority of generalized seizures (convulsive and 
nonconvulsive) (Hauser et al, 1993). 
Paragraph 2, fourth sentence:
Generalized epilepsies can be further classified as primary/idiopathic and secondary/symptomatic 
epilepsies.
Has been changed to:
Generalized seizures typically occur with idiopathic generalized (genetic) or symptomatic 
generalized epilepsy syndromes.
Paragraph 6 has been removed.
The following paragraph (after Paragraph 8) has been added:
Preliminary safety and PK data suggest that exposure-response in pediatric and adult subjects 
treated with LCM will be similar. Lacosamide is being evaluated in pediatric subjects 1 month to 
17 years of age in 3 ongoing studies: SP847 (open-label, Phase 2, PK, tolerability, and safety 
study), SP848 (open-label long-term safety study), and SP1047 (PK study with a 1-day evaluation 
period).
Paragraph 9
Considering the significant unmet medical need for new treatment options for patients with PGTC 
seizures, the efficacy and tolerability profiles for LCM were evaluated in a series of animal models 
followed by a Phase 2 pilot study of subjects with uncontrolled PGTC seizures.
Has been changed to:
Considering the significant unmet medical need for new treatment options for patients with IGE 
and PGTC seizures, the efficacy and tolerability profiles for LCM were evaluated in a series of 
animal models followed by a Phase 2 pilot study of subjects with IGE and uncontrolled PGTC 
seizures.
Paragraph 11, first sentence:
The Phase 2, multicenter, open-label, pilot study (SP0961) designed to assess the safety of 
adjunctive LCM (400mg/day) for uncontrolled PGTC seizures in adult subjects, aged 16 to 
65 years, with IGE is clinically complete.
Has been changed to:
The Phase 2, multicenter, open-label, pilot study (SP0961) designed to assess the safety of 
adjunctive LCM (400mg/day) for uncontrolled PGTC seizures in subjects, aged 16 to 65 years, 
with IGE is complete.
REDACTED 
is b
is 
(open
(open
ty stu
y stu
COPY 
n a
n 
sure
ure-re
bein
bei
This document
adjun
djun
65
65
canno
aph 1
ph 
 Phas
Phas
unc
nc
be 
11
11
used
es
follow
follo
to
, the
, th
support 
to:
o:
ficant 
fican
any
udy o
udy o
marketing 
medica
medic
lity
ity p
y
authorization 
esp
sp
ng ev
ng ev
n-labe
labe
udy),
y), a
application 
ded:
ed:
pons
pon
and 
tic)
ic)
any 
) or 
) or
extensions 
ry/sy
/sy
y
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 134 of 267
Paragraph 12:
The purpose of this study (SP0982) is to evaluate the efficacy and safety of LCM for uncontrolled 
PGTC seizures in subjects ≥12 years of age with IGE.
Has been changed to:
The purpose of this study (SP0982) is to evaluate the efficacy and safety of LCM 
(LCM 8mg/kg/day to 12mg/kg/day for pediatric subjects weighing <30kg, LCM 6mg/kg/day to 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 300mg/day to 400mg/day 
for adult subjects [≥18 years of age] and pediatric subjects [<18 years of age] weighing ≥50kg) 
(see Table 7-3) for uncontrolled PGTC seizures in subjects ≥4 years of age with IGE.
Change #7
Section 3.1 Primary objective
The primary study objective is to demonstrate the efficacy of oral LCM (400mg/day [200mg bid]) 
vs placebo as adjunctive therapy for uncontrolled PGTC seizures in subjects with IGE currently 
taking 1 to 3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
Has been changed to:
The primary study objective is to demonstrate the efficacy of oral LCM (Table 7‒3) vs placebo as 
adjunctive therapy for uncontrolled PGTC seizures in subjects with IGE currently taking 1 to 
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
Change #8
Section 4.1.2 Secondary efficacy variables
The key secondary efficacy variable is:
•
Time to the first PGTC seizure during the 24-week Treatment Period
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 5 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period
Has been changed to:
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures for the 24-week Treatment Period
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 6 weeks of the 
Treatment Period
REDACTED 
er o
er o
acy
acy v
y
is:
is:
COPY
fficac
ffica
es in s
es in 
of p
of
This document
The k
he 
•
cannot 
rere
bee
bee
k
be 
-fre
fre
used
chan
chan
Treatm
reatm
to 
d
ng
support
PGT
PGT
Histo
Histo
any
ariab
aria
TC
TC
marketing 
during
durin
ble
b
authorization
subj
ubj
prior 
prior 
varia
aria
application 
or f
r f
y of ora
of or
y
bject
ject
and
ubje
ubje
fail
fail
any 
400m
400m
ctst
extensions or
≥50
≥50
variations 
to
mg/day
mg/day
0kg
0kg
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 135 of 267
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period
•
Time to the first PGTC seizure during the 24-week Treatment Period
Change #9
Section 4.1.3 Other efficacy variables
Bullets 1, 3, 9 and 15:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 5 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 5 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 5 weeks of the Treatment Period; a responder 
is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the first 5 weeks of the Treatment Period
•
EuroQol-5 Dimension (EQ-5D-3L) items
Have been changed to:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 6 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 6 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 6 weeks of the Treatment Period; a responder 
is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the first 6 weeks of the Treatment Period
•
Change from Baseline to end of treatment or ET in the 3-Level EuroQol-5 Dimension Quality 
of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in utility as 
converted from the 5 dimensions (for subjects ≥12 years of age)
Change #10
Section 4.2 Safety variables
Bullet 3:
•
Changes in hematology, chemistry, and urinalysis parameters
Has been changed to:
•
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
Section 4.2.1 Other safety variables
Other safety variables are:
•
Achenbach CBCL
•
Cognitive function assessment BRIEF
REDACTED 
c seizu
c seiz
eriod
eriod
s dur
s dur
COPY 
per 2
per 2
This document 
•
cannot
anges
nges
s be
s be
be used
Safe
Safe
to 
t
support 
Q-5D
-5
5 dimen
dime
any
nd of
nd o
D-
D 3
marketing
ring t
ring t
eductio
ducti
6 wee
6 we
f t
authorization
28 da
8 da
zures p
zures p
application 
day
ay
and 
ncy
cy
any
ment
men
per
pe
extensions 
ned B
ed B
t
or 
ne t
e
variations 
toto
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 136 of 267
Has been changed to:
Other safety variables are:
•
Behavioral assessment (Achenbach CBCL/1½-5 or CBCL/6-18)
•
Cognitive function assessment (BRIEF-P or BRIEF)
Change #11
Section 5.1 Study description
Paragraph 1, first sentence:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study
designed to assess the efficacy of oral LCM (400mg/day [200mg bid]) vs placebo as adjunctive 
therapy for uncontrolled PGTC seizures in subjects ≥12 years of age with IGE currently taking 1 to 
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
Has been changed to:
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy of oral LCM (see Table 7-3) vs placebo as adjunctive therapy for 
uncontrolled PGTC seizures in subjects ≥4 years of age with IGE currently taking 1 to 
3 concomitant AEDs independent of the number of prior failed AEDs (see Section 7.8).
Paragraphs 2 through 4:
Approximately 200 subjects across approximately 150 sites in the US, Canada, Europe, Asia, and 
Australia with possible extension to other countries and regions, will be randomized in this study.
The study will last a maximum of 32 weeks per subject. The study consists of a 4-week 
Prospective Baseline Period, a 5-week (minimum) to 24-week (maximum) Treatment Period 
(including a 3-week titration), and a 3- to 4-week End of Study Period.
Subjects who choose to enter the open-label extension study (EP0012) after the completion of 
Visit 9 (Week 24) or the ET Visit will complete a 4-week blinded transition. Subjects who choose 
not to continue in EP0012 must complete a 1-week blinded taper followed by a 2-week Safety 
Follow-up Period. 
Have been changed to:
Approximately 200 subjects across approximately 150 sites in the US, Canada, Europe, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized in 
this study.
The study will last a maximum of 36 weeks per subject. The study is comprised of the following: a 
4-week Prospective Baseline Period and a 6-week (minimum) to 24-week (maximum) Treatment 
Period, which includes a 6-week Titration Period and an 18-week (maximum) Maintenance Period. 
Eligible subjects who choose to enter the open-label extension study (EP0012) after the completion 
of Visit 10 (Week 24) or the Early Termination (ET) Visit will complete a 4-week blinded 
transition. Subjects who choose not to continue in EP0012 must complete an up to 4-week blinded 
taper followed by a 30-day Safety Follow-up Period.
REDACTED 
ximate
imate
her cou
er cou
2 wee
2 wee
k
COPY 
ge e
f prior
f prior
This document
4-we
we
Per
Per
E
cannot 
dy.
e study
study
ee
be
with
with
used 
an
an
y 200
200
y
to
nge
ng
support 
T V
2 must
2 mus
d
any
he op
e o
Visit w
Visit w
marketing
eks p
ks p
k (mini
(min
a 3- to 
to
pen
pe
authorization 
ely 150
15
y
untrie
untrie
pe
application
lel
lel-gr
g
s placeb
place
th IGE
h IGE
failed
failed
and any
 Sec
Se
extensions 
enter s
nter s
bo as 
bo as 
E cur
cur
ct
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 137 of 267
Paragraph 5 sentence 4:
Thus, a total of ≥3 PGTC seizures in the 16-week Combined Baseline Period (12-week Historical 
and 4-week Prospective Baseline) are required for study randomization to treatment (see 
Section 6.1, Inclusion Criterion 6).
Has been changed to:
Thus, a total of ≥3 PGTC seizures in the 16-week Combined Baseline Period (12-week Historical 
and 4-week Prospective Baseline) are required for study randomization to treatment (see 
Section 6.1, Inclusion Criterion 5)
Paragraph 6, sentence 1 through 5:
At Visit 1, subjects will be given a seizure diary to document all types of seizures, concomitant 
AEDs, and any other pertinent health status information. Seizure frequency and type eligibility will 
be verified by reliably documented seizure history collected (eg, in a seizure diary) over the 
12 weeks prior to Visit 1. In addition, prior to Visit 1, subjects are required to have had an EEG 
showing discharges consistent with IGE (generalized >3Hz epileptiform discharges and a normal 
EEG background). A confirmatory EEG may be performed during the Prospective Baseline, if 
approved by the Central Reviewer. Investigators will send a copy of the EEG tracing and report to 
the Central Reviewer.
Has been changed to:
At Visit 1, subjects and/or caregivers will be given a seizure diary to document all types of 
seizures, concomitant AEDs, and any other pertinent health status information. Seizure frequency 
and type eligibility will be verified by reliably documented seizure history collected (eg, in a 
seizure diary) 12 weeks prior to Visit 1. In addition, prior to Visit 1, subjects are required to have 
had an EEG showing discharges consistent with IGE (eg, generalized ≥3Hz epileptiform 
discharges and a normal EEG background). A confirmatory EEG may be performed during the 
Prospective Baseline, if approved by the Central Reviewer. Investigators will send a copy of the 
EEG report to the Central Reviewer.
Paragraph 7, sentence 5:
Subjects will be contacted via telephone 2 weeks following Visit 1 to assess continued eligibility 
and will be reminded of the importance of accurate seizure diary completion.
Has been changed to:
Subjects and/or caregivers will be contacted via telephone 2 weeks following Visit 1 to assess 
continued eligibility and will be reminded of the importance of accurate seizure diary completion.
Paragraph 8 through the end of the section:
At the end of the Prospective Baseline (Visit 2), eligible subjects will be randomized to receive 
LCM (400mg/day [200mg bid]) or placebo in a 1:1 fashion (active:placebo) and stratified by 
Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined 
Baseline Period prior to randomization) and by age at informed consent (≥12 to <18 years of age 
vs ≥18 years of age). The Treatment Period starts at the time of the Randomization Visit (Visit 2). 
At the Randomization Visit (Visit 2) subjects will complete the Visit 2 assessments and take the 
first dose of study drug at the clinic. Subjects will begin with a dose titration at LCM 100mg/day 
given
give
r perti
r perti
eliabl
eliabl
t 1. I
t 1. In
nsis
nsis
COPY 
This document
At th
At th
LC
L
cannot
ed el
ed el
ragrap
agrap
be
nd/or
nd/o
lili
used
hang
hang
to
ed o
ed o
support 
cted vi
cted v
of th
of
any
ewer
ewe
marketing 
n ad
ad
stent w
ent w
ground)
ound
by the
y th
r
authorization 
n a seiz
a seiz
tinent 
nent 
y doc
y doc
addit
ddit
application
ng the
ng the
opy of 
y of
and 
uire
ire
form d
orm d
any
re d
re d
ed to
ed to
extensions 
es, co
s, co
and typ
nd ty
dia
dia
or variations 
ical
cal
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 138 of 267
(50mg bid) or placebo for 1 week. Subjects will receive a telephone call at the end of the first week 
of dose titration reminding them to increase their dose to LCM 200mg/day (100mg bid) or 
placebo. Subjects will return to the clinic at Visit 3 (end of Week 2) and will receive 
LCM 300mg/day (150mg bid) or placebo. At the end of Week 3, subjects will receive a telephone 
call reminding them to increase their dose to LCM 400mg/day (200mg bid) or placebo for the 
remaining duration of the Treatment Period. Five additional clinic visits will occur during the 
Treatment Period: Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), Visit 8 (Week 20), and 
ET Visit/Visit 9 (Week 24).
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
•
Completion of ≥5 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
Subjects must complete the first 5 weeks of the Treatment Period after randomization. Upon 
experiencing 2 PGTC seizures and completion of the first 5 weeks, the subject will complete the 
ET Visit. The seizures may occur on the same day, but the initiation and completion of each 
individual seizure must be distinguishable allowing reliable counting of individual seizures. 
If a subject has <2 PGTC seizures during the first 5 weeks of the Treatment Period, the subject will 
continue until a total of 2 PGTC seizures have occurred or the 24-week Treatment Period has been 
completed. Subjects experiencing ≥2 PGTC seizures before the end of the 24-week Treatment 
Period will complete an ET Visit. Subjects who complete the 24-week Treatment Period will 
complete Visit 9 (Week 24). Eligible subjects who choose to enter EP0012 will complete a 4-week 
blinded transition followed by completion of the Final Clinic Visit. During the 4-week blinded 
transition, subjects receiving placebo during SP0982 will be titrated to LCM 400mg/day. For those 
subjects continuing participation in EP0012, the Final Clinic Visit will be the same as Visit 1 of 
EP0012 (see Section 7.2).
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 9 (Week 24), and a 1-week blinded taper 
followed by an End of Taper Visit. Following the End of Taper Visit, the subject will return 
2 weeks after the last dose of study drug for a Final Clinic Visit (see Section 7.2).
Unscheduled visits may be performed at any time after Visit 1 at the discretion of the investigator. 
No dose reduction is allowed until the subject reaches the randomized target dose. If the subject is 
unable to tolerate the target dose, a single dose reduction of study drug to LCM 300mg/day or 
placebo is permitted. No other dose reductions are allowed. In the case of intolerable AEs during 
the titration, the subject must be withdrawn from the study. If a dose reduction is required, the 
subject must come in for a visit (scheduled or unscheduled). If the subject is not able to tolerate the 
study drug after 1 dose reduction, the subject must be withdrawn from the study. All dose 
reductions should be discussed with the Medical Monitor. Once the dose has been reduced, it 
cannot be increased.
A schematic diagram of the study is provided in Section 5.3.
Has been changed to:
At the end of the Prospective Baseline (Visit 2), eligible subjects will be randomized to receive 
LCM or placebo (see Table7-1) in a 1:1 fashion (active:placebo) and stratified by Baseline PGTC 
REDACTED
s who
s wh
of the
of the
uring 
uring 
EP001
EP001
COPY 
ed d
es bef
es bef
comp
comp
This document
reduc
edu
can
can
cannot 
ion
on
ct mus
t mu
dy dru
dr
y
be
perm
erm
n, th
n, th
used 
n i
n i
ate th
te th
mit
mit
to
is al
is a
support
e of st
of s
ay
ay be p
be p
y
any 
ete
et
Visit.
Visit
t
marketing 
12, 
2, 
e study
stud
te the
th
authorization
plete t
plete 
o choo
o choo
e Fina
e Fina
SP09
SP09
the
th
application 
ing 
ng
the
he Tre
Tr
the 24
he 24
ore the
re th
h
and
and c
nd c
g of
of
any 
om
o
ubject
ubjec
com
extensions
eizure
izure
GTC 
GTC 
miz
miz
or variations 
and 
and 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 139 of 267
seizure frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline Period 
prior to randomization) and by age at informed consent (≥4 to <12 years of age, ≥12 to <18 years 
of age, and ≥18 years of age). The Treatment Period starts at the time of the Randomization Visit 
(Visit 2). 
At the Randomization Visit (Visit 2) eligible subjects will complete the Visit 2 assessments and 
take the first dose of study drug at the clinic and enter a 6-week Titration Period. The 
recommended LCM (or matching placebo) dosing during the Titration Period to achieve the target 
Maintenance Period doses is provided in Table7-1. All subjects should follow the recommended 
dosing schedule, unless dose adjustments based on tolerability are needed. Table7-2 provides LCM 
(or matching placebo) dosing with flexibility based on tolerability during the Titration Period. 
During the Titration Period, subjects must achieve a target Maintenance Period dose range (see 
Table7-3). 
During the Maintenance Period, a single dose reduction of study drug or placebo is permitted as 
long as the minimum target dose is maintained (Table7-3). No other dose reductions are allowed. 
If a dose reduction is required, a (un)scheduled visit, either telephone or clinic visit, is required. If 
the subject is not able to tolerate the study drug after 1 dose reduction, the subject must enter the 
Taper Period and be withdrawn from the study. All dose reductions should be discussed with the 
Medical Monitor. Once the dose has been reduced, it cannot be increased.
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
Subjects who experience >2 PGTC seizures and who also complete ≥6 weeks (ie, ≥42 days) of the 
treatment period after randomization will be required to exit and complete the ET Visit 
(Section 6.3). The seizures may occur on the same day, but the initiation and completion of each 
individual seizure must be distinguishable allowing reliable counting of individual seizures. 
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment
Period or after completing the 24-week Treatment Period (whichever comes first), eligible subjects 
may, at the ET Visit or Visit 10 (Week 24), respectively, choose to continue in EP0012. Subjects 
completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded transition followed 
by a Final Clinic Visit. The Final Clinic Visit is the same as Visit 1 of EP0012 (see Section 7.2.3). 
During the 4-week blinded transition, subjects receiving placebo during SP0982 will have their 
dose titrated to LCM (see Table7-4).
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24), and an up to 4-week 
blinded taper followed by an End of Taper Visit. Following the End of Taper Visit, there will be a
30-day Safety Follow-up Period (see Section 7.2.4).
Unscheduled visits may be performed at any time after Visit 1 at the discretion of the investigator. 
Schematic diagrams of the study are provided in Section 5.3.
REDACTED 
Per
Per
ent P
ent P
izures
izure
n wil
n wil
COPY 
owing 
wing
riod
rio
This document
30-d
U
cannot 
bjec
jec
12, the
2, th
nded t
ded 
be 
ect d
ect d
used
eek b
ek b
o L
o LC
to
isit.
isit
bl
support 
the 
he 
Visit 10
isit 1
Week 2
Week 
T
any
d exp
d ex
24
24
marketing
ll be r
l be r
r on the
r on th
uishabl
ishab
pe
authorization 
o
d and 
and 
eriod 
riod 
and w
and 
application
tion
ion
ions sh
ons s
be inc
be in
occurs
ccur
and
e or c
or c
n, t
n t
any 
ace
ac
e redu
 redu
lin
l
extensions
on Pe
n Pe
ose ran
se ra
cebo
ebo
or
vide
vid
eri
variations 
arget 
arget 
ended
nded
des
des
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 140 of 267
Change #12
Section 5.1.1 Study duration per subject
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 32 weeks per subject, consisting of the following study periods:
•
4-week Prospective Baseline Period
•
5-week (minimum) to 24-week (maximum) Treatment Period (including a 3-week titration)
•
3- to 4-week End of Study Period consisting of either: 
−
4-week blinded transition (required for subjects participating in EP0012)
−
1-week blinded taper followed by a 2-week Safety Follow-up Period (required for subjects
not participating in EP0012)
Subjects can enter EP0012 after the completion of Visit 9 (Week 24) or ET Visit and a 4-week 
blinded transition. Subjects who choose not to continue in EP0012 must complete a 1-week 
blinded taper followed by a 2-week Safety Follow-up Period (see Section 7.2).
The end of the study is defined as the date of the last visit of the last subject in the study.
Has been changed to:
The maximum duration of study drug administration is 28 weeks. The study will last a maximum 
of 36 weeks per subject, consisting of the following study periods:
•
4-week Prospective Baseline Period
•
6-week (minimum) to 24-week (maximum) Treatment Period (including a 6-week titration)
•
4-week End of Study Period consisting of either: 
−
4-week blinded transition (required for subjects participating in EP0012)
−
Up to 4-week blinded taper followed by a 30-day Safety Follow-up Period (required for 
subjects not participating in EP0012)
Subjects can enter EP0012 after the completion of Visit 10 (Week 24) or ET Visit and a 4-week 
blinded transition. Subjects who choose not to continue in EP0012 must complete an up to 4-week 
blinded taper followed by a 30-day Safety Follow-up Period (see Section 7.2.4). 
The end of the study is defined as the date of the last visit of the last subject in the study.
Change #13
Section 5.1.2 Subject completers
The following subjects will be considered study completers:
•
Subjects who meet any of the predetermined exit criteria (Section 6.3)
Subjects who do not experience 2 PGTC seizures within the 24-week Treatment Period
Has been changed to:
The following subjects will be considered study completers:
REDACTED
lowin
lowin
maxim
maxim
COPY 
tion i
tion 
This document 
The 
The 
cannot
ge #
e #
ction
ction
be 
he
#1
used
llow
low
e stu
e stu
to
Subj
Sub
wed
support
ipatin
patin
0012 a
012 a
bjec
bje
any 
taper 
taper
ng
marketing 
mum
mu
isting o
isting 
(requir
(requ
authorization
is 28 
is 28
g stud
g stud
um) 
m)
application 
Sec
Sec
he last 
he last
and
ust c
ust c
ectio
ctio
any 
ET Vi
ET V
om
extensions 
equire
equire
or variations 
on)
n)
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 141 of 267
•
Subjects who meet any of the predetermined exit criteria (Section 6.3)
•
Subjects who experience <2 PGTC seizures within the 24-week Treatment Period
Change #14
Section 5.1.3 Planned number of subjects
The number of screened subjects may vary according to the observed screen failure rate. 
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a total of 
125 events, where an event is defined as the occurrence of the second PGTC seizure. There will be 
approximately 150 sites.
Has been changed to:
The number of screened subjects may vary according to the observed screen failure rate. 
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a total of 
125 events, where an event is defined as the occurrence of the second PGTC seizure. 
Subjects will be enrolled in the following age categories:
•
≥4 years of age to <12 years of age (approximately 50 subjects)
•
≥12 years of age to <18 years of age (approximately 50 subjects)
•
≥18 years of age (approximately 100 subjects)
There will be approximately 150 sites 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 <18 years of age. Of these 100 subjects, 50% will be enrolled in each of the 
2 age categories <18 years of age.
Change #15
Section 5.1.4 Anticipated regions and countries
The study will be conducted in the US, Canada, Europe, Asia, and Australia, with possible 
extension to other countries and regions.
Has been changed to:
The study is planned to be conducted in the US, Canada, Europe, Asia, and Australia, with 
possible extension to other countries and regions.
Change #16
Section 5.2 Schedule of study assessments
Paragraph 1 and Table 5‒1:
The schedule of study assessments is provided in Table 5‒1.
REDACTED
er to r
er to 
appro
appro
f these
f these
COPY 
ely 
ely
)
This document 
ara
ar
The
The
cannot 
ion 5
on 5
ragr
agr
be
#16
#16
used 
ned
ne
sion to
ion to
o
ed to
d to
support
es and
s an
ed to:
d to:
any 
n the 
n the
d
marketing 
egion
egio
authorization 
ecruit 
cruit
oxima
xima
e 100 
100 
application 
ectcts)s)
0 subjec
subje
and any 
ac
a
GTC s
TC s
extensions 
failure
ailure
achie
chi
or variations 
f 
e wil
e wil
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 142 of 267
Table 5‒1:
Schedule of study assessments for SP0982
Prospective 
Baseline
Treatment Period
End of Study Period
Unscheduleda
Duration
4 weeks
5 to 24 weeks (maximum)b
Taper
Transition
NA
1-week
taper
2-week 
safety 
follow-up
4-week 
transition
Visitc
V1
TC
V2d
TCe
V3
TCf
V4
V5
V6
V7
V8
V9/
ETg
End of
Taperh
Final 
Clinic 
Visiti
Final 
Clinic 
Visit
Visit
Study week 
-4
-2
1
2
3
4
8
12
16
20
24
25
27
28
NA
Informed Consent/Assent
X
Inclusion/Exclusion criteria
X
X
X
Subject ID card dispensing
X
Concomitant medications and AED(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical history/Epilepsy history
X
Physical exam (complete)j
X
X
X
X
X
Physical exam (brief)k
X
X
X
X
X
X
Neurological exam (complete)l
X
X
X
X
X
Neurological exam (brief)m
X
X
X
X
X
X
12-lead ECGn
X
X
X
X
X
X
X
X
X
Vital signs (BP and pulse) including 
orthostatic assessmentsz
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and heighto
X
X
X
X
X
X
EEGp
X
Tanner Stageq
X
X
Laboratory tests:
Chemistry/hematology
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Pregnancy testr
X
X
X
X
X
X
X
X
X
X
X
X
LCM plasma concentrations
X
X
X
Contact IVRS/IWRSt
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense subject diary
X
X
X
X
X
X
X
X
X
X
Subject diary return/review
X
X
X
X
X
X
X
X
X
X
X
Dispense study drugu
Xv
X
X
X
X
X
X
X
Study drug review/return
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Achenbach CBCLw
X
X
X
REDACTED
X
D
ED
ED
ED
ED
ED
CT
AC
DA
X
ED
R D
COPY
X
Y
PY
OP
CO
C
This document t
en cannot t
no
an
c
be 
e
be
b
used 
d
X
ed
us
to 
to suppo
X
port 
X
X
rt
po
up
up
up
up
up
s
any y
any
a
marketing 
eti
eti
eti
eti
eti
rk
ma
ma
ma
ma
ma
m
authorization 
n
X
tio
za
za
za
za
X
or
th
th
th
th
uth
au
application 
2
n
tio
tio
tio
tio
tio
ca
pli
X
X
X
plpli
pli
ppl
ap
and 
E
nd
20
nd
nd
an
a
any 
/
ETg
E
ny extensions 
aper
per
s
week
ek
taper
aper
sioioioio
e
or 
ud
u
o variations 
on
dy P
dy P
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 143 of 267
Table 5‒1:
Schedule of study assessments for SP0982
Prospective 
Baseline
Treatment Period
End of Study Period
Unscheduleda
Duration
4 weeks
5 to 24 weeks (maximum)b
Taper
Transition
NA
1-week
taper
2-week 
safety 
follow-up
4-week 
transition
Visitc
V1
TC
V2d
TCe
V3
TCf
V4
V5
V6
V7
V8
V9/
ETg
End of
Taperh
Final 
Clinic 
Visiti
Final 
Clinic 
Visit
Visit
Study week 
-4
-2
1
2
3
4
8
12
16
20
24
25
27
28
NA
BRIEFx
X
X
X
EQ-5D-3L
X
X
QOLIE-31-P/PedsQLy
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
X
X
X
Work/school days lost
X
X
X
X
X
X
X
X
X
X
X
X
Days with help from a caregiver
X
X
X
X
X
X
X
X
X
X
X
X
Socio-professional data
X
AE=adverse event; AED=antiepileptic drug; bid=twice daily; BP=blood pressure; exam=examination; BRIEF= Behavior Rating Inventory of Executive Function®; 
CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EEG=electroencephalogram; EQ-5D-3L= EuroQol-5D; 
ET=Early Termination; ID=identification; IGE=idiopathic generalized epilepsy; IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; 
PEDsQL=Pediatric Quality of Life Inventory; PGTC=primary generalized tonic-clonic; QOLIE-31-P= Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31; 
TC=telephone contact; V=Visit
a
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments indicated above, further 
assessments can be completed as needed and may include ECG, vital signs, laboratory tests, etc. The C-SSRS must be performed if the unscheduled visit is due to an AE. 
b
The Treatment Period starts at the time of the Randomization Visit (Visit 2). The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
completion of ≥5 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures, or completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC 
seizures. 
c
A window of ±2 days relative to Visit 1 is applicable for all visits and Telephone Contacts. 
d
All assessments at Visit 2 should be conducted prior to the first dose of study drug. At the end of the Prospective Baseline, subjects will be randomized at Visit 2 to receive 
LCM (400mg/day [200mg bid]) or placebo in a 1:1 fashion (active:placebo) and commence the Treatment Period with a double-blind 3-week titration. Randomization will be 
stratified based on the PGTC seizure frequency during the Combined Baseline Period (ie, ≤2 per 28 days vs >2 per 28 days) and age at informed consent (≥12 to <18 years of 
age vs ≥18 years of age).
e
At the Randomization Visit (Visit 2), subjects will begin with a dose titration at LCM 100mg/day (50mg bid) or placebo for 1 week followed by LCM 200mg/day 
(100mg bid) or placebo for 1 week. Subjects will receive a telephone call at the end of the first week of titration reminding them to increase their dose to LCM 200mg/day 
(100mg bid) or placebo.
f
Subjects will return to the clinic at Visit 3 (end of Week 2) and will receive LCM 300mg/day (150mg bid) or placebo. At the end of Week 3, subjects will receive a telephone 
call reminding them to increase their dose to LCM 400mg/day (200mg bid) or placebo for the remaining duration of the Treatment Period.
REDACTED
X
D
ED
ED
ED
ED
CTED
ure; exa
re; ex
Rating
Rating
pilepsy
pilepsy
d to
d t
COPY
X
Y
P
X
X
PY
OP
X
CO
C
This document 
the
he
m to inc
to inc
cannot
sit 2
t 
week. 
week. 
e cli
e cli
be 
2), s
2), 
used
bo in a
o in a
requenc
quen
to
d pri
d pri
support 
ccurren
curre
able for
able fo
or
any 
, vi
, v
n Visi
n Visi
nc
marketing 
; IVRS
IVR
nic
nic-clon
-clon
t the dis
the di
vital s
vita
authorization 
n
X
n
X
tio
za
za
za
hor za
am=exa
m=exa
Scale;
cale
S
application 
2
n
tio
tio
tio
tio
tio
ca
pli
X
X
X
plpli
pli
ppl
X
ap
and 
E
nd
20
nd
nd
an
a
any 
/
ETg
E
ny extensions 
aper
per
s
week
ek
taper
aper
sioioioio
e
or 
ud
u
o variations 
on
dy P
dy P
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 144 of 267
g
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor to confirm whether the subject has met the exit criteria. If the exit criteria are 
met, sites will be advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure (Section 6.3). 
h
After the second PGTC seizure and completion of at least 5 weeks of the Treatment Period, or after completion of the 24-week Treatment Period; the subject may, at the ET 
Visit or Visit 9, respectively, enter EP0012. Subjects not entering EP0012 will taper study drug during a 1-week blinded taper at LCM 200mg/day/week or matching placebo 
before entering a 2-week Safety Follow-up Period.
i
For subjects completing the End of Taper Visit, a Final Clinic Visit will be completed 2 weeks after the last dose of study drug. 
j
The complete physical examination will include cardiac and respiratory function via auscultation, temperature, and review of all body systems.
k
The brief physical examination will include review of the following body systems: cardiovascular, pulmonary, abdominal (hepato-gastrointestinal), and dermatologic.
l
The complete neurological examination will include selected assessments of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function.
m
The brief neurological examination will include selected assessments of mental status, cranial nerves, and coordination/cerebellar function.
n
The ECG recordings should be performed at approximately the same time of day and prior to blood sample collection. Care should be taken to assure proper lead placement 
and quality ECG recordings. Subjects should rest in a supine position at least 5 minutes prior to each recording and should be motionless during the recording.
o
Height will be recorded at Visit 1, at Visit 9/ET Visit, and at the Final Clinic Visit (after the 4-week blinded transition).
p
Subjects are required to have had an EEG showing discharges consistent with IGE prior to Visit 1. A confirmatory EEG may be performed during the Prospective Baseline, if 
approved by the Central Reviewer. Investigators will send a copy of the EEG tracing and report to the Central Reviewer. The information provided will be reviewed and any 
questions regarding the subject’s eligibility will be discussed with the investigator prior to the subject being randomized.
q
The Tanner Stage will be performed for subjects who are <18 years of age at Visit 1. At Visit 9/ET Visit, if subject is >18years of age, a repeat assessment is not necessary.
r
Serum pregnancy tests will be conducted at the following visits: Visit 1, Visit 9/ET Visit, and the Final Clinic Visit. At Visit 2, a urine dipstick pregnancy test should be 
performed prior to IVRS/IWRS contact. The result of the urine dipstick test must be negative prior to administration of the first dose of study drug. All other pregnancy tests 
(ie, Visits 3 through Visit 8 and the End of Taper Visit) will be urine dipstick.
s
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 2 successive bid doses.
t
An IVRS/IWRS will be used to control all drug distribution and inventory for this study.
u
No dose reduction is allowed until the subject reaches the randomized target dose. If the subject is unable to tolerate the target dose, a single dose reduction of study drug to 
LCM 300mg/day or placebo is permitted. No other dose reductions are allowed. In the case of intolerable AEs during the titration, the subject must be withdrawn from the 
study. If a dose reduction is required, the subject must come in for a visit (scheduled or unscheduled). If the subject is not able to tolerate the study drug after 1 dose reduction, 
the subject must be withdrawn from the study. All dose reductions should be discussed with the Medical Monitor. Once the dose has been reduced, it cannot be increased.
v
At Visit 2, subjects should take the first dose of study drug in the clinic.
w
The Achenbach CBCL to be used is the CBCL/6 to 18 for children ≥12 years to <18 years of age; to be completed by the parent(s)/legal representative(s) 
(estimated completion time 45 minutes). The same scale will be completed again by the same parent(s)/legal representative(s) later in the open-label 
extension study EP0012. 
x
The BRIEF should be used for subjects ≥12 to <18.
y
The QOLIE-31-P will be performed for subjects who are ≥18 and the PedsQL will be performed for subjects <18. The version of the PedsQL used should be consistent 
with the subject’s age at each visit when it is administered.
z
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements.
REDACTED 
prio
prio
Visit 1. 
Visit 1.
Visit 9/E
isit 9/
k test m
k test m
e dipstic
e dipstic
lele
COPY 
4-
4
r to Vis
r to Vis
and rep
and re
or t
or t
This document cannot
me
ach vis
ch vi
ments sh
nts sh
be 
cts
ed for
ed for
used 
). . 
s ≥12
≥12
to
B
The 
The
support
me
e reduc
reduc
dy drug
dy dru
CL/6 t
CL/6 t
any 
ctions
ction
e in for
in for
ti
marketing 
ck.k.
cted at a
ted at a
ventory f
entory
mized t
mized 
a
authorization
port to
ort to
o the su
the s
At Vis
At Vis
ET Visi
Visi
ust be n
st be 
application 
le collec
le colle
ecording
cordin
k blinde
blind
1. A c
1. A c
th
and 
dinati
dinati
any 
nctions
nction
extensions 
20
f all bo
all bo
(hepa
hep
or 
Per
Pe
0mg
0mg
variations 
on
riteria. 
iteria.
eriod
riod
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 145 of 267
Has been changed to:
The schedule of study assessments is provided in Table 5‒1 (Prospective Baseline, Titration 
Period, Maintenance Period, ET Visit, and Unscheduled Visits), Table 5‒2 (Transition Period), 
and Table 5‒3 (Taper Period and Safety Follow-up Period).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 146 of 267
Table 5‒1:
Schedule of study assessments for SP0982 (Prospective Baseline, Titration Period, 
Maintenance Period, ET Visit, and Unscheduled Visits)
Assessments
Prospective 
Baseline
4 weeks
Treatment Perioda
Unscheduled
b
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period (18 weeks)
Visitc
V1
TC
V2d
TCe
V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/ETf
Visit
Study week
-4
-2
1
2
3
4
5
6
8
12
16
20
24
NA
Informed Consent/Assent
X
Inclusion/Exclusion criteria
X
X
X
Subject ID card dispensing
X
Concomitant medications and 
AED(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical history/Epilepsy history
X
Physical exam (complete)g
X
X
X
Physical exam (brief)h
X
X
X
X
X
X
X
Neurological exam (complete)i
X
X
X
Neurological exam (brief)j
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
X
Vital signs (BP and pulse) 
including orthostatic assessmentsl
X
X
X
X
X
X
X
X
X
X
Body weight 
X
X
X
X
X
X
X
X
X
X
Height
X
X
EEGm
X
Tanner Stagen
X
X
Laboratory tests:
Chemistry/hematology
X
X
X
X
X
X
X
Endocrinology
X
X
Urinalysiso
X
X
X
X
X
X
X
Pregnancy testp
X
X
X
X
X
X
X
X
X
X
LCM plasma concentrationq
X
X
Contact IVRS/IWRSr
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense subject diarys
X
X
X
X
X
X
X
X
X
X
Subject diary return/reviews
X
X
X
X
X
X
X
X
X
Dispense study drugt
Xu
X
X
X
X
X
X
X
X
REDACTED 
D
TE
TE
TE
TE
TE
AC
DA
ED
COPY 
Y
OP
OP
OP
OPY
OP
X
CO
This document 
nt cannot t
ot
nn
ca
be 
X
be
b
used 
ed
us
us
us
us
us
to 
o
to support 
o
X
ort
po
X
pp
X
su
any y
ny
a
marketing 
tin
ke
rk
ma
authorization 
on
at
za
X
riz
X
tho
aut
au
au
au
au
application 
X
X
tio
at
pl
ap
ap
ap
ap
ap
and 
nd
an
a
any 
1
y
an
an
an
an
a
extensions 
io
nce Pe
ce Pe
en
V8
V8
xt
e
or 
or variations 
on
od,
d,
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 147 of 267
Table 5‒1:
Schedule of study assessments for SP0982 (Prospective Baseline, Titration Period, 
Maintenance Period, ET Visit, and Unscheduled Visits)
Assessments
Prospective 
Baseline
4 weeks
Treatment Perioda
Unscheduled
b
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period (18 weeks)
Visitc
V1
TC
V2d
TCe
V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/ETf
Visit
Study drug review/return
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Achenbach CBCLv
X
X
BRIEF-P/BRIEFw
X
X
EQ-5D-3Lx
X
X
QOLIE-31-P/PedsQLy
X
X
C-SSRSz
X
X
X
X
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
Work/school days lost
X
X
X
X
X
X
X
X
X
Days with help from a caregiver
X
X
X
X
X
X
X
X
X
Socio-professional data
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; bid=twice daily; BP=blood pressure; exam=examination; BRIEF=Behavior Rating Inventory of Executive Function; 
BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; EEG=electroencephalogram; EQ-5D-3L=EuroQol-5D; ET=Early Termination; ID=identification; IGE=idiopathic generalized 
epilepsy; IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; PEDsQL=Pediatric Quality of Life Inventory; 
PGTC=primary generalized tonic-clonic; QOLIE-31-P=Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31; TC=telephone contact; V=Visit
a
The Treatment Period starts at the time of the Randomization Visit (Visit 2). The Treatment Period continues until 1 of the following occurs (whichever 
occurs first): completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures, or completion of 24 weeks of the Treatment Period 
without occurrence of 2 PGTC seizures. 
b
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or TCs, at the discretion of the investigator. In addition to the required 
assessments indicated above, depending on the type of visit (clinic or telephone), further assessments can be completed as needed and may include ECG, 
vital signs, laboratory tests, etc. The C-SSRS must be performed (for subjects ≥6 years of age) if the unscheduled visit is due to an AE. 
c
A window of ±2 days relative to Visit 1 is applicable for all protocol specified visits and TCs. During the Treatment Period, each visit should occur at the 
end of the week indicated in accordance with this time window.
d
All assessments at Visit 2 should be conducted prior to the first dose of study drug. At the end of the Prospective Baseline, subjects will be randomized at 
Visit 2 to receive LCM or placebo in a 1:1 fashion (active:placebo) and commence the Treatment Period with a 6-week, double-blind, flexible dose titration 
(see Section 7.2.1). 
e
Subjects and/or caregivers will receive TCs throughout titration (Study Weeks 1, 3, and 5) to discuss titration dosing options. 
REDACTED 
X
D
TE
TE
TE
TE
TE
AC
DA
blood 
blood 
choo
choo
COPY 
Y
P
X
OP
OP
OPY
OP
X
CO
This document
regiv
egiv
cannot
hould
ould
r place
place
be 
ord
ord
d b
d b
used
SSR
SS
isit 1 i
sit 1 
dan
dan
to
on th
on th
SRS
SRS
support 
ment
ent
y time a
y time a
he t
he
any 
mization
mizatio
t Pe
t P
marketing 
pre
pre
ol Versi
l Versi
D-3L
3L=
LCM=la
CM=
-Weig
Wei
authoriz
X
rization 
on
a
X
ati
za
riz
X
ho
au
aut
au
essu
ssu
application 
ion
at
ca
pli
ap
ap
ap
ap
ap
and 
X
X
nd
an
a
any
X
y
an
an
an
an
an extensions 
io
nce Pe
ce Pe
en
V8
V8
xt
e
or 
or variations 
on
od,
d,
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 148 of 267
f
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor to confirm whether the subject has met the exit criteria. If 
the exit criteria are met, sites will be advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure (Section 6.3). 
g
The complete physical examination will include cardiac and respiratory function via auscultation, and review of all body systems.
h
The brief physical examination will include review of the following body systems: cardiovascular, pulmonary, abdominal (hepato-gastrointestinal), and 
dermatologic.
i
The complete neurological examination will include selected assessments of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function.
j
The brief neurological examination will include selected assessments of general neurological status, reflexes, muscle strength, and coordination/cerebellar 
function.
k
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample collection and vital sign assessments. Care 
should be taken to assure proper lead placement and quality ECG recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to 
each recording and should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
l
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
m
Subjects are required to have had an EEG showing discharges consistent with IGE prior to Visit 1. A confirmatory EEG may be performed during the 
Prospective Baseline, if approved by the Central Reviewer. Investigators will send a copy of the EEG report to the Central Reviewer. The information 
provided will be reviewed and any questions regarding the subject’s eligibility will be discussed with the investigator prior to the subject being randomized.
n
The Tanner Stage will be performed only for subjects who are pubescent at Visit 2 or who enter puberty during the course of the study. 
o
Urinalysis will be required for subjects ≥5 years of age only.
p
Serum pregnancy tests will be conducted at the following visits: Visit 1, Visit 10/ET Visit. At Visit 2, a urine dipstick pregnancy test should be performed 
prior to IVRS/IWRS contact. The result of the urine dipstick test must be negative prior to administration of the first dose of study drug. All other pregnancy 
tests (ie, Visits 3 through Visit 9) will be urine dipstick. Pregnancy tests will be performed for female subjects of childbearing potential only.
q
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 2 successive bid doses.
r
An IVRS/IWRS will be used to control all drug distribution and inventory for this study.
s
At all visits, subjects and/or caregivers will be reminded to report the occurrence of all seizure types, including days without seizures.
t
During the Maintenance Period, a single dose reduction is allowed as long as the minimum target dose is maintained (see Table 7‒3). Once the dose has been 
reduced, it cannot be increased. Subjects who are not able to tolerate the minimum target dose during the Maintenance Period will be withdrawn from the 
study. All dose reductions should be discussed with the Medical Monitor.
u
At Visit 2, subjects should take the first dose of study drug in the clinic.
v
The Achenbach CBCL/1½-5 is for children <5 years and 11 months of age and the CBCL/6-18 is for children ≥6 years to <18 years of age; the questionnaire 
is to be completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). For each subject, the same version of the scale that was 
completed at Visit 2 (CBCL/1½-5 or CBCL/6-18) should be maintained for the duration of the study and should be completed by the same parent/legal 
representative. 
w
The BRIEF-P should be used for subjects who are <5 years of age at Visit 2 and the BRIEF should be used for subjects who are ≥5 years of age at Visit 2. 
The same version of the scale that was completed at Visit 2 (BRIEF-P or BRIEF) should be maintained for each subject for the duration of the study.
x
The EQ-5D-3L will be performed in subjects who are ≥12 years of age.
REDACTED
bility
bilit
cent at 
cent at 
ts: Visi
ts: Vis
test m
test m
COPY 
er s
r
IGE pr
GE pr
l send
send
y w
This document 
f thth
will be 
will be
cannot 
e used 
used
he sc
e sc
be
(s)/)
½-5 o
5 o
used 
t d
childre
hildre
/lega
/lega
to
dose 
dose
support 
nd
duction
uction
are not
are n
sed w
ed witi
any
ion
ion
ed to 
ed to 
marketing 
it 1
must be
must b
ancy tes
ancy te
will be 
will be
n and
n an
authorization
o
a cop
a cop
will be
ill be
Visit
Visit 2
1, Vi
, Vi
application
sh
of age)
of age
d cuff t
d cuff 
or to V
r to V
and
samp
samp
hould
ould
any 
, m
, m
plel
extensions
al (h
(h
r funct
funct
mus
mus
or 
em
em
hep
hep
variations 
on
met th
met t
zure (S
ure (S
ms.
ms
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 149 of 267
y
The QOLIE-31-P will be performed for subjects who are ≥18 years of age and the PedsQL will be performed for subjects <18 years of age. The version of 
the PedsQL used should be consistent with the subject’s age at Visit 2 and should be maintained for each subject for the duration of the study. 
z
The C-SSRS will be completed for all subjects ≥6 years of age. 
aa
Thyroid function will be required in subjects <18 years of age only.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations 
on
rs of ag
 of ag
n of th
of th
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 150 of 267
Table 5‒2:
Schedule of study assessments for SP0982 (Transition Period)
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=Early Termination; IVRS/IWRS=interactive voice/web response system; 
TC=telephone contact 
Note: For all transition visits, a window of ±2 days relative to Visit 1 (Baseline Period) is applicable. Each visit 
should occur at the end of the week indicated in accordance with this time window.
a
At the end of Visit 10/ET, subjects who complete the study may be eligible to participate in an open-label 
extension study (EP0012). Subjects who choose to enroll in the open-label extension study will proceed to a 
blinded 4-week Transition Period. 
b
A Transition TC is required. A Transition Clinic Visit is optional, at the discretion of the investigator. Subjects 
requiring a clinic visit will have the same assessments conducted as an Unscheduled Visit.
c
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain 
accurate measurements.
d
The complete physical examination will include cardiac and respiratory function via auscultation, and review of 
all body systems.
Assessment
Transition Period 
(4 weeks)a
Transition TC or 
Visitb
Final Clinic Visit 
(EP0012 Visit 1)
2 weeks after 
Visit 10/ET
Concomitant medications and AED(s)
X
X
Body weight
X
Height
X
Physical exam (complete)d
X
Neurological exam (complete)e
X
12-lead ECGf
X
Vital signs (BP and pulse) including orthostatic assessmentsc
X
Laboratory tests:
Chemistry/hematology
X
Urinalysisi
X
Endocrinology
X
Pregnancy testj
X
Contact IVRS/IWRS
X
Subject diary return/reviewg
X
Study drug review/return
X
Withdrawal criteria
X
X
AE reporting
X
X
C-SSRSh
X
Healthcare resource use
X
Work/school days lost
X
Days with help from a caregiver
X
Socio-professional data
X
REDACTED 
ED
ACT
ED
R
COPY 
PY
CO
This document 
A
cannot 
on
on
or all t
r all t
d occu
d occu
At
At
be 
card
ard
ne con
ne co
used
nt; AED
t; AE
diog
diog
ed 
da
da
ed to 
ata
ata
o support 
ort
caregiv
aregi
pp
s
any 
ny marketing 
ing
ke
m
authorization 
n
on
za
ho
au
application 
tio
lic
app
a
and 
d
an
any y
a
extensions 
X
ns
si
xte
ex
or 
X
or variations 
n
on
ari
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 151 of 267
e
The complete neurological examination will include selected assessments of mental status, sensory systems, 
motor functions, cranial nerves, reflexes, and coordination/cerebellar function.
f
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample 
collection and vital sign assessments. Care should be taken to assure proper lead placement and quality ECG 
recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to each recording and 
should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs 
(2 interpretable recordings) approximately 20 to 30 minutes apart must be performed.
g
The subject diary will be dispensed at Visit 1. At all subsequent visits, subjects and or caregivers will be 
reminded to report the occurrence of all seizure types, including days without seizures.
h
The C-SSRS will be completed for all subjects ≥6 years of age.
i
Urinalysis will be required for subjects ≥5 years of age only.
j
Urine pregnancy tests will be performed for female subjects of childbearing potential only.
k
Thyroid function will be required in subjects <18 years of age only.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 152 of 267
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=early termination; IVRS/IWRS=interactive voice/web response system; TC=telephone 
contact
a
Subjects completing Visit 10 (Week 24) or the ET Visit who choose not to continue in EP0012 must complete a 
blinded taper followed by the End of Taper Visit. 
b
An End of Taper Visit will be scheduled at the end of the Taper Period (up to 4 weeks) depending on dose level 
achieved; see Table 7-5. Of note, for subjects who enter the Taper Period at ≤2mg/kg/day (oral solution) or 
100mg/day (tablets), the End of Taper Visit will take the place of the ET Visit.
c
There will be a 30-day (-1/+3 days) Safety Follow-up Period for subjects who complete the End of Taper Visit. 
The Safety Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks 
later by a TC.
d
The last subject diary will be returned at the End of Taper Visit.
Table 5‒3:
Schedule of study assessments for SP0982 (Taper Period and 
Safety Follow-up Period) 
Assessment
Taper Perioda
(up to 4 weeks)
Safety Follow-up Periodc
End of Taper 
Visitb
Safety Follow-up Visit
Safety Follow-up TC
2 weeks (±2 days) 
after last dose of 
study drug
30 days (-1/+3 days) 
after last dose of 
study drug
Concomitant medications and AED(s)
X
X
X
Physical exam (complete)k
X
X
Neurological exam (complete)l
X
X
12-lead ECGh
X
Xi
Vital signs (BP and pulse) including 
orthostatic assessmentsj
X
X
Body weight
X
X
Laboratory tests:
Chemistry/hematology
X
Xi
Endocrinologym
Xi
Urinalysisf
X
X
Pregnancy testg
X
X
Contact IVRS/IWRS
X
Subject diary return/reviewd
X
Study drug review/return
X
Withdrawal criteria
X
AE reporting
X
X
X
C-SSRSe
X
X
Healthcare resource use
X
X
Work/school days lost
X
X
Days with help from a caregiver
X
X
Socio-professional data
X
X
REDACTED 
D
X
CT
DA
RE
COPY 
Y
CO
CO
CO
CO
CO
This document 
S
b
b
cannot
se e
e e
lectroc
ectro
act
Sub
Sub
be
eve
eve
be 
sion
io
be used
from a
om a
d
onal
nal
us
to 
stst
t
support t
p
su
any y 
a
marketing 
X
X
g 
ket
ma
m
authorization 
n
at
riz
or
X
ut
application 
X
on
ca
pp
and 
d any y
ny
a
extensions 
y d
y
X
ns
sio
te
e
or
o
dru
dru
variations 
n
TC
TC
n
on
days)
days)
ose o
se o
at
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 153 of 267
e
The C-SSRS will be completed for all subjects ≥6 years of age.
f
Urinalysis will be required for subjects ≥5 years of age only.
g
Urine pregnancy tests will be performed for female subjects of childbearing potential only.
h
The ECG recordings should be performed at the same time of day (when possible) and prior to blood sample 
collection and vital sign assessments. Care should be taken to assure proper lead placement and quality ECG 
recordings. If possible, subjects should rest in a supine position at least 5 minutes prior to each recording and 
should be motionless during the recording. In pediatric subjects (<18 years of age), 12-lead ECGs 
(2 interpretable recordings) approximately 20 to 30 minutes apart must be performed.
i
The assessment will be required only for subjects with an abnormal value (clinical chemistry, hematology, or 
endocrinology) or reading (ECG) at the previous clinic visit.
j
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain 
accurate measurements. 
k
The complete physical examination will include cardiac and respiratory function via auscultation, and review of 
all body systems.
l
The complete neurological examination will include selected assessments of mental status, sensory systems, 
motor functions, cranial nerves, reflexes, and coordination/cerebellar function.
m
Thyroid function will be required in subjects <18 years of age only.
Change #17
Section 5.3 Schematic diagrams for SP0982
Paragraph 1 and Figure 5-2:
The schematic diagrams are provided in Figure 5-1 and Figure 5-2.
REDACTED COPY
and
and F
This document cannot be used to support any marketing authorization application 
igure 5
gure 
and any extensions
n, and 
 and
 senso
senso
or 
n n
variations 
or 
n
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 154 of 267
Figure 5-2: SP0982 overall schematic diagram
TED 
DACTE
REDA
Y
COPY 
C
This document cannot be
be 
ed 
used to 
port 
suppo
s
any 
any
ting 
marketin
ma
on 
rization
authoriz
au
ation 
pplicati
app
and 
an
any 
any
sions 
xtensio
ext
or 
o
riations 
on
vari
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 155 of 267
Have been changed to:
The schematic diagram for the Combined Baseline Period eligibility is provided in Figure 5-1. 
A schematic diagram for the Prospective Baseline Period through the Taper Period with 
successive panels for pediatric subjects weighing <30kg, pediatric subjects weighing ≥30kg to 
<50kg, and adult subjects and pediatric subjects weighing ≥50kg is provided in Figure 5-2. The 
schematic diagram for the Transition Period is provided in Figure 5-3.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 156 of 267
Figure 5‒2: SP0982 Prospective Baseline Period through the Taper Period schematic diagram
V1
V2
V3-V4 
V5
V6-V10/ET
V10
Taper 
Prospective 
Baseline Period
Titration Period
Maintenance Perioda
Taper Periodb
12mg/kg/day or
placebo
10mg/kg/day or 
placebo
8mg/kg/day or 
placebo
9 or 
8mg/kg/day 
or placebo
Subjects
6mg/kg/day or 
placebo 
6mg/kg/day 
or placebo
<30kg
4mg/kg/day or 
placebo
4mg/kg/day or 
placebo
2mg/kg/day or 
placebo 
2mg/kg/day 
or placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum dose 
achieved during the Maintenance 
Period.
W -4 to 0
W1
W2
W3
W4
W5
W6
W 7 through W 24
W1
W2
W3
W4
V1
V2
V3-V4 
V5
V6 –V10/ET
V10
Taper
Prospective 
Baseline Period
Titration Period
Maintenance Perioda
Taper Periodb
8mg/kg/day or
placebo
Subjects
6mg/kg/day or 
placebo
6 mg/kg/day 
or placebo
≥30kg and 
<50kg
4mg/kg/day or 
placebo
4mg/kg/day or 
placebo
2mg/kg/day or 
placebo
2mg/kg/day or 
placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum 
dose achieved during the 
Maintenance Period.
W-4 to 0
W1
W2
W3
W4
W5
W6
W7 through W24
W1
W2
W3
W4
REDACTED
usted 
usted
dgmen
dgmen
W5
TE
TE
TE
TE
TE
TE
TE
TE
TE
AC
AC
AC
AC
AC
AC
AC
AC
ED
ED
ED
ED
ED
ED
ED
ED
R
COPY 
Y
PY
PY
PY
PY
PY
PY
PY
PY
PY
P
This document cannot t be 
o
W
be
be
be
be
be
be used 
d
ring th
ing th
or d
or d
d o
to 
o support 
y
acebo
cebo
bo
ppor
ppor
or
or
or
p
upp
pp
p
up
up
up
su
su
su
su
sup
up
up
up
any
plac
pla
or 
or 
o
ny
ny
ny
ny
n
an
an
an
a
marketing
od
day or
day or
ceb
ce
ng 
ing authorization 
p 
p
t.
A sin
A sin
th
t
itititititi
ati
ati
ati
at
at
at
at
a
W6
W6
riririririririri
th
th
th
th
th
th
th
th
th
a
application and
and 
an
y
any y
ensions 
oioioioioioioioioi
exten
exten
e
or r variations 
on
ar
ar
ari
ari
ari
aririririri
v
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 157 of 267
Figure 5-2:
SP0982 overall schematic diagram
V1
V2
V3-V4 
V5
V6–V10/ET 
V10
Taper
Prospective 
Baseline Period
Titration Period
Maintenance Perioda
Taper Periodb
400mg/day or 
placebo
Subjects
300mg/day or 
placebo
300mg/day 
or placebo
≥50kg
200mg/day or
placebo
200mg/day or 
placebo
100mg/day or 
placebo
100mg/day or 
placebo
During the Titration Period, dosage may be adjusted up 
or down based on investigator’s clinical judgment.
A single dose reduction is allowed during 
the Maintenance Period as long as the 
minimum target dose is maintained.
Taper based on the maximum 
dose achieved during the 
Maintenance Period.
W-4 to 0
W1
W2
W3
W4
W5
W6
W7 through W24
W1
W2
W3
W4
ET=Early Termination; LCM=lacosamide; V=Visit; W=Week
Note: Lacosamide dosing is designated as “mg/kg/day” (oral solution) and “mg/day” (tablets) and matching placebo is shown as “placebo.”
a Subjects will be required to achieve and maintain a minimum LCM (or matching placebo) dose for at least the final 3 days of Week 6 to be eligible for entry 
into the Maintenance Period.
b If the subject discontinues from the study at any time and is not eligible or chooses not to enter EP0012, the subject must complete the ET Visit or Visit 10 
(Week 24) and an up to 4-week blinded taper followed by an End of Taper Visit. There will be a 30-day Safety Follow-up Period for subjects who complete the 
End of Taper Visit.
“mg/da
“mg/da
or matc
r mat
eligib
eligib
d o
d o
COPY 
Y
PY
PY
PY
PY
W6
PY
PY
PY
PY
PY
PY
PY
PY
PY
CO
CO
CO
CO
CO
CO
CO
COPY
PY
PY
PY
P
This document cannot be used to support any marketing 
le or 
e or 
of Taper
f Taper
authorization 
n
ay”
y” (ta
(ta
ching p
hing p
ch
application 
dose red
ose re
Maintena
ainten
minimum
nimum
pp
pp
pp
pp
pp
pp
pp
pp
a
and any y
ensions 
n
exten
exten
e
or r variations 
on
ar
ar
ari
ar
ari
ari
ari
aririririri
v
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 158 of 267
Figure 5‒3: SP0982 Transition Period schematic diagram 
Maintenance 
Period 
(18 weeks)
Transition Period
(4 weeks)
Entry into 
EP0012
(Follow-up study)
12mg/kg/day 
12mg/kg/day
10mg/kg/day 
10mg/kg/day
10mg/kg/day
9mg/kg/day
9mg/kg/day
Subjects
8mg/kg/day
8mg/kg/day
<30kg
6mg/kg/day
4mg/kg/day
2mg/kg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
Maintenance 
Period 
(18 weeks)
Transition Period
(4 weeks)
Entry into 
EP0012
(Follow-up study)
8mg/kg/day 
8mg/kg/day
8mg/kg/day
7mg/kg/day
7mg/kg/day
Subjects
6mg/kg/day
6mg/kg/day
≥30kg and
4mg/kg/day
<50kg
2mg/kg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
Maintenance 
Period 
(18 weeks)
Transition Period
(4 weeks)
Entry into 
EP0012
(Follow-up study)
400mg/day 
400mg/day 
400mg/day
400mg/day
350mg/day
350mg/day
Subjects
300mg/day
300mg/day
≥50kg
200mg/day
100mg/day
Placebo
Week 7 through
TW1
TW2
TW3
TW4
Week 24
TW=transition week
Note: Lacosamide dosing is designated as “mg/kg/day” (oral solution) and “mg/day” (tablets) and matching placebo 
is shown as “placebo.”
REDACTED 
ED
4m
4
CT
ay
ay
A
ED
COPY
COPY 
ee
e
PY
This document 
e
m
um
um
um
um
um
u
cannot 
g
be 
be
b
used
00mg
00mg
350m
350m
ed
3
u
to
/
to
to support 
ks)
ks)
o
po
po
po
po
po
po
p
any y
a
marketing 
W1
ke
ke
ke
ke
ke
ke
ke
authorization 
7
on
at
mg/kg/d
g/kg/d
or
th
application 
d
pp
and 
d
a
any 
W4
extensions 
n
en
en
en
en
en
e
e
or variations 
n
y
n
on
on
on
on
on
on
on
o
tio
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 159 of 267
Change #18
Section 5.4.1 Rationale for dose
The LCM 100mg/day dose was selected to be the starting dose for this study to ensure a safe and 
well-tolerated up-titration scheme. The LCM 400mg/day maintenance dose was well tolerated 
and demonstrated efficacy in 3 primary efficacy studies as adjunctive therapy in subjects with 
partial-onset seizures. In SP0961, the Phase 2 pilot study in subjects with uncontrolled PGTC 
seizures with IGE, the 400mg/day dose was also well tolerated. Generally, the doses of AEDs 
used for the treatment of partial-onset seizures are similar to those used to treat generalized 
seizures. Thus, the 400mg/day target dose is considered the optimal maintenance dose for the 
population with uncontrolled PGTC seizures with IGE. 
Has been changed to:
For adult subjects, the LCM 100mg/day dose was selected to be the starting dose for this study to 
ensure a safe and well-tolerated up-titration scheme. The LCM 400mg/day maintenance dose 
was well tolerated and demonstrated efficacy in 3 primary efficacy studies as adjunctive therapy 
in subjects with partial-onset seizures. In SP0961 (the Phase 2 pilot study) and SP0962 (the 
open-label extension study) in subjects with uncontrolled PGTC seizures with IGE, the 
400mg/day dose was also well tolerated. Generally, the doses of AEDs used for the treatment of 
partial-onset seizures are similar to those used to treat generalized seizures. Thus, the 300mg/day 
to 400mg/day target dose range is considered the optimal maintenance dose for the population 
with uncontrolled PGTC seizures with IGE. 
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, as 
well as on information available in the medical literature, the pediatric dosing recommendations 
for SP0982 are to achieve LCM plasma concentrations similar to the average steady-state LCM 
plasma concentration reached after a LCM 400mg/day dose administration in adult studies, 
which is approximately 8μg/mL.
Change #19
Section 5.4.2 Rationale for second PGTC seizure
Paragraph 1, last 2 sentences:
In the time to nth seizure design, subjects are required to remain in the study for a minimum of 
5 weeks. If a subject experiences ≥2 seizures while on treatment, then after 5 weeks the subject 
exits the study, rather than continuing to have PGTC seizures, while remaining eligible to receive 
LCM in the open-label extension study (EP0012). 
Have been changed to:
In the time to nth seizure design, subjects are required to remain in the study for a minimum of 
6 weeks. If a subject experiences ≥2 seizures while on treatment, then after 6 weeks the subject 
exits the study, rather than continuing to have PGTC seizures, while remaining eligible to receive 
LCM in the open-label extension study (EP0012). 
Paragraph 2, fourth sentence:
Lacosamide, by comparison, reaches a minimally effective dose in the second week 
(200mg/day).
REDACTED 
diatric
iatric
medic
medic
sma co
sma co
L
COPY
eat ge
at ge
 optim
optim
This document 
n thth
6 w
6 w
e
cannot 
e bee
 bee
he t
he t
be
dy
e op
e op
used
ubject
ject
y, rat
, ra
to
izur
izu
support 
le f
nten
ntence
c
re
any 
for
fo
marketing 
onc
onc
LCM
CM 40
40
authorization
mal m
mal m
c safet
c safet
cal lit
cal lit
en
en
application
ot st
t st
C seizu
C seiz
es of A
s of A
neraliz
eraliz
ma
m
and
udie
udie
stud
tud
any 
g d
g d
ay
ay ma
ma
y
extensions 
e fo
dose
dos
or
or th
or t
variations 
Ds s 
d
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 160 of 267
Has been changed to:
Lacosamide, by comparison, reaches a minimally effective dose in the second week (200mg/day) 
for a majority of trial subjects
Change #20
Section 5.4.3 Rationale for minimum duration of treatment
Paragraph 1:
The minimum duration of the Treatment Period for each subject will be 5 weeks. There are 
2 reasons for the requirement of a minimum Treatment Period duration:
Has been changed to:
The minimum duration of the Treatment Period for each subject will be 6 weeks. There are 
3 reasons for the requirement of a minimum Treatment Period duration:
The following third bullet was added:
•
To allow for increased flexible dosing during titration
Last paragraph, third sentence:
By allowing subjects to exit the study after completing 5 weeks of the Treatment Period, 
sufficient double-blind safety data can be collected from a high proportion of subjects to be 
meaningful.
Has been changed to:
By allowing subjects to exit the study after completing 6 weeks of the Treatment Period, 
sufficient double-blind safety data can be collected from a high proportion of subjects to be 
meaningful.
Change #21
Section 5.4.4 Rationale for selected age range
The following paragraph was added to the end of the section:
The ≥4-year age cutoff was established based on the difficulty of establishing a clear diagnosis 
of IGE in younger subjects with PGTC seizures. This is further supported by epidemiology data, 
which indicates that the incidence and prevalence of generalized epilepsies is lower in 
preschoolers compared to older children (Olafsson et al, 2005). 
Change #22
Section 6.1 Inclusion criteria
Inclusion criterion 4 was removed and subsequent criteria were renumbered.
Inclusion criterion 3, 5, and 9:
3. Male and female subjects 12 years of age and older with a body weight ≥50kg. 
5. Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset at 
5 to 30 years of age, consistent with IGE experiencing PGTC seizures (Type IIE) that are 
classifiable according to the ILAE Classification of Epileptic Seizures (ILAE, 1981) 
REDACTED 
y after
 after
y
an b
an b
COPY
ting 5 
ing 5
ed fro
ed fro
This document 
e
Incl
Inc
cannot
nge #
ge #
ctio
ctio
be
rs co
rs co
used
er su
r su
es tha
es tha
om
to 
toff
tof
sub
sub
support 
e 
e 
ph was 
h was
ff wa
ff w
any 
for 
for 
marketing 
r c
be coll
e col
authorization
om a
om a
comp
omp
application 
weeks
week
hih
and any extensions 
eeks. T
eks. T
or 
are
are
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 161 of 267
9. Subjects are required to have had an EEG tracing and report showing discharges consistent 
with IGE (generalized >3Hz epileptiform discharges and a normal EEG background) 
confirmed by a Central Reviewer. 
Have been changed to:
3. Male and female subjects ≥4 years of age. 
4. Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset 
prior to 30 years of age, consistent with IGE experiencing PGTC seizures (Type IIE) that are 
classifiable according to the ILAE Classification of Epileptic Seizures (ILAE, 1981).
8. Subjects are required to have had an EEG report consistent with IGE (eg, generalized ≥3Hz 
epileptiform discharges and a normal EEG background) confirmed by a Central Reviewer. 
Change #23
Section 6.2 Exclusion criteria
Exclusion criterion 5 was removed and subsequent criteria were renumbered.
Exclusion criterion 1, 4, 6, 17, and 22:
1. Subject has previously participated in this study or subject has previously received LCM, 
with the exception of subjects whose exposure was limited to a single iv dose.
4. Subject has a diagnosis of developmental delay or mental retardation including mild forms.
6. Subject has a history of status epilepticus. 
17. Subject has impaired renal function, ie, creatinine clearance (CLcr) is lower than 50mL/min.
22. Female subject who is pregnant or nursing, and/or a woman of childbearing potential who is 
not surgically sterile, 2 years postmenopausal or does not practice 2 combined methods of 
contraception, unless sexually abstinent, for the duration of the study. Male subject who does 
not agree to practice 2 combined methods of contraception (eg, condom, spermicide), unless 
sexually abstinent, for the duration of the study.
Have been changed to:
1. Subject has previously participated in this study or subject has previously been assigned to 
treatment in a study of LCM.
4. Subject has symptomatic generalized epilepsy ([ILAE, 1989] eg, Lennox-Gastaut Syndrome) 
or evidence of both focal and generalized epilepsy.
5. Subject has a history of convulsive status epilepticus 1 year prior to Screening. 
16. Subject has impaired renal function (ie, creatinine clearance [CLcr] is <30mL/min) at 
Screening (see Section 10.6). 
21. Female subject who is pregnant or nursing and/or a woman of childbearing potential who is 
not surgically sterile, 2 years postmenopausal, or does not practice 1 highly effective method 
of contraception (according to International Conference on Harmonisation [ICH] guidance, 
defined as those that result in a failure rate of <1% per year when used consistently and 
correctly), unless sexually abstinent, for the duration of the study. 
REDACTED 
us.
us.
, ie, cr
, ie, cr
or nu
or nu
COPY
was li
was l
ay
ay or
or
y
This document
.
S
2
cannot
bject 
ject 
Subj
Subj
be
ence
ence
used 
s
as sy
s sym
y
to
tud
tudy
support 
d to:
to:
ously
usly
any 
ne
n
durat
dura
marketing
ursing
ursin
menop
meno
abstine
bstin
ned m
ed m
authorization
r men
r men
reatin
eatin
application 
ct has 
ct has
mite
mited t
d 
t
and 
numbe
umbe
any extensions
alized
lized
ral Re
l Re
or variations 
hat are
at are
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 162 of 267
Female subject of childbearing potential taking enzyme-inducing antiepileptic drugs 
(EI-AEDs: carbamazepine, phenytoin, barbiturates, primidone, topiramate, oxcarbazepine) 
who is not surgically sterile, 2 years postmenopausal, or does not practice 1 highly effective 
method of contraception according to the World Health Organization recommendation 
(ie, depot medroxyprogesterone acetate, norethisterone enantate, intrauterine devices, 
combined injectables, and progestogen implants) with administration of EI-AEDs or does not 
practice 2 combined methods of contraception (ie, combined hormonal contraception plus 
barrier method with spermicidal agent), unless sexually abstinent, for the duration of the 
study.
Change #24
Section 6.3 Exit criteria
Subjects must complete the first 5 weeks of the Treatment Period after randomization and will be 
required to exit the study if either of the following events occur:
•
Subject completes the first 5 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTC seizures during that time
•
Subject experiences a second PGTC seizure after the first 5 weeks of the Treatment Period
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure.
Has changed to:
Subjects will be required to exit the study if either of the following events occur:
•
Subject completes the first 6 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTC seizures during that time
•
Subject experiences a second PGTC seizure after the first 6 weeks of the Treatment Period
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure.
Change #25
Section 6.4 Withdrawal criteria
Bullet 1, 2, and 8:
•
In the case of intolerable AEs during the titration, the subject must be withdrawn from the 
study. No dose reduction is allowed during titration.
•
The subject requires a subsequent dose increase after dose reduction to LCM 300mg/day 
during the Treatment Period or the subject requires more than 1 dose reduction during the 
Treatment Period.
•
Subject has actual suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject 
REDACTED
isit w
sit 
tudy
tudy ifi
y
eks
ek
COPY
the s
the s
riteria
riteria
wi
wi
This document 
s
•
cannot 
2, ,
In the 
n the 
stud
stud
be 
and
and
used 
4 Wit
Wit
to support
enc
enc
ubject 
bjec
cts retu
cts retu
any
d P
d P
ced 
ced
marketing 
s of the
of the
during 
uring
PGT
PGT
authorization
a. If 
If 
ithin 1
hin 1
eithe
eithe
application 
5 week
 we
te shou
e sho
f the
the
and
r rand
ran
any 
d
extensions 
miza
miza
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 163 of 267
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study.
Have been changed to:
•
The subject is unable to attain at least the minimum Maintenance Period target dose 
(Table 7‒3).
•
The subject requires a subsequent dose increase after dose reduction during the Maintenance 
Period or the subject requires more than 1 dose reduction during the Maintenance Period.
•
Subject ≥6 years of age has actual suicidal ideation as indicated by a positive response 
(“Yes”) to either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. 
The subject should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
The following bullet was added after Bullet 13:
•
Subject develops an intolerable AE during the course of the study.
Change #26
Section 7.1 Description of investigational medicinal product
Lacosamide and matching placebo will be provided as white, film-coated tablets. Oral tablets of 
LCM 100mg and LCM 50mg and matching placebo will be packaged in wallet cards and 
administered during the Treatment Period.
Has been changed to:
Investigational medicinal product will be provided as LCM oral solution (syrup) 
(LCM 10mg/mL), LCM tablets (LCM 50mg), and matching placebos.
The LCM 10mg/mL oral solution and matching placebo oral solution are colorless to pale yellow 
in appearance. Both oral solutions will be packaged in amber polyethylene terephthalate (PET) 
bottles. Oral solution doses will be measured and administered via a dosing syringe.
The LCM 50mg tablets and matching placebo are white, oval tablets debossed with “SP” on one 
side. Tablets will be packaged in high-density polyethylene (HDPE) bottles.
Change #27
Section 7.2 Treatments to be administered
At Visit 2, the subject will be randomized to receive either LCM or matching placebo. Subjects 
will then begin a dose titration at LCM 100mg/day (50mg bid) or placebo for 1 week. Subjects 
will receive a telephone call at the end of the first week of titration reminding them to increase 
their dose to LCM 200mg/day (100mg bid) or placebo. Subjects will return to the clinic at Visit 3 
(end of Week 2) and will receive LCM 300mg/day (150mg bid) or placebo. At the end of 
Week 3, subjects will receive a telephone call reminding them to increase their dose to 
LCM 400mg/day (200mg bid) or placebo for the remaining duration of the Treatment Period. 
Five additional clinic visits will occur during the Treatment Period: Visit 5 (Week 8), Visit 6 
(Week 12), Visit 7 (Week 16), Visit 8 (Week 20), and ET Visit/Visit 9 (Week 24).
REDACTED 
ill be p
ill be p
M 5
COPY 
d as w
d as w
ebo w
ebo w
This document
heir
heir
(en
(en
cannot 
2, t, 
hen be
en be
l rece
rece
d
be 
the 
the 
used 
2 Tre
Tre
to support 
and 
nd ma
m
ackage
ackag
any 
ns 
ns
ill be 
ll be
marketing
pro
ro
50mg)
50mg)
and ma
nd m
s will
wi
authorization
will b
will b
ovid
ovid
application 
cinal 
cina
hite, f
hite, f
and 
y.
any extensions 
ons
he C
he C
onal an
nal an
or 
se 
se 
variations 
nce
nce
od.d.
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 164 of 267
After completing ≥5 weeks and experiencing the second PGTC seizure during the Treatment
Period, or after completing the 24-week Treatment Period (whichever comes first), the subject 
may, at the ET Visit or Visit 9 (Week 24), respectively, choose to continue in EP0012. Subjects 
completing Visit 9 (Week 24) or the ET Visit must complete a 4-week blinded transition 
followed by a Final Clinic Visit. The Final Clinic Visit is the same as Visit 1 of EP0012. All 
subjects’ first dose in EP0012 will be LCM 400mg/day (200mg bid) (see Table 7-1). 
The following schematic displays the scenario for subject dispensation: subject completes the 
Visit 9 (Week 24) or the ET Visit on LCM 300mg/day (150mg bid), or LCM 400mg/day 
(200mg bid), or placebo and continues into EP0012.
Table 7-1 summarizes the transition steps for each treatment dose for subjects entering EP0012.
Table 7-1:
Dose transition steps for subjects entering EP0012
Treatment dose
Transition (4 weeks)
Week 1
Week 2
Week 3
Week 4
LCM 300mg/day
300mg/day
300mg/day
300mg/day
400mg/day
LCM 400mg/day
400mg/day
400mg/day
400mg/day
400mg/day
Placebo
100mg/day
200mg/day
300mg/day
400mg/day
LCM=lacosamide
Subjects completing Visit 9 (Week 24) or the ET Visit who choose not to continue in EP0012 
must complete a 1-week blinded taper followed by the End of Taper Visit. Subjects completing 
Visit 9 (Week 24) or the ET Visit on LCM 400mg/day (200mg bid), LCM 300mg/day (150mg 
bid), or placebo will have their doses tapered over 1 week. Two weeks after the last dose of study 
drug following the End of Taper Visit, subjects will complete a Final Clinic Visit 
(see Table 7-2).
The following schematic displays the scenario for subject dispensation: subject completes Visit 9 
(Week 24) or ET Visit on LCM 300mg/day (150mg bid), LCM 400mg/day (200mg bid), or 
placebo and does not continue into EP0012.
Table 7-2 summarizes the transition steps for each treatment dose for subjects not entering 
EP0012.
Visit 9 
(Week 24)/ 
ET Visit
Visit 9 
(Week 24)/
ET Visit
4 weeks
Final Clinic 
Visit=EP0012
Visit 1
End of 
Taper Visit
Final 
Clinic Visit
1 week 
2 weeks
REDACTED 
3
ED
C
y
AC
AC
ACT
AC
/day
/day
ED
COPY 
Tran
Tra
Y
Wee
We
CO
This document 
m
(W
c
not
and
and
canno
Vis
be
or E
or E
d d
d d
used 
g schem
schem
ET
ET
to support
T Vi
V
ve their
e thei
nd of T
d of T
any
ed tap
ed ta
Visit
Visi
marketing
ting
n
k 24) 
k 24)
authorization 
ek 2
k 2
n
300mg
00mg
at
40
40
ho
a
application 
e for 
for
ering E
ering 
sition
sition
pl
a
and 
s
any 
a
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 165 of 267
Table 7-2:
Taper steps for subjects not entering EP0012
Treatment dose
Taper
(1 week)
Safety Follow-up
(2 weeks)
Week 1
Week 1
Week 2
LCM 300mg/day
100mg/day
-
-
LCM 400mg/day
200mg/day
-
-
Placebo
Placebo
-
-
LCM=lacosamide
Has been changed to:
Study medication will be administered orally bid (at approximately 12-hour intervals in the 
morning and in the evening).
At Visit 2, subjects will be randomized to receive either LCM (oral solution for pediatric subjects 
[≥4 to <18 years of age] weighing <50kg or tablets for adult subjects [≥18 years of age] and 
pediatric subjects weighing ≥50kg) or matching placebo. At the end of Visit 2, subjects should 
take the first dose of study drug while in the clinic. 
SP0982 will target Maintenance Period doses of LCM or matching placebo as presented in 
Table 7‒3.
7.2.1 Titration Period
Table 7‒1 provides the recommended LCM (or matching placebo) dosing during the Titration 
Period for subjects to reach the target doses for the Maintenance Period. All subjects should 
follow this recommended dosing schedule, unless dose adjustments based on tolerability are 
needed. 
Table 7-1:
Recommended dosing schedule for LCM (or matching placebo) 
during the Titration Period
Body weight 
category 
(formulation)
Target LCM (or matching placebo) doses for the Titration Period
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<30kg (oral 
solution)a
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/day
12mg/kg/day
≥30kg to <50kg 
(oral solution)a
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
8mg/kg/day
8mg/kg/day
≥50kg (tablets)b
100mg/day
200mg/day
300mg/day
400mg/day
400mg/day
400mg/day
LCM=lacosamide
a The oral solution formulation is for pediatric subjects weighing <50 kg.
b The tablet formulation is for adult subjects (≥18 years of age) and pediatric subjects weighing ≥50kg.
Table 7-2 provides LCM (or matching placebo) dosing with flexibility based on tolerability 
during the Titration Period.
REDACTED 
CM (o
CM (o
doses
dose
hedul
hedu
COPY
M or
M o
This document
LCM=
CM
a Th
Th
b
cannot 
ution)
tion)
kg (tab
g (tab
n
c
be 
0kg
0kg
a
used
2mg
2mg
u
to 
/k
to support 
Tar
Ta
rt
ek 1
k 1
pp
any 
d d
tratio
trati
marketing
ule, un
le, un
dosi
dos
authorization 
or mat
r mat
for th
for th
application
end o
end o
matchi
match
and 
luti
uti
s [≥18
[≥18
f
any 
ion f
on
extensions 
nterva
erva
or 
or variations 
ns
on
-
ria
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 166 of 267
Table 7-2:
Dosing of LCM (or matching placebo) with flexibility based on 
tolerability during the Titration Period
Body weight category
(formulation)
Target LCM (or 
matching 
placebo) dose 
increase/weeka
(titration)
LCM (or matching placebo) 
dose decrease per
back-titration step
Subsequent LCM (or 
matching placebo) dose 
increase
(dose increase after 
back-titration step)
Min
Max
Min
Max
<30kg (oral solution)
2mg/kg/day
1mg/kg/day
2mg/kg/day
1mg/kg/day
2mg/kg/day
≥30kg to <50kg (oral 
solution)
≥50kg (tablets)
100mg/day
50mg/day
100mg/day
50mg/day
100mg/day
LCM=lacosamide; Max=maximum; Min=minimum
Note: Asymmetrical dosing with no more than 50mg difference between morning and evening doses will be allowed 
for subjects who require back titration in a 50mg increment.
a Titration step to achieve a dose not previously administered
All subjects are required to complete Week 1 dosing before study drug dosing flexibility based 
on tolerability is allowed. Investigators will assess whether a subject would tolerate a further 
study drug dose increase or whether a subject should hold the dose for a longer duration. There is 
no limit to the number of back-titration steps or dose holds allowed and all are at the 
investigator’s discretion; however, subjects must achieve the minimum LCM (or matching 
placebo) target dose by the end of the Titration Period (Table 7‒3). If it becomes apparent that a 
subject is unable to attain at least the minimum Maintenance Period target dose, then the subject 
must enter the Taper Period and be withdrawn from the study.
Subjects who titrate to a next higher dose level should remain at that dose prior to a dose increase
for ≥7 days unless a back-titration step is required based on tolerability. Subjects who have their 
study drug back titrated must remain on the lower dose for ≥3 days (in order to reach steady 
state) before a subsequent dose increase. 
As outlined in Table 7‒3, subjects will be required to achieve and maintain a minimum LCM (or 
matching placebo) dose for at least the final 3 days of Week 6 (to achieve steady-state 
concentrations) to be eligible for entry into the Maintenance Period. Subjects may have a 
back-titration step as late as the last day of Week 6 as long as the minimum target dose is 
maintained.
Table 7-3: 
Required LCM (or matching placebo) dose for at least the final 3 days 
of Week 6
Body weight category
(formulation)
LCM (or matching placebo) dose for at least the final 3 days of Week 6
Min
Max
<30kg (oral solution)
8mg/kg/day
12mg/kg/day
≥30kg to <50kg (oral solution)
6mg/kg/day
8mg/kg/day
≥50kg (tablets)
300mg/day
400mg/day
LCM=lacosamide; Max=maximum; Min=minimum
REDACTED
st 
on Pe
on Pe
imum
mum
thdraw
thdraw
dos
dos
COPY
hol
ho
ose ho
se ho
ach
ach
This document 
Bo
(for
(for
me
m
cannot 
dy w
dy w
n
be 
3:
3:
used to
as la
as la
support
ubje
bje
u
for at 
for at
eligib
eligib
ate
any
incr
inc
ect
ec
marketing
se leve
e lev
ep is re
p is r
ain on 
in on
crea
cre
authorization
old
hieve t
ieve t
eriod (
riod (
m Main
Main
wn fro
wn fro
application
y y drug
dru
subjec
subje
the dos
he do
ds all
s all
and any
ening
enin
extensions
2m
2m
on
/day
day
ns
xte
or variations 
on
Max
ax
at
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 167 of 267
7.2.2 Maintenance Period
Subjects will enter a 18-week Maintenance Period at the dose they received on the last day of the 
Titration Period in accordance with targeted Maintenance Period dosing (Table 7-3). 
During the Maintenance Period, a single dose reduction is allowed as long as the minimum dose 
requirement is maintained. Once the dose has been reduced, it cannot be increased. Subjects who 
are not able to tolerate the minimum target dose during the Maintenance Period (Table7-3) will 
be withdrawn from the study and enter an up to 4-week blinded Taper Period. All dose 
reductions should be discussed with the Medical Monitor.
7.2.3 Transition Period (for subjects who enter EP0012)
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period, or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24), respectively, choose to continue in EP0012. 
Subjects completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded 
transition followed by a Final Clinic Visit. Two weeks after Visit 10 (Week 24) or the ET Visit, a 
Transition telephone contact is required; a subsequent Clinic Visit is at the discretion of the 
investigator (Table 5‒2). The Final Clinic Visit is the same as Visit 1 of EP0012. 
The following schematic displays the scenario for subject dispensation: 
Visit 10 
or ET Visit
2 weeks
Transition 
TC/Visita
2 weeks 
Final Clinic Visit 
(EP0012 Visit 1)
ET=Early Termination; TC=telephone contact 
a
A Transition telephone contact is required. A Transition Clinic Visit is optional, at the discretion of the 
investigator.
Subjects will transition in a double-blind fashion to LCM dosing as described Table 7‒4. At the 
completion of the Transition Period, subjects eligible to enter EP0012 will be placed on a 
common dose (see Figure 5‒3).
REDACTED
TC
TC
CT
ct 
d. A Tr
d. A Tr
COPY 
bjec
bje
ansiti
ansit
/V
PY
This document cannot be used to support any marketing 
ind fas
nd fa
d, sub
d, subjb
authorization 
on 
on 
Visit
Visita
ori
ansitio
nsitio
application
t is a
is 
Visit
isit 1
dispens
spen
ap
and
(Wee
Wee
at t
at
any 
c
4-we
we
ek
extensions 
he Trea
e Trea
first), 
irst),
cont
on
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 168 of 267
Table 7-4:
Transition Period LCM dosing schedule for subjects 
randomized to placebo
Body weight category 
(formulation)
LCM (or matching placebo) doses for the Transition Period 
Week 1
Week 2
Week 3
Week 4
<30kg (oral solution)
LCM 2mg/kg/day
LCM 
4mg/kg/day
LCM 
6mg/kg/day
LCM 
8mg/kg/day
≥30kg to <50kg 
(oral solution) 
LCM 2mg/kg/day
LCM 
4mg/kg/day
LCM 
6mg/kg/day
LCM 
8mg/kg/day
≥50kg (tablets)
LCM 100mg/day
LCM 200mg/day
LCM 300mg/day
LCM 400mg/day
LCM=lacosamide
7.2.4 Taper Period
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24) and an up to 4-week 
blinded taper followed by an End of Taper Visit (Table 7-5). 
A slower taper is permitted if medically necessary. Whenever possible, these cases should be 
discussed with the Medical Monitor prior to withdrawing the subject from the study, especially 
in cases in which exit criteria have been met. In case of an emergency, a faster taper is permitted 
after discussion with the Medical Monitor, whenever possible.
Following the End of Taper Visit, there will be a 30-day Safety Follow-up Period. The Safety 
Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed by a 
Safety Follow-up telephone contact 30 days after the last dose of study drug.
The following schematic displays the scenario for subject dispensation
Visit 10 or 
ET Visit
0-4 week 
taper
End of 
Taper Visit
Final Clinic 
Visit 
Safety 
Follow-up 
TC
2 weeks after 
last dose of 
study drug
(±2 days)
30 days after last 
dose of study 
drug
(-1/+3 days)
ET=Early Termination; TC=telephone contact 
Note: An End of Taper Visit will be scheduled at the end of the Taper Period (up to 4 weeks) depending on the dose 
level achieved; see Table 7-5. Of note, for subjects who enter the Taper Period at ≤2mg/kg/day (oral solution) or 
100mg/day (tablets), the End of Taper Visit will take the place of the ET Visit.
Table 7-5 summarizes the Taper Period dosing for each treatment dose for subjects not entering 
EP0012.
REDACTED
ene
ene
illll be a
be a
sit 2 w
sit 2 w
30 day
30 da
COPY
wing
win
ase of
ase o
eve
eve
This document cannot 
7-5 su
5 s
0012.
012
be 
ble
used 
per V
er 
e Tabl
Tabl
ets), 
ets), 
to 
TC
TC
Vis
Vis
support 
ape
ap
up
u
C=tel
C=te
any
d of
d o
er V
er V
marketing 
ys a
s a
scenar
scena
f
ark
rk
rk
authorization
f an
an
er poss
r poss
a 30
30-d
weeks
weeks
aft
aft
application 
er poss
r pos
the sub
he su
n em
n em
and 
e o o
24) an
4) an
any 
or 
or ch
c
extensions 
mg/g
LCM 4
CM 4
ns
ns
or
/kg/
kg/
variations 
ay
ay
on
M 
M
ari
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 169 of 267
Table 7-5:
Taper Period dosing of LCM (or matching placebo)
LCM (or matching 
placebo) dose achieved
LCM (or matching placebo) doses for the Taper Period 
Week 1
Week 2
Week 3
Week 4
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
NA
5 or 6mg/kg/day
4mg/kg/day
2mg/kg/day
NA
NA
3 or 4mg/kg/day
2mg/kg/day
NA
NA
NA
2mg/kg/day
NA
NA
NA
NA
350 or 400mg/day
300mg/day
200mg/day
100mg/day
NA
250 or 300mg/day
200mg/day
100mg/day
NA
NA
150 or 200mg/day
100mg/day
NA
NA
NA
100mg/day
NA
NA
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: The oral solution is dosed as “mg/kg/day” and tablets are dosed as “mg/day.”
Change #28
Section 7.3 Packaging
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing Practice 
guidelines and applicable laws or regulations. The IMP is suitably packaged in such a way as to 
protect the IMP from deterioration during transport and storage. Lacosamide and matching 
placebo will be packaged in treatment kits including wallet cards. Each wallet card will contain 
IMP for 7 days plus 3 reserve days.
Has been changed to:
Lacosamide (tablets and oral solution) and matching placebos 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 tablets and matching placebos will be packaged in HDPE bottles.
Lacosamide 10mg/mL oral solution and matching placebo will be packaged in amber PET 
bottles and will be measured and administered via a dosing syringe.
Change #29
Section 7.5 Handling and storage requirements
Paragraphs 2, 3, and 4:
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 
(eg, once a week), showing minimum and maximum temperatures reached over the time interval.
REDACTED 
nd lab
nd lab
ations
ations
during 
uring 
nt k
nt
COPY 
This document 
Sec
Sec
cannot
and w
and w
ange
ange
be
de 10
de 10
used 
ablets 
blets 
to
d st
d st
support
al so
l so
od Man
d Ma
is suit
is suit
tora
any 
solut
olu
marketing
tran
tra
kits inc
kits inc
authorization 
beled a
led a
s. The
The
ansp
ans
application 
on
as
as “mg/
mg
and 
NA
N
n
any 
an extensions
N
on
ns
te
ex
or 
A
NA
NA
or variations 
on
tio
A
ar
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 170 of 267
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Clinical Project Manager (CPM) (or designee) before further use of the IMP.
The CPM (or designee) will transmit the out-of-range temperature (copy of the temperature log 
and duration of the out-of-range temperature, if available) to the Drug Supply Coordinator. 
Based on discussion with a UCB Quality Assurance representative, the Drug Supply Coordinator 
will then provide the CPM (or designee) with instructions for the site regarding use of the IMP.
Have been changed to:
Appropriate storage conditions must be ensured by controlled room temperature and by 
completion of a temperature log (showing minimum and maximum temperatures reached over 
the time interval) in accordance with local requirements on a regular basis.
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Clinical Project Manager (CPM) (or designee) before further use of the IMP and communicated 
to the sponsor’s designee in accordance with the pharmacy manual.
Change #30
Section 7.6 Drug accountability
Paragraph 1, sentence 2:
Details of any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or 
returned to the sponsor or designee must also be recorded on the appropriate forms.
Has been changed to:
Details of any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or 
returned to the sponsor’s designee must also be recorded on the appropriate forms.
Paragraph 5, sentence 1:
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) and unused IMP containers must be reconciled and returned to UCB (or designee), 
preferably in their original package.
Has been changed to:
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.
Change #31
Section 7.7 Procedures for monitoring subject compliance
Paragraph 3:
Timely completion of the subject diary is essential for evaluation of safety and efficacy. Subject 
diary completion, including AED usage, will be evaluated at each visit. Sites are encouraged to 
call subjects to inquire about their diary completion.
REDACTED 
be r
be r
age
age o
must a
must a
COPY 
tage),
tage)
reco
rec
This document
Para
Para
T
cannot
ge #
e #
ction
tion
be 
n t
#3
#3
used
unu
unu
their
heir
to
r aft
r af
suppor
pack
pac
d to:
d to:
ter
any
onta
onta
ckag
cka
marketing
also b
lso b
ion o
ion o
authorization 
no
no
orded 
rded
r was
was
be
b
application 
otot us
u
and any 
P a
extensions
ched
hed
cated
cated
and
and
or 
d o
d o
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 171 of 267
Has been changed to:
Timely completion of the subject diary is essential for evaluation of safety and efficacy. Subject 
diary completion, including AED usage, will be evaluated at each clinic visit and telephone 
contact. Sites are encouraged to call subjects to inquire about their diary completion. 
Investigators should advise subjects and/or caregivers about the importance of reporting 
non-PGTC seizures. Subjects should be reminded that diaries must include daily entries even if 
no seizures have occurred.
Change #32
Section 7.8.1 Permitted concomitant treatments (medications and 
therapies)
The following 2 sentences were added to the end of the section:
Contraceptive treatment is allowed as described in Section 6.2 (Exclusion Criteria 21).
Stable use of amphetamines and sedative antihistamines is allowed during the study. 
Change #33
Section 7.8.2 Prohibited concomitant treatments (medications and 
therapies)
Last bullet:
•
Only stable, low doses of non-benzodiazepine anxiolytics or once-daily hypnotics are 
allowed for nonepilepsy indications.
Has been changed to:
•
Only stable, low doses (<50% of the maximum daily dose recommended by the
country-specific product label) of non-benzodiazepine anxiolytics or once-daily hypnotics 
are allowed for nonepilepsy indications.
Change #34
Section 8 STUDY PROCEDURES BY VISIT
Sentence 2:
A detailed schedule of study assessments is provided in Table 5‒1.
Has been changed to:
A detailed schedule of study assessments is provided in Table 5‒1, Table 5‒2, and Table 5‒3. 
Change #35
Section 8.1.1 Visit 1 (Week -4)
The following Bullets 12, 13, 14, and 15 were deleted:
•
Healthcare resource use
•
Work/school days lost
REDACTED 
azepin
zepin
COPY 
This document
Cha
ha
Se
Se
cannot 
ailed s
ailed 
ang
ang
be
n ch
n c
used 
hedule
edule
to support 
PROC
PRO
any 
ind
in
marketing 
the ma
the m
) of non
of no
dica
dic
authorization 
ne anx
e anx
application 
ts (me
s (m
and
uring
ring
any
Crit
Cri
g t
extensions 
t
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 172 of 267
•
Days with help from a caregiver
•
Tanner Stage (for subjects under 18 years of age at Visit 1)
Bullets 3, 7, and 9:
•
EEG (Subjects are required to have had an EEG showing discharges consistent with IGE 
prior to Visit 1.)
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
Have been changed to:
•
EEG report
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
Change #36
Section 8.1.2 Telephone Contact (Week -2)
Paragraph 1, first sentence:
The investigator (or designee) should contact the subject by telephone 2 weeks following Visit 1.
Has been changed to:
The investigator (or designee) should contact the subject by telephone 2 weeks following Visit 1 
to assess continued eligibility and will remind the subject of the importance of accurate seizure 
diary completion.
Change #37
Section 8.2 Treatment Period
The following text was added:
The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
Change #38
Section 8.2.1 Visit 2 (Day 0)
Has been changed to:
8.2.1 Visit 2 (Day 0) Randomization
The following bullet was added:
•
Body weight
act the
act th
d co
d co
COPY 
-2)
2)
This document
Sec
Sec
H
cannot
mplet
plet
ange
ange
be 
tion
titi
used
Perio
erio
on o
n o
to 
as
od
od
support 
ent Pe
nt P
s add
s add
any marketing 
ontact 
ontact
ill rem
ll rem
authorization 
he subj
subj
application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 173 of 267
Bullets 5, 7, 8, 11, and 13:
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Dispense study drug (At Visit 2, subjects should take the first dose of study drug 
[LCM 50mg or placebo] in the clinic)
•
BRIEF
Have been changed to:
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, and a urine pregnancy test [for women of childbearing 
potential])
•
Dispense study drug
•
BRIEF-P/BRIEF
•
Tanner Stage (will be performed only for subjects who are pubescent at Visit 2 or who enter 
puberty during the course of the study)
•
The following text was added to the end of the section:
The subject will take the first dose of study drug in the clinic.
Change #39
Section 8.2.2 Telephone Contact (end of Week 1)
The investigator (or designee) should contact the subject by telephone at the end of Week 1. 
Subject will be reminded to increase their dose to LCM 200mg/day (100mg bid) or placebo. 
During the telephone contact, the following assessments will be performed:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
REDACTED 
onl
only fo
y f
stud
stud
COPY 
pre
pr
This document
•
W
cannot 
epo
epo
Conco
onco
W
be 
orti
orti
used
remi
emi
epho
epho
to
r de
r de
support 
phone
phon
esig
esi
any 
se 
se
marketing 
dy
dy)
the en
the e
e of s
e of
authorization 
or sub
r sub
application 
nts (inc
ts (inc
nancy
ncy te
y
and any extensions or variations 
)
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 174 of 267
Has been changed to:
8.2.2 Titration Period
8.2.2.1 Week 1 to Week 6
Both clinic visits and telephone contacts will be conducted during the Titration Period, beginning 
with a telephone contact at the end of Week 1 and continuing through clinic Visit 5 at the end of 
Week 6.
At each clinic visit and telephone contact, the investigator, in conjunction with the subject and/or 
parent(s)/legal representative(s), will decide how to proceed with study drug dosing based on 
tolerability (including vital signs, body weight, 12-lead ECG, and AE reporting, as applicable to 
the type of visit contact). If the withdrawal of study drug is required during the Titration Period, 
the subject will enter the blinded Taper Period (Table 7-5).
8.2.2.1.1 Telephone contact (Week 1, Week 3, Week 5, and unscheduled)
The following assessments will be performed during telephone contacts (both scheduled 
[Week 1, Week 3, and Week 5] and unscheduled) during the Titration Period:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
Change #40
Section 8.2.3 Visit 3 (end of Week 2)
Has been changed to:
8.2.2.1.2 Visit 3 (end of Week 2)
The following bullet was removed:
•
Urine pregnancy test (for women of childbearing potential)
The following bullets were added:
•
Body weight
•
ECG 12-lead assessment (see Section 10.7.1)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Socioprofessional data
Bullet 4:
•
C-SSRS assessment
Has been changed to:
•
C-SSRS assessment (for subjects ≥6 years of age)
eek 2
eek 2
COPY 
This document 
Bull
Bull
cannot
mistr
mistr
Socio
Socio
be
and u
and 
used 
ad ass
d ass
to support
or w
r w
were ad
ere ad
any 
ed:
ed:
wom
wom
marketing 
k 2)
k 2)
d
authorization 
2)
application 
tion
ion
and
actsts (b
(b
on P
n P
any
d un
un
bo
b
extensions
ase
applic
applic
Titratio
itratio
or
ed o
ed o
variations 
and/
and/
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 175 of 267
Change #41
Section 8.2.4 Telephone Contact (end of Week 3)
The investigator (or designee) should contact the subject by telephone at the end of Week 3. 
Subjects will be reminded to increase their dose to LCM 400mg/day (200mg bid) or placebo for 
the remaining duration of the Treatment Period. During the telephone contact, the following 
assessments will be performed:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
8.2.5 Visit 4 (end of Week 4)
During Visit 4 (end of Week 4), the following assessments will be performed:
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, a urine pregnancy test [for women of childbearing potential], and LCM 
plasma concentration)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Achenbach CBCL
•
BRIEF
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
REDACTED
iastol
iasto
nical la
nical la
gn
gn
COPY
for at
for a
i
This document 
W
•
cannot 
ealthc
althc
Wo
Wo
be used 
h CBC
CBC
to
ew/
ew/
support 
g
/ret
/
any marketing
abo
bo
nancy
ancy t
y
authorization 
icic BP
BP
orat
ora
application 
prior to
prior 
least 5
east 
and any 
med:
med
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 176 of 267
•
Contact IVRS/IWRS
Have been changed to:
8.2.2.1.3 Visit 4 (end of Week 4)
During Visit 4 (end of Week 4), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.7.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Urine pregnancy test (for women of childbearing potential)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IVRS/IWRS
Change #42
Section 8.2.6 Visit 5 (end of Week 8)
Has been changed to:
8.2.2.1.4 Visit 5 (end of Week 6)
Sentence 1:
During Visit 5 (end of Week 8), the following assessments will be performed:
Has been changed to:
During Visit 5 (end of Week 6), the following assessments will be performed:
REDACTED COPY 
This document
8.2.
8.2.
S
cannot 
n 8
s bee
bee
2
be 
8.2
8.2
used 
/I/I
2
to
IWR
WR
support 
ons a
ns a
a
any 
an
marketing authorization application and any extensions 
 asses
asses
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 177 of 267
The following bullets have been added:
•
Body weight
•
Socio-professional data
Bullets 3 and 5:
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
Have been changed to:
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
Change #43
Section 8.2.7 Visit 6 (end of Week 12)
Has been changed to:
8.2.3 Maintenance Period
8.2.3.1 Visit 6 (end of Week 8)
Sentence 1:
During Visit 6 (end of Week 12), the following assessments will be performed:
Have been changed to:
During Visit 6 (end of Week 8), the following assessments will be performed:
The following bullet has been added:
•
Socio-professional data
Bullet 5:
•
C-SSRS assessment
Has been changed to:
•
C-SSRS assessment (for subjects ≥6 years of age)
Change #44
Section 8.2.8 Visit 7 (end of Week 16)
Sentence 1:
During Visit 7 (end of Week 16), the following assessments will be performed:
REDACTED 
e follo
e follo
COPY 
This document
Sec
Sec
S
cannot
SRS
RS
ange
ange
be 
c
S a
S a
sed
ssm
sm
chan
ha
to 
me
me
support 
atata
any 
added
adde
marketing 
owin
wi
he foll
he fol
authorization 
ing 
ng
application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 178 of 267
Have been changed to:
8.2.3.2 Visit 7 (end of Week 12)
During Visit 7 (end of Week 12), the following assessments will be performed:
The following bullets have been added:
•
Body weight
•
Socio-professional data
Bullets 3 and 5:
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
Have been changed to:
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
Change #45
Section 8.2.9 Visit 8 (end of Week 20)
Sentence 1:
During Visit 8 (end of Week 20), the following assessments will be performed:
Have been changed to:
8.2.3.3 Visit 8 (end of Week 16)
During Visit 8 (end of Week 16), the following assessments will be performed:
The following bullets have been added:
•
Socio-professional data
•
Body weight
Bullet 4:
•
C-SSRS assessment
Has been changed to:
•
C-SSRS assessment (for subjects ≥6 years of age)
Change #46
Section 8.2.10 ET Visit/Visit 9 (end of Week 24) 
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
REDACTED 
0)
0)
e follow
 follo
COPY 
This document
•
C
C
cannot
SRS
RS
s bee
s bee
be 
S a
S a
used to support 
e been
bee
al data
l data
any 
6),), tht
marketing 
owi
wi
k 16
16)
authorization 
ing 
ng 
application and any extensions 
ws an
ws an
ding E
ing E
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 179 of 267
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure 
(see Section 6.3).
During the ET Visit/Visit 9 (end of Week 24), the following assessments will be performed:
•
Body weight and height
•
Physical examination (complete)
•
Neurological examination (complete)
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, a serum pregnancy test [for women of childbearing potential], and 
LCM plasma concentration)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Achenbach CBCL
•
BRIEF
•
EQ-5D-3L
•
QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age)
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
Tanner Stage (for subjects under 18 years of age)
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IVRS/IWRS
REDACTED COPY 
This document 
•
W
cannot
repo
repo
Conc
Conc
be 
Stata
used
elp f
lp f
age
age
to 
ys
fro
f
support 
use
se
s lost
lost
any 
8 y
8 year
ea
marketing authorization application 
hild
ild
and
udes 
udes
dbe
dbe
any 
he
h
extensions
ECG
CG
asses
asses
or
d, if
d, i
G
variations 
ifif
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 180 of 267
Has been changed to:
8.2.3.4 Visit 9 (end of Week 20)
During Visit 9 (end of Week 20), the following assessments will be performed:
•
Body weight
•
Physical examination (brief)
•
Neurological examination (brief)
•
ECG 12-lead assessment (see Section 10.7.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a urine pregnancy test [for women of childbearing potential])
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IVRS/IWRS
8.2.3.5 Visit 10/ET Visit (end of Week 24) 
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure 
(see Section 6.3).
During the Visit 10/ET Visit (end of Week 24), the following assessments will be performed:
•
Body weight 
•
Height
•
Physical examination (complete)
•
Neurological examination (complete)
REDACTED COPY 
This document 
Duri
ur
•
cannot 
o h
o 
ection
ectio
ring 
ing
be 
whe
whe
hav
hav
used 
ect has
ct has
heth
eth
to
/ET
ET
support 
S
T V
T V
any 
d d 
marketing 
AED
AE
authorization application and 
ildb
db
any
hem
hem
bear
bea
extensions 
essme
ssme
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 181 of 267
•
ECG 12-lead assessment (see Section 10.7.1)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, a serum pregnancy test [for women of childbearing 
potential], and LCM plasma concentration)
•
Subject diary return/review
•
Dispense subject diary
•
Dispense study drug
•
Study drug review/return
•
Achenbach CBCL (same version used at Visit 2)
•
BRIEF/ BRIEF-P (same version used at Visit 2)
•
EQ-5D-3L (for subjects ≥12 years of age)
•
QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age, same version 
used at Visit 2)
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
Tanner Stage (will be performed only for subjects who are pubescent at Visit 2 or who enter 
puberty during the course of the study)
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs 
•
Withdrawal criteria
•
Contact IVRS/IWRS
Change #47
Section 8.3.1 Transition and Final Clinic Visit 
Has been changed to:
8.3.1 Transition Period
8.3.1.1 Transition Clinic Visit/telephone contact
Paragraph 1:
Subjects who experience their second PGTC seizure and have completed at least 5 weeks of the 
Treatment Period, or who complete the 24-week Treatment Period without experiencing their 
REDACTED 
on
o
COPY 
(su
(s
This document
Has
as
8.3
8.3
cannot 
ion
on 8
s b
s b
be
#47
47
used 
RS/I
RS/IW
to
teria
eria
support 
atitions
on
a
any marketing 
nly for 
y for
study
study)
authorization application 
ects <1
cts <
and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 182 of 267
second PGTC seizure will be eligible to enroll in EP0012. Eligible subjects who choose to 
continue in EP0012 must complete a 4-week blinded transition followed by a Final Clinic Visit. 
For subjects participating in EP0012, the Final Clinic Visit will serve as Visit 1 of EP0012. 
Subjects choosing to enter EP0012 must sign and date the EP0012 extension IEC/IRB-approved 
informed consent prior to receiving EP0012 study drug. 
Has been changed to:
A Transition telephone contact is required. The following assessments will be performed during 
the Transition telephone contact:
•
AE reporting
•
Concomitant medications and AEDs
•
Withdrawal criteria
A Transition Clinic Visit is optional, at the discretion of the investigator. Subjects requiring a 
clinic visit will have the same assessments conducted as an Unscheduled Visit (see Section 8.4).
8.3.1.2 Final Clinic Visit
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment
Period or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24), respectively, choose to continue in EP0012. 
Subjects completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded 
transition followed by a Final Clinic Visit. The Final Clinic Visit is the same as Visit 1 of 
EP0012. Subjects choosing to enter EP0012 must sign and date the EP0012 extension 
IEC/IRB-approved informed consent prior to receiving EP0012 study drug. 
Bullets 4 and 6:
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a serum pregnancy test [for women of childbearing potential])
Have been changed to:
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, urinalysis, and a urine pregnancy test [for women of childbearing 
potential])
REDACTED 
 ET
ET
The Fi
The Fi
012 m
012 m
prior t
prior
COPY
eriod
erio
4), res
4), re
T V
T V
This document
•
B
cannot 
12
12
C-SSR
-SSR
Bl
be 
2-le
-le
used 
ina
na
cha
cha
to 
sa
alalys
ys
support 
ampl
ampl
any 
the
th
marketing 
ecordin
cordi
he su
e su
authorization
spec
pe
Visit m
isit m
inal C
nal C
must si
ust si
o rec
o rec
application 
TC seiz
TC sei
(which
whic
ectiv
ctiv
and
uled V
led 
any 
Subje
Subj
Vi
V
extensions or variations 
ring
ing
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 183 of 267
Change #48
Section 8.3.2 Taper
Has been changed to:
8.3.2 Taper and Safety Follow-up Period
8.3.2.1 End of Taper Visit
Paragraph 1:
Subjects completing Visit 9 (Week 24) or the ET Visit who choose not to continue in EP0012 
must complete a 1-week blinded taper followed by the End of Taper Visit. At the End of Taper 
Visit, the following assessments will be performed:
Has been changed to:
Subjects completing Visit 10 (Week 24) or the ET Visit who choose not to continue in EP0012 
must complete an up to 4-week blinded taper followed by the End of Taper Visit. At the End of 
Taper Visit, the following assessments will be performed:
The following Bullets have been added:
•
Physical examination (complete)
•
Neurological examination (complete)
•
Socio-professional data
Bullets 2 and 4:
•
ECG (12-lead) assessment (1 recording to be performed prior to any blood draws and, if 
possible, with the subject in the supine position for at least 5 minutes preceding ECG 
recording)
•
C-SSRS assessment
Have been changed to:
•
ECG 12-lead assessment (see Section 10.7.1)
•
C-SSRS assessment (for subjects ≥6 years of age)
The following section has been added:
8.3.2.2 Safety Follow-up Visit
Following the End of Taper Visit, the subject will return 2 weeks (±2 days) after the last dose of 
study drug for a Safety Follow-up Visit. During the Safety Follow-up Visit, the following 
assessments will be performed:
•
Body weight 
•
Physical examination (complete)
•
Neurological examination (complete)
REDACTED 
cordin
cordi
COPY 
This document 
ud
ud
asses
asses
cannot 
Sa
Sa
owing
wing
dy dr
d
y
be 
afe
afe
used 
ssm
sm
secti
secti
to
men
men
support 
to:
o:
ssment
smen
any marketing
ing to
ing to
upine p
upine 
authorization application and
Tape
Tap
any 
to con
to co
er
extensions
EP
nd of 
nd of
or
P00
P00
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 184 of 267
•
ECG 12-lead assessment (see Section 10.7.1) (required only for subjects with an abnormal 
reading at the previous clinic visit)
•
Vital signs (pulse rate, systolic BP, and diastolic BP, including orthostatic assessments) 
•
C-SSRS assessment (for subjects ≥6 years of age)
•
Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology [required only for subjects with an abnormal value at the previous 
clinic visit], urinalysis, and a urine pregnancy test [for women of childbearing potential]).
•
Healthcare resource use
•
Work/school days lost
•
Days with help from a caregiver
•
Socio-professional data
•
AE reporting
•
Concomitant medications and AEDs
8.3.2.2. Safety Follow-up telephone contact
Thirty days (-1/+3 days) after the last dose of study drug, the subject will receive a Safety 
Follow-up telephone contact. During the Safety Follow-up telephone contact, the following 
assessments will be performed:
•
AE reporting
•
Concomitant medications and AEDs 
Change #49
Section 8.4 Unscheduled Visit
Paragraphs 1 and 2:
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the
investigator. During an Unscheduled Visit, the following assessments are required:
If an Unscheduled Visit is due to an AE, then the C-SSRS is required.
Has been changed to:
Unscheduled Visits may be performed at any time after Visit 1, as clinic visits or telephone 
contacts, at the discretion of the investigator. During an Unscheduled Visit, the following 
assessments are required:
If an unscheduled visit is due to an AE, then the C-SSRS (for subjects ≥6 years of age) is 
required.
Last paragraph:
In addition to the required assessments listed above, further assessments can be completed as 
needed and may include ECG, laboratory tests, dispense study drug, diary review, etc.
REDACTED 
EDs 
EDs 
COPY 
y drug
drug
y
Follo
Follo
This document 
If an
If an
rere
cannot 
ule
ule
ts, at 
s, at 
essme
ssme
be 
ed V
ed V
used 
d d V
chan
han
to
Visi
is
support 
be per
be pe
an Unsc
n Uns
any marketing 
Visit
Visit
authorization
g,
w-up
up
application 
the s
the s
t
and any extensions or variations 
ous 
us 
l]).
]).
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 185 of 267
Has been changed to:
In addition to the required assessments listed above, depending on the type of visit (clinic or 
telephone), further assessments can be completed as needed and may include ECG, vital signs, 
laboratory tests, dispense study drug, diary review, etc.
Change #50
Section 9.2 Secondary efficacy variables
The key secondary efficacy variable is:
•
Time to the first PGTC seizure during the 24-week Treatment Period 
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 5 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period 
Has been changed to:
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures for the 24-week Treatment Period
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 6 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period 
•
Time to the first PGTC seizure during the 24-week Treatment Period
Change #51
Section 9.3 Other efficacy variables
Bullets 1, 3, 9 and 15:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 5 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 5 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 5 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 5 weeks of the Treatment Period
REDACTED 
or the
or the
es are
s are
COPY 
r th
r t
This document
f
•
cannot
1
t
, 3,
, 3,
Perce
Perce
fifi
be
9.3 
3 
9
used 
3 Ot
Ot
to 
P
support 
PGT
GT
eriod 
eriod
PGTC
GTC
any 
TC s
TC
marketing 
:
ure fre
ure fr
and 4
nd 4
authorization 
24-w
24-w
application 
om
24-wee
we
and 
m Co
Co
any
e firs
e fir
extensions 
mbine
mbine
rst
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 186 of 267
•
EuroQol-5 Dimension (EQ-5D-3L) items
Have been changed to:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 6 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 6 weeks of the Treatment Period
•
50% response for PGTC seizures during the first 6 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 6 weeks of the Treatment Period
•
EuroQol-5 Dimension (EQ-5D-3L) items (for subjects ≥12 years of age)
Change #52
Section 9.3.1 Seizure frequency
The following paragraph was added to the end of the section:
Investigators should advise subjects and/or caregivers about the importance of reporting 
non-PGTC seizures. Subjects should be reminded that diaries must include daily entries even if 
no seizures have occurred.
Change #53
Section 9.3.2 Patient-Weighted Quality of Life in Epilepsy Inventory-Form 
31 (QOLIE-31-P)
First sentence:
The QOLIE-31-P Version 2 will be used to evaluate the health-related quality of life (HRQoL) 
of study subjects (Cramer and Van Hammée, 2003). 
Has been changed to:
The QOLIE-31-P Version 2 will be used to evaluate the health-related quality of life (HRQoL) 
of study subjects ≥18 years of age (Cramer and Van Hammée, 2003).
Change #54
Section 9.3.3 Pediatric Quality of Life Inventory
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 Measurement Model consists of developmentally appropriate forms for pediatric 
subjects 12 years of age and ≥13 years to <18 years of age. Self-report is measured for pediatric 
subjects ≥5 years to <18 years of age, and parent proxy report of child HRQoL is measured for 
pediatric subjects ≥2 years to ≤18 years of age. 
The multidimensional 23-item PedsQL generic core scales encompass the essential core domains 
for pediatric HRQoL measurement: Physical Functioning (8 items), Emotional Functioning 
(5 items), Social Functioning (5 items), and School Functioning (5 items). The PedsQL 
Qualit
ualit
COPY 
t di
t d
This document 
he 
he 
subj
subj
su
s
cannot 
sQL
QL
tric po
ric po
e Pe
Pe
be 
L is
L is
used 
3.3 P
.3 P
to support 
n 2 wi
n 2 w
years 
ears 
any marketing 
used to
sed 
n Ham
n Ha
authorization 
ty
ty of 
of 
y
application 
he imp
e imp
ies mu
es mu
and any extensions 
er 2
or
28
28 d
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 187 of 267
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 always). A total health summary score 
ranging between 0 and 100 is calculated from the sum of the raw scores of the 23 items, with 
higher scores indicating higher HRQoL.
Has been changed to:
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 version of the PedsQL used at Visit 2 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 ≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to 
<18 years of age. Self-report is measured for pediatric subjects ≥5 years to <18 years of age, and 
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 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
Change #55
Section 9.3.4 ED-5D-3L Quality of Life Assessment 
Has been changed to:
9.3.4 EQ-5D-3L Quality of Life Assessment 
First sentence:
The EQ-5D-3L (EuroQol Group, 2011) is a self-administered questionnaire designed to measure 
health status. 
Has been changed to:
The EQ-5D-3L (EuroQol Group, 2011) is a self-administered questionnaire designed to measure 
health status in subjects ≥12 years of age.
Change #56
Section 9.3.6 Number of working days or school days lost
The number of working or school days lost by the subject will be recorded.
Has been changed to:
The number of working or school days lost by the subject will be recorded, as applicable.
REDACTED
h hi
h h
ty
ty of 
of
y
COPY
point 
point
mary
mary s
y
high
igh
This document 
The 
The
cannot
ge #
ge #
ction
ction
be
s inin
#5
use
L
ed 
 (Eur
(Eur
n su
n su
to
ged
ge
support
Grou
Grou
d t
d
any 
p
marketing 
ife A
fe A
authorization
scor
cor
her sc
er sc
Life 
Life 
application 
essss
nal Fun
al Fu
ent is re
nt is 
Likert s
ikert
re r
re r
and 
sent
en
any
sured
sure
extensions 
for ped
or pe
≥13
13 y
18 ye
ye
d
or variations 
001). 
01). 
dy
dy inin
y
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 188 of 267
Change #57
Section 9.3.7 Number of days with help from a caregiver
The number of days with help from a caregiver will be recorded.
Has been changed to:
The number of days with help from a caregiver will be recorded, as applicable.
Change #58
Section 9.3.8 Socio-professional data
Socio-professional data, such as highest level of education, current professional status, housing 
status, and regular assistance will be collected only at Visit 2.
Has been changed to:
Socio-professional data, such as highest level of education, current professional status, housing 
status, and regular assistance will be collected throughout the study, as applicable.
Change #59
Section 10.1.6 Pregnancy
Should a subject become pregnant after the first intake of any IMP, UCB’s Drug Safety 
department should be informed immediately. The subject should be withdrawn from the study as 
soon as pregnancy is known and the following should be completed:
•
The subject should return for an ET Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the ET Visit.
•
A Safety Follow-up Visit (Final Clinic Visit) should be scheduled 2 weeks after the subject 
has discontinued their IMP.
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, UCB 
will ask the investigator or designee to contact the subject and his partner to request consent via 
the Partner Pregnancy Consent form. If the partner agrees to provide additional information, the 
Pregnancy Report and Outcome form will be forwarded to the subject’s partner for completion.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed-up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. The health of the child must be followed for 
30 days after birth for any significant medical issues.
In certain circumstances, UCB may request that follow-up is continued for a period longer than 
30 days.
REDACTED 
The 
The
ing sh
ing sh
 Visit
Visit
stop
stop
COPY 
ntake 
ntake
e su
e su
This document
follo
ollo
rep
rep
cannot 
regnan
egnan
estiga
stiga
be
Rep
Rep
used
estiga
stig
egnan
egnan
to
part
part
at
support
orm th
rm t
atment 
men
rtner
tn
any 
he
h
marketing 
p the i
the i
al Clin
al Cl
authorization
of a
of 
ubject 
bject
hould b
ould b
t.
i
application 
f an
any
and 
fes
fes
as ap
as ap
any 
ssion
ssio
extensions 
atus, h
atus, h
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 189 of 267
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be additionally reported using the 
Investigator SAE Report Form.
Has been changed to:
If an investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the investigator must immediately notify UCB’s Drug Safety department by providing the 
completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event 
reporting information at the beginning of this protocol). The subject should be withdrawn from 
the study as soon as pregnancy is known (by positive pregnancy test), and the following should 
be completed:
•
The subject should return for an ET Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the ET Visit.
•
A Safety Follow-up Visit (Final Clinic Visit) should be scheduled 2 weeks after the subject 
has discontinued her IMP.
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the investigator and filed at the site. 
UCB’s Drug Safety department is the primary contact for any questions related to the data 
collection for the pregnancy, eventual birth, and follow up.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the investigator site file. In case of questions about the consent process, the 
investigator may contact the UCB/CRO contract monitor for the study. The investigator will 
complete the Pregnancy Report and Outcome form and send it to UCB’s Drug Safety department 
(for contact details see Serious Adverse Event reporting information at the beginning of this 
protocol) only after the partner has agreed that additional information can be captured and has 
provided the signed Partner Pregnancy Consent form. UCB’s Drug Safety department is also the 
primary contact for any questions related to the data collection for the partner pregnancy, 
eventual birth, and follow up.
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
REDACTED
cy
cy and
an
y
nd Ou
nd Ou
of the 
of the 
day
days a
s a
at f
at
COPY 
ancy
ancy
d
This document
prov
prov
pr
pr
cannot
e thth
ontac
ontac
tocol
ocol
be
r ma
m
he P
he
used 
cy C
y C
n the in
the in
ay
ay
to 
gne
Con
Con
support 
y, ev
, ev
ner of 
ner of
ee is 
ee is 
any
nt is t
nt is 
even
eve
marketing
afte
fte
follow 
ollow 
or refus
r refu
eds to 
ds to
h
authorization
Repo
Repo
d the e
d the e
utcom
com
child.
child
er b
er b
application 
entl
ently k
y
and 
d 2 w
d 2 w
any 
itit
extensions 
ng g
trate
rat
r
sho
sho
variations 
vent 
nt 
from
from
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 190 of 267
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form.
Change #60
Section 10.3 Adverse events of special interest
The following adverse event of special interest was added.
•
Emergence of non-preexisting or worsening of any existing epileptic seizure types.
Change #61
Section 10.6 Laboratory measurements
First sentence:
Blood and urine specimens for routine assay of hematology, clinical chemistry, and urinalysis 
parameters will be collected according to the schedule of study assessments in Table 5‒1.
Has been changed to:
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis parameters will be collected according to the schedule of study assessments in 
Section 5.2. A central laboratory will perform the routine analysis of blood and urine specimens. 
Pregnancy testing will also be performed (see Section 10.6.2). The procedures for handling and 
shipping these specimens will be provided to the sites.
The laboratory tests to be performed are presented in Table 10-2:
Table 10-2: Laboratory tests
Hematology
Clinical chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count
RBC count
WBC count
Differential count
Calcium
Phosphorus
Serum electrolytes (sodium, potassium, 
chloride, bicarbonate)
Creatinine
BUN
AST
ALT
Total bilirubin
Alkaline phosphatase
GGT
Glucose
Albumin
Total serum protein
Uric acid
pH
Ketones
Glucose
Albumin
Specific gravity
Microscopic exam for blood cells 
or casts/hpf
Urine pregnancy test
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; GGT=gamma glutamyl transferase; 
hpf=high power field; RBC=red blood cell; WBC=white blood cell
REDACTED 
he s
he 
resent
resent
al c
al
RE
COPY
utine
utin
ction 1
ction 
site
sit
This document
ALT=
ALT=
hpf
hpf
t cannot 
c
be used to support 
C
rt any
erum
eru
chlor
chlor
C
marke
m
osphoru
sphor
m e
m
keting 
hemist
hemist
g
ket
authorization
10.6
0.6
es.s.
ted in 
d in 
application 
nical c
nical c
schedu
chedu
anal
nalys
y
.6.2)
6 2)
and any 
tr
nts in
nts in
extensions 
ry, a
, a
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 191 of 267
Has been changed to:
Table 10-2: Laboratory tests
Hematology
Clinical chemistry
Endocrinologya
Urinalysisb
Hematocrit
Hemoglobin
Platelet count
RBC count
WBC count
Differential count
Calcium
Phosphorus
Serum electrolytes (sodium, 
potassium, chloride, bicarbonate)
Creatinine
BUN
AST
ALT
Total bilirubin
Alkaline phosphatase
GGT
Glucose
Albumin
Total serum protein
Uric acid
TSH
T3 (total and serum-free)
T4 (total and serum-free)
pH
Ketones
Glucose
Albumin
Specific gravity
Microscopic exam for blood 
cells or casts/hpf
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; GGT=gamma glutamyl transferase; 
hpf=high power field; RBC=red blood cell; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; 
WBC=white blood cell
a    Thyroid function will be required in subjects <18 years of age only.
b    Urinalysis will be required for subjects ≥5 years of age only.
Creatinine clearance will be estimated using 2 different formulas. In subjects ≥12 years of age, 
creatinine clearance will be estimated using the Cockcroft-Gault formula (Cockcroft and 
Gault, 1976). In subjects <12 years of age, creatinine clearance will be estimated using the 
updated Schwartz bedside formula (Schwartz and Work, 2009).
Change #62
Section 10.6.2 Pregnancy testing
Females of childbearing potential (who have not been surgically sterilized or who are not at least 
2-years postmenopausal) will have serum and urine dipstick pregnancy testing performed 
according to the schedule of study assessments in Table 5‒1.
Has been changed to:
Females of childbearing potential (who have not been surgically sterilized or who are not at least 
2 years postmenopausal) will have serum and urine dipstick pregnancy testing performed 
according to the schedule of study assessments in Table 5‒1, Table 5‒2, and Table 5‒3.
Change #63
Section 10.7.1 12-lead ECG
Standard 12-lead ECGs will be performed according to the schedule of study assessments in 
Table 5‒1. 
The 12-lead ECG recording should be performed at approximately the same time of day and 
prior to blood sample collection. Care should be taken to assure proper lead placement and 
REDACTED 
g 2 dif
g 2 dif
ing the
ng th
f age, c
f age, 
Schw
Schw
COPY 
f age on
f age on
only.
only.
This document 
Sec
Sec
cannot
ing to
ng to
ange
ange
be
stme
stme
used 
ang
ng
hildbe
ildbe
to
ged
ge
support
tent
ent
) will h
will 
dule of
dule of
any 
y te
t
ntial 
tia
marketing
wartz
wartz
test
es
authorization 
fferen
feren
he Coc
e Coc
creatin
reati
application 
nitrogen
itrogen
e; TSH=
e; TSH
ly.y.
n and 
an
any extensions or
or b
or b
variations 
blo
blo
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 192 of 267
quality ECG recordings. Subjects should rest in a supine position at least 5 minutes prior to each 
recording and should be motionless during the recording.
Has been changed to:
Standard 12-lead ECGs will be performed according to the schedule of study assessments in 
Table 5‒1, Table 5‒2, and Table 5‒3.
The ECG recordings should be performed at the same time of day (when possible) and prior to 
blood sample collection and vital sign assessments. Care should be taken to assure proper lead 
placement and quality ECG recordings. If possible, subjects should rest in a supine position at 
least 5 minutes prior to each recording and should be motionless during the recording. In 
pediatric subjects (<18 years of age), 12-lead ECGs (2 interpretable recordings) approximately 
20 to 30 minutes apart must be performed.
Change #64
Section 10.7.2 Vital signs and body weight
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits in a 
supine position after at least 3 minutes at rest, according to the schedule of study assessments in 
Table 5‒1. Assessment of orthostatic changes will be as follows: after the 3-minute measurement 
in a supine position, the subject is asked to stand and BP and pulse rate are taken 1 minute and 
3 minutes after standing up as feasible. Blood pressure measurements should be taken with the 
proper placement and proper sized cuff to obtain accurate measurements.
Body weight will be determined without shoes and wearing light clothing and height will be 
measured without shoes. Body weight and height will be measured using equipment that is age 
appropriate and assessed according to the tabular schedule of study assessments (Table 5‒1).
Has been changed to:
10.7.2 Vital signs, body weight, and height
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits in a 
supine position after at least 3 minutes at rest, according to the schedule of study assessments in 
Table 5‒1, Table 5‒2, and Table 5‒3. Assessment of orthostatic changes will be as follows: after 
the 3-minute measurement in a supine position, the subject is asked to stand and BP and pulse 
rate are taken approximately 1 minute and approximately 3 minutes after the subject stands up, 
as feasible. Blood pressure measurements should be taken with the proper placement and proper 
sized cuff to obtain accurate measurements.
Body weight will be determined without shoes and wearing light clothing and height will be 
measured without shoes. Body weight and height will be measured using equipment that is age 
appropriate and assessed according to the tabular schedule of study assessments (Table 5‒1, 
Table 5‒2, and Table 5‒3).
REDACTED
ain a
ain 
hoes a
hoes a
and he
and he
to the 
to the 
COPY
d BP 
d BP
essure 
essure
acc
ac
This document
ppro
ppr
Tab
Tab
cannot
weigh
eigh
sured 
ured 
rop
rop
be 
o ob
ob
used 
prox
ro
ood p
ood p
bta
bta
to 
rem
oxim
oxim
support
ast 3 m
st 3 
and
nd Ta
T
ment
ment
any 
diasto
diast
marketing
tab
ab
eight,
ight
authorization
 me
me
curate
urate
and w
nd w
eight w
ight 
bul
bul
application 
asur
sur
schedu
ched
ows: af
ows: a
and pu
nd pu
easu
easu
and 
ured
red
any extensions
g. In
. In
pproxi
proxi
or
ion
ion
variations 
o
ead 
ead 
n at
n at
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 193 of 267
Change #65
Section 10.7.3 Physical examination
Sentence 1:
Physical examinations will be performed by a medically qualified clinician licensed to perform 
the examination, according to the schedule of study assessments in Table 5‒1.
Has been changed to:
Physical examinations will be performed by a medically qualified clinician licensed to perform 
the examination, according to the schedule of study assessments in Table 5‒1, Table 5‒2, and 
Table 5‒3.
Change #66
Section 10.7.3.1 Complete physical examination
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems.
Has been changed to:
The complete physical examination will include cardiac and respiratory function via auscultation 
and review of all body systems.
Change #67
Section 10.7.4 Tanner Stage
At Visit 1 and Visit 9/ET Visit, the investigator or qualified designee will evaluate the subject’s 
sexual development using a 3-item scale. The Tanner Stage will be performed for subjects who 
are <18 years of age at Visit 1. At Visit 9/ET Visit, if subject is >18years of age, a repeat 
assessment is not necessary.
Has been changed to:
At Visit 2 and Visit 10/ET Visit, the investigator or qualified designee will evaluate the subject’s 
sexual development using the 3-item Tanner scale, according to the tabular schedules of study 
procedures (Section 5.2). The investigator should use clinical judgment in deciding which 
subjects are selected for evaluation of Tanner Stage (ie, those subjects who are pubescent at 
Visit 2 or who will enter puberty during the course of the study).
Change #68
Section 10.7.5 Neurological examination
First sentence:
Neurological examinations will be performed by a medically qualified clinician with 
documented training in the conduct of neurological examinations, according to the schedule of 
study assessments in Table 5‒1.
REDACTED 
nvesti
nvesti
cal
cal
COPY
diac 
diac
This document
First
irst
N
cannot 
e #
e #
tion
tion
be 
#68
68
used
ected
cted
o will
will
to
n 5.2
5.
d f
support 
ET Visi
T Vi
sing th
sing th
2)
any marketing 
igat
ga
le. The
e. The
Visit 9/E
sit 9
authorization 
ator 
tor
application 
nd resp
d res
and
ory fu
ry fu
any 
un
extensions 
5‒2
‒2
or
erfo
erf
2 a
variations 
form
form
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 194 of 267
Has been changed to:
Neurological examinations will be performed by a medically qualified clinician with 
documented training in the conduct of neurological examinations, according to the schedule of 
study assessments in Table 5‒1, Table 5‒2, and Table 5‒3.
Change #69
Section 10.7.5.2 Brief neurological examination
The brief neurological examination will include selected assessments of mental status, cranial 
nerves, and coordination/cerebellar function.
Has been changed to:
The brief neurological examination will include selected assessments of general neurological 
status, reflexes, muscle strength, and coordination/cerebellar function.
Change #70
Section 10.7.6 Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2012). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed according to the 
schedule of study assessments in Table 5‒1.
Has been changed to:
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2012). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed according to the 
schedule of study assessments in in Table 5‒1, Table 5‒2, and Table 5‒3.
All subjects who are ≥6 years of age will complete the “Baseline/Screening” version of the 
C-SSRS at Visit 1 and will complete the “Since Last Visit” version at subsequent visits. If a 
subject becomes 6 years of age during the study, the "Already Enrolled" version of the C-SSRS 
should be used at the first visit at which the subject is 6 years of age, and the “Since Last Visit” 
version should be used at subsequent visits.
The C-SSRS is not validated for subjects <6 years of age and will not be used for this population. 
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 younger than 
6 years old, reference should be made to the current version of the Diagnostic and Statistical 
Manual of Mental Disorders published by the American Psychiatric Association. 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.
REDACTED 
study
study p
y
ill be 
ill be 
the
th
COPY 
een
ee
C-SS
-SS
This document
Man
Man
pare
pare
a
cannot
depre
depre
ars ol
rs ol
nua
nua
be
. The
. Th
used
not v
not v
ld be
ld be
to 
sed
support
of age
f age
irst visi
st vis
d at s
d at s
any 
f ag
a
mplet
mple
d
marketing
use
use
e study
study
Table 
Table
age w
ge
authorization 
perso
perso
sed
ed
application 
he C
he C-S
ng as w
g as w
RS wi
RS wi
and any extensions 
ral neu
al ne
or variations 
nial
nial
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 195 of 267
Change #71
Section 10.7.7 Achenbach CBCL
Paragraphs 1 and 2:
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). For subjects ≥12 years to <18 years of age, the CBCL/6 to 18 
version will be used.
The same scale will be completed at Visit 2, Visit 4, and Visit 9/ET Visit by the parent(s)/legal 
representative(s). The completion of the Achenbach CBCL will require approximately 
45 minutes. 
Have been changed to:
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). 
The Achenbach CBCL/1½ -5 is for children <5 years and 11 months of age, and the 
CBCL/6-18is for children ≥6 years to <18 years of age; the questionnaire is to be completed by 
the parent(s)/legal representative(s). For each subject, the same version of the scale that is 
completed at Visit 2 should be maintained for the duration of the study in accordance with the 
tabular schedules of study procedures (Table 5‒1) and should be completed by the same 
parent/legal representative. The completion of the Achenbach CBCL will require approximately 
45 minutes.
Last paragraph:
In addition, the Achenbach CBCL/6 to 18 includes ratings related to performance in school, 
activities in leisure time, and special interests
Has been changed to:
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests
Change #72
Section 10.7.8 BRIEF
The BRIEF is a validated tool that will be used for the evaluation of subjects ≥5 years of age. 
The BRIEF will be administered at Visit 2, Visit 4, and Visit 9/ET Visit.
The BRIEF includes rating forms used by parents to assess subjects’ executive functioning and 
include validity scales to measure negativity and inconsistency of responses.
The BRIEF Rating form contains items in nonoverlapping clinical scales and validity scales. 
These theoretically and statistically derived scales form 2 broader Indexes: Behavioral 
Regulation (3 scales) and Metacognition (5 scales), as well as a Global Executive Composite 
score. Factor analytic studies and structural equation modeling provide support for the 2 factor 
model of executive functioning as encompassed by the 2 Indexes.
REDACTED
5‒1
‒1)
n of th
n of th
COPY 
e; ;
ect, the
ect, th
e dura
e dur
This document 
he 
he
inclu
inclu
T
cannot 
EF
EF
RIEF
RIEF
e BR
BR
be 
F is 
F is 
used 
.7.8 
7.8 
to support 
ch CB
h CB
me, and
me, an
any marketing 
to 18 i
to 18
ial int
ial in
authorization
ration
ation
and sh
and s
he Ac
e Ac
application 
months
month
questi
ques
e same
sam
and
ms w
ms w
any 
ate a c
te a 
wili
extensions 
t(s
elyly
or
s)/le
)/le
variations 
8 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 196 of 267
Has been changed to:
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of subjects 
≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P and BRIEF will be 
used only in countries where a translated scale is available. For each subject, the same version 
(BRIEF-P or BRIEF) that is used at Visit 2 should be maintained for the duration of the study in 
accordance with the tabular schedules of study procedures (Table 5‒1).
The BRIEF-P and BRIEF include 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. 
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).
The BRIEF rating form contains items in nonoverlapping clinical scales. These theoretically and 
statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score.
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses. 
Change #73
Section 13.1.5 Per Protocol Set
First sentence:
The Per Protocol Set (PPS) is a subset of the FAS excluding subjects who completed fewer than 
5 weeks of treatment or subjects with important protocol violations affecting the interpretation of 
the primary efficacy analysis.
Has been changed to:
The Per Protocol Set (PPS) is a subset of the FAS excluding subjects who completed fewer than 
6 weeks of treatment or subjects with important protocol violations affecting the interpretation of 
the primary efficacy analysis.
Change #74
Section 13.1.5 Safety set
First sentence:
The Safety Set (SS) is a subset of the RS and consists of all subjects who have been treated with 
at least 1 tablet of study drug, either LCM or placebo.
Has been changed to:
The Safety Set (SS) is a subset of the RS and consists of all subjects who have been treated with 
at least 1 dose of study drug, either LCM or placebo.
REDACTED 
et o
et o
COPY 
ales
le
This document 
he
he
at lea
at lea
H
cannot 
enten
nten
e Saf
Saf
be
13.1
13.
used 
1
to
y an
an
y
support 
PS) is a
S) is a
or subj
r subj
naly
na
any marketing 
of the F
f the 
h impo
imp
authorization application 
gulul
osite sc
site s
o measu
mea
and
ales. T
es. T
latio
ati
any 
Th
T
extensions 
v
ive
ve
ganize
ganize
d Eme
Eme
or 
ior.
or.
variations 
nsibl
nsibl
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 197 of 267
Change #75
Section 13.3.1 Analysis of the primary efficacy variable
First sentence:
The primary efficacy variable, time to second PGTC seizure during the Treatment Period, will be 
evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for 
treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs 
>2 per 28 days in the 16 weeks prior to randomization) and age at informed consent (≥12 to 
<18 years of age vs ≥18 years of age).
Has been changed to:
The primary efficacy variable, time to second PGTC seizure during the Treatment Period, will be 
evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for 
treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs 
>2 per 28 days in the 16 weeks prior to randomization) and age at informed consent (≥4 to 
<12 years of age, ≥12 to <18 years of age vs ≥18 years of age).
Fourth paragraph:
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted 
in order to assess the effect of dropouts and protocol deviations on the primary endpoint:
Has been changed to:
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted 
in order to assess the effect of dropouts, protocol deviations, and operational bias on the primary 
endpoint:
The following fourth bullet was added:
•
Repeat the primary analysis using the FAS, comparing the event rates prior to vs after each 
interim analysis to examine possible operational bias due to unblinding.
Change #76
Section 13.3.2 Secondary efficacy analysis
Paragraphs 1, 2, and 3:
Analysis of the key secondary efficacy variable, time to first PGTC seizure during the Treatment 
Period, will be analyzed in the same manner as the primary endpoint using the FAS. A 
gatekeeping strategy will be employed to control the Type I error (Marcus et al, 1976). If the 
primary endpoint is statistically significant at the 5% level, then the key secondary efficacy 
endpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach 
statistical significance, then the key secondary efficacy endpoint will be exploratory only.
The percent of subjects seizure-free at the end of the 24-week Treatment Period will be estimated 
from the Kaplan-Meier estimates of time to first seizure using 2-sided 95% confidence intervals.
Analyses of the secondary efficacy variable will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
REDACTED 
es on 
es on 
, proto
, proto
d
COPY 
rim
im
ol dev
ol dev
This document 
ndp
d
statis
statis
T
cannot
ping
ing
ary
ary en
en
y
poin
poin
be
l be 
l be
g s
g s
used 
an
an
he key
e key
a
to
nd 3
nd 3
support 
econd
cond
any
pos
po
marketing 
d:
sing th
ing t
si
authorization 
n the p
the p
ocol d
col d
application 
y effica
effi
y
iations
ation
and 
rme
m
any
≤2
≤2 p
med c
ed
extensions 
ent Pe
ent Pe
with an
ith an
or variations 
o
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 198 of 267
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described above), will be exploratory only. 
Has been changed to:
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 
24-week Treatment Period, will be analyzed in the same manner as the primary endpoint using 
the FAS. The percentage of seizure-free subjects at the end of the 24-week Treatment Period will 
be estimated from the KM estimates of time to first seizure using 2-sided 95% confidence 
intervals. A gatekeeping strategy will be employed to control the Type I error 
(Marcus et al, 1976). If the primary endpoint is statistically significant at the 5% level, then the 
key secondary efficacy endpoint will also be assessed at the 5% significance level. If the primary 
endpoint fails to reach statistical significance, then the key secondary efficacy endpoint will be 
exploratory only.
Analyses of the secondary efficacy variables will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described above) will be exploratory only. 
Time to the first PGTC seizure for the 24-week Treatment Period will be analyzed in the same 
manner as the primary endpoint using the FAS.
Change #77
Section 13.5 Handling of protocol deviations
After all eCRFs have been retrieved and entered, all queries issued and answered to the extent 
possible, and prior to unblinding and locking the clinical database, a Data Review Meeting will 
be held. Important protocol deviations (ie, those considered to have an impact on interpretation 
of safety, efficacy, or study conduct) will be identified and reviewed by a panel consisting of the 
CPM, the study biostatistician, study physician, a representative of the monitoring team, and 
other appropriate team members.
Has been changed to:
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 (DCP). To 
the extent feasible, 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 in a blinded manner a part of the ongoing data 
cleaning process prior to database lock to confirm exclusion from analysis sets.
REDACTED 
devi
devi
d ente
d ente
d locki
d lock
ns (
ns
COPY 
This document
algor
gor
all s
all s
cannot
nd wit
d wit
sible, 
ible, 
orith
rit
be
feasi
feas
used
teria 
eria 
tocol
ocol
to
on 
on 
f
support 
o:
viation
viation
eiti
any 
rs.
rs.
marketing
king 
ng
(ie, tho
(ie, tho
t) will b
 will
udy
udy ph
p
y
authorization 
iation
ation
ered, a
red, a
g th
g th
application
lorato
lorat
eriod w
eriod 
and 
d ot
d o
3.1) 
3.1) 
any
FAS
FAS
other
the
extensions
 th
If the 
If the
ndpoin
dpoin
S
or
hen 
hen
variations 
will
ill
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 199 of 267
Change #78
Section 13.7 Planned interim analysis and data monitoring
Paragraph 2, added the following after sentence 1:
The IDMC will oversee the safety of the study by reviewing safety data periodically. Details will 
be provided in an IDMC charter.
Change #79
16 REFERENCES
The following references were added:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
Olafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. 
Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy 
syndrome classification: a prospective study. Lancet Neurol. 2005;4:627-34.
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009;4:1832-43.
REDACTED COPY 
This document cannot be used to support any marketing authorization application 
;4:
in chil
chi
and
ment 
ent
:627
627
any
O, Ha
O, Ha
of
extensions 
nine. 
nine. 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 200 of 267
17.5
Protocol Amendment 3
Rationale for the amendment
In order to optimize study operations, ECGs will be evaluated locally and not centrally.
Specific changes
Change #1
Title page:
The title was updated from “Protocol SP0982 Amendment 2” to “Protocol SP0982 
Amendment 3.”
The information below was revised to include Protocol Amendment 3 and the type of protocol 
amendment:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Has been changed to:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
XX Dec 2014
Non-substantial
Change #2
The sponsor declaration page was deleted, as sponsor signatures are now captured electronically.
Change #3
Study contact information
Clinical Project Manager
Name:
, MBA, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
USA
Phone:
Fax:
PPD
PPD
REDACTED 
Date
Date
D
T
5
TE
CT
DA
R
COPY 
4
Y
C
This document 
dd
d
um
cannot t
dres
dres
nn
be
Proj
ro
b
used
ct in
t in
oje
oje
to 
nf
support 
page w
page 
any marketing 
g
ng
rk
m
authorization 
tio
5 Aug 
Aug
riz
25
25
ut
application 
n
at
pp
and 
N
d
an
a
any 
Type o
ype o
y
a
extensions 
ype of
pe o
y
e
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 201 of 267
Has been changed to:
Clinical Project Manager
Name:
, MSc
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Fax:
Change #4
Section 10.7.1.1 Overall ECG interpretation
Electrocardiograms will be initially reviewed locally by the investigator, subinvestigator, or 
qualified designated reader and also transmitted to and evaluated by a central ECG laboratory. If 
the reading identifies a second- or third-degree AV block 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 6.4). 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.
Has been changed to:
Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified 
designated reader. If the reading identifies a second- or third-degree AV block 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 6.4). The 
investigator may consult with a cardiologist 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.
REDACTED
to c
to c
ility
lity of
of
y
basis o
basis o
ipatio
ipatio
COPY
y is c
is 
y
ection
ection
con
con
This document cannot be
luen
uen
used 
y. I I
linica
inica
nce
nce
to 
nsu
It re
t re
support
on the
n the
n the s
n the
sult w
ult w
any 
idid
asses
asse
marketing 
ed loca
ed lo
dent
den
authorization
n 6.4
6.4
nfirm t
firm 
f the i
the i
of the
of the
n in th
in t
application 
by a
y
other a
ther a
en the E
n the 
onfirm
onfirm
4). T
)
and
tor, s
or, s
a ce
a c
any 
sub
extensions s
sio
or 
o variations 
on
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 202 of 267
17.6
Protocol Amendment 4
Rationale for the amendment
The primary purpose of this substantial amendment is to clarify elements of the study design 
including inclusion and exclusion criteria, exit criteria, and withdrawal criteria, as well as the 
duration of the Baseline Period, procedure for dividing the daily dose for the tablet formulation 
without breaking tablets, permitted and prohibited concomitant medication, consent for 
prescreening EEG, seizure count, temperature for storage of plasma samples, and determination 
of sample size. The protocol was also updated according to the new UCB protocol template, for 
example, with the addition of text regarding potential drug-induced liver injury (PDILI).
Modifications and changes
Specific changes
Change #1
Title page:
The title was updated from “Protocol SP0982 Amendment 3” to “Protocol SP0982 
Amendment 4.”
The information below was revised to include Protocol Amendment 4 and the type of protocol 
amendment:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
09 Jan 2015
Non-substantial
Has been changed to:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
09 Jan 2015
Non-substantial
Protocol Amendment 4
08 Jun 2016
Substantial
Date
Date
D
T
5
TE
CT
DA
R
COPY
col
col A
C
This document cannot
Am
Am
ocol A
col A
no
c
be
en
en
be 
end
n
be used
ment 
ent 
dme
dme
se
to 
1
to support 
mber
mber
rt
upp
any marketing 
g
ng
rke
m
authorization 
tio
5 Aug 
Aug
riz
25
25
ut
application
“Prot
Pro
mendm
mend
and any extensions 
I).)
or variations 
tion
ion
te, fo
e, fo
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 203 of 267
Change #2
STUDY CONTACT INFORMATION
Sponsor Study Physician
Name:
, MD, PhD
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Fax:
Clinical Project Manager
Name:
, MSc
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
, MA
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
USA
Phone:
Fax:
Interactive Voice/Web Response System
Name:
Perceptive eClinical Limited
Address:
Lady Bay House
Meadow Grove, Nottingham, NG23HF
UK
Phone:
+44 115 955 7333
Fax:
+44 115 955 7555
PPD
PPD
PPD
PPD
REDACTED 
D
CT
RE
CT
RE
COPY 
OP
This document 
m
um
cannot 
ess:s:
t be 
b
used
Voice
Voic
us
to
to sup
u
t
upport any 
h, N
h, 
A
a
marketing 
, MA
, MA
g
co Corp
o Cor
 NC 
NC
ke
ket
authorization 
ati
hor
application 
ap
and 
a
any 
a
extensions s
sio
xte
or 
o variations 
n
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 204 of 267
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 2421
USA:  +1 770 970 8858      
or +1 800 880 6949
or  +1 866 890 3175
Canada: +1 877 582 8842
Email
Global: DSICT.-@ucb.com
Has been changed to:
Sponsor Study Physician
Name:
, MD
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Email:
Clinical Project Manager
Name:
Address:
Allée de la Recherche 60
1070 Brussels
BELGIUM
Phone:
Email:
AC
REDAC
COPY 
PY
This document cannot 
ot be used 
d
u
to support 
Allée 
Allée
10
10
t
u
t a y
any market
m
keting 
thorization 
ho
autho
application 
at
pp
and any 
any extensions 
xte
or variations 
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 205 of 267
Clinical Trial Biostatistician 
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
USA
Phone:
Email:
Interactive Response Technology
Name:
Perceptive eClinical Limited
Address:
Lady Bay House
Meadow Grove, Nottingham, NG23HF
UK
Phone:
+44 115 955 7333
Fax:
+44 115 955 7555
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 2421
USA:        +1 800 880 6949
or  +1 866 890 3175
Email
Global: DS_ICT@ucb.com
Change #3
LIST OF ABBREVIATIONS
ALP
alkaline phosphatase
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EDC
electronic data capture
HLA
human leukocyte antigen
ICH
International Conference on Council for Harmonisation 
IRT
interactive response technology
IVRS/IWRS
interactive voice/web response system
MAO
monoamine oxidase 
REDACT
the W
the W
CTED 
rse eve
rse ev
D
80 6
80 6
CT
COPY 
PY
NG
NG
This document
HLA
HLA
I
cannot 
C
be used
RE
RE
to 
EV
EV
support 
S_I
S_IC
po
any 
CT
CT
ny marketing 
6949
6949
90 317
0 317
autho
World:
orld:
horization 
vent re
ent re
ati
ho
application 
n
ca
app
and any extensions 
sio
xt
or 
or variations 
on
on
on
on
ari
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 206 of 267
MAO-A
monoamine oxidase A
PDILI
potential drug-induced liver injury
PS
Patient Safety
RDC
remote data capture
These abbreviations have also been changed wherever they occur throughout the protocol.
Change #4
Section 1, SUMMARY
Paragraph 2
Approximately 200 subjects across approximately 150 sites in the US, Canada, Europe, Asia, 
and Australia, with possible extension to other countries and regions, are planned to be 
randomized in this study.
Paragraph 7
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); 
withdrawal due to AEs; changes in hematology, chemistry, endocrinology, and urinalysis 
parameters; changes in 12-lead electrocardiograms (ECGs); changes in vital sign measurements; 
and changes in physical and neurological examination findings. In addition, for pediatric subjects 
<18 years of age, safety will be evaluated using a behavioral assessment (Achenbach Child 
Behavior Checklist [CBCL]) and a cognitive function assessment (Behavior Rating Inventory of 
Executive Function® [BRIEF®]/Behavior Rating Inventory of Executive Function Preschool 
Version [BRIEF-P]).
Has been changed to:
Paragraph 2
Approximately 200 subjects across approximately 150 sites in the US, Europe, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized 
in this study.
Paragraph 7
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); 
withdrawal due to AEs; changes in hematology, chemistry, endocrinology, and urinalysis 
parameters; changes in 12-lead electrocardiograms (ECGs); changes in vital sign measurements; 
incidence of new seizure types, increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period; and changes in physical and neurological 
examination findings. In addition, for pediatric subjects <18 years of age, safety will be 
evaluated using a behavioral assessment (Achenbach Child Behavior Checklist [CBCL]) and a 
cognitive function assessment (Behavior Rating Inventory of Executive Function®
[BRIEF®]/Behavior Rating Inventory of Executive Function Preschool Version [BRIEF-P]).
REDACTED 
mina
mina
sing a
sing a
itive f
tive f
vior R
vior R
COPY
mistr
mist
ms (EC
(EC
natio
ati
This document 
ncid
ci
seizu
seiz
ex
ex
cannot
awal 
wal 
meter
meter
den
den
be
ed PG
ed P
d
used 
y obje
 obje
y
G
to support 
s ac
ac
extensi
xten
any 
cros
cro
marketing authorization
CGs
Gs
on fin
on fin
a beha
beha
functio
unctio
ating 
ting
application 
of LCM
f LCM
are ad
are ad
y, endo
 end
s); c
s); c
and any 
an
an
extensions 
a, Eur
, Eur
nned
nne
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 207 of 267
Change #5
Section 2, INTRODUCTION
Paragraph 1
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). Epileptic 
seizures occur in the context of a wide range of epilepsy syndromes that may be of genetic, 
structural/metabolic, or of unknown origin. The most common seizure type in patients with 
epilepsy is partial seizures (57%), followed by tonic-clonic (23%), absence (6%), and myoclonic 
(3%); the latter 3 seizure types comprise the majority of generalized seizures (convulsive and 
nonconvulsive) (Hauser et al, 1993).
Paragraph 8
Preliminary safety and PK data suggest that exposure-response in pediatric and adult subjects 
treated with LCM will be similar. Lacosamide is being evaluated in pediatric subjects 1 month to 
17 years of age in 3 ongoing studies: SP847 (open-label, Phase 2, PK, tolerability, and safety 
study), SP848 (open-label long-term safety study), and SP1047 (PK study with a 1-day 
evaluation period).
Has been changed to:
Paragraph 1
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated to affect 
almost 70 million people worldwide (Ngugi et al, 2011). Epileptic seizures occur in the context 
of a wide range of epilepsy syndromes that may be of genetic, structural/metabolic, or of 
unknown origin. The most common seizure type in patients with epilepsy is partial seizures 
(57%), followed by tonic-clonic (23%), absence (6%), and myoclonic (3%); the latter 3 seizure 
types comprise the majority of generalized seizures (convulsive and nonconvulsive) (Hauser et 
al, 1993).
Paragraph 8
Preliminary safety and PK data suggest that exposure-response in pediatric and adult subjects 
treated with LCM will be similar. Lacosamide has been evaluated in 2 completed pediatric 
studies, both in subjects aged 1 month to 17 years (SP847 [open-label, adjunctive therapy, 
pharmacokinetic study in partial-onset seizures] and SP1047 [open-label pharmacokinetic study 
in epilepsy]). Subjects from SP847 were also able to enroll into an ongoing open-label long-term 
safety study (SP848). In addition, lacosamide is being evaluated in the following ongoing 
pediatric efficacy and safety studies: 
•
SP0967 (ages ≥1 month to <4 years) as adjunctive therapy in partial-onset seizures
•
SP0969 (ages ≥4 to <17 years) as adjunctive therapy in partial-onset seizures 
•
EP0034, open-label extension study to SP0967 and SP0969
•
SP0966 (ages ≥1 month to <18 years) as adjunctive therapy, exploratory study in subjects 
with epilepsy syndromes associated with generalized seizures
REDACTED 
logica
logica
ugi
ugi et 
et
s that m
s that m
seizu
seizu
%
COPY 
This document 
•
cannot 
udy
ric eff
ric eff
SP0
SP0
be 
). S
y (S
y (S
used
ubjb
ic stu
c stu
Sub
Sub
to
ject
jec
support 
PK dat
PK da
l be s
l be s
any marketing
ure ty
ure ty
%), abse
%), abs
eralize
raliz
authorization 
al diso
l diso
alal, 20
, 20
may b
may b
application
PK st
PK s
and 
dia
dia
K, tole
K, tole
t
any
c and
c an
atric 
atric 
extensions
sive
ive
nd
nd
or 
yo
yoc
e a
e a
variations 
clo
clo
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 208 of 267
Change #6
Sections 4.1.2 and 9.2, Secondary efficacy variables
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures for the 24-week Treatment Period
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days from the Combined Baseline 
(combined 12-week Historical and 4-week Prospective Baseline) to the first 6 weeks of the 
Treatment Period
•
The percent change in PGTC seizure frequency per 28 days from Combined Baseline to the 
24-week Treatment Period
•
Time to the first PGTC seizure during the 24-week Treatment Period
Sections 4.1.3 and 9.3, Other efficacy variables
Other efficacy variables are:
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
first 6 weeks of the Treatment Period
•
Percent change in days with absence seizures per 28 days from the Combined Baseline to the 
24-week Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the first 6 weeks of the Treatment Period
•
Percent change in days with myoclonic seizures per 28 days from the Combined Baseline to 
the 24-week Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period 
among subjects who completed the first 12 weeks of the Treatment Period
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the first 12 weeks of the Treatment 
Period among subjects who completed the first 12 weeks of the Treatment Period
•
Seizure-free status (yes, no) for all seizure types for the 24-week Treatment Period among 
subjects who completed the 24-week Treatment Period
•
50% response for PGTC seizures during the first 6 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 6 weeks of the Treatment Period 
•
50% response for PGTC seizures during the first 12 weeks of the Treatment Period; a 
responder is a subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days 
from the Combined Baseline to the first 12 weeks of the Treatment Period
REDACTED 
ic seiz
ic sei
Period
Period
oclo
oclo
COPY 
s per 2
per 2
This document
r
cannot
jects
cts
50% 
50% 
es
be
e-fre
fre
used
tat
ta
ong su
ng su
to
atus 
tus
support 
es, no)
es, no
pleted 
leted
(
any 
fo
pleted
leted
marketing 
onic se
nic se
or PG
r PG
authorization
28 da
28 da
zures 
zures 
d
application 
from t
from
ay
and any extensions 
Baseli
asel
or
of 
of
variations 
ne
f th
f th
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 209 of 267
•
50% response for PGTC seizures during the 24-week Treatment Period; a responder is a 
subject experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the 
Combined Baseline to the 24-week Treatment Period
•
50% response for days with absence seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with absence seizures per 
28 days from the Combined Baseline to the 24-week Treatment Period
•
50% response for days with myoclonic seizures during the 24-week Treatment Period; a 
responder is a subject experiencing ≥50% reduction in days with myoclonic seizures per 
28 days from the Combined Baseline to the 24-week Treatment Period
•
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or 
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age
•
Change from Baseline to end of treatment or ET in the 3-Level EuroQol-5 Dimension 
Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age)
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject
•
Number of days with help from a caregiver
Have been changed to:
Sections 4.1.2 and 9.2, Secondary efficacy variables
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures during the 24-week Treatment Period, estimated using 
Kaplan-Meier analysis
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline) 
•
The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline
•
Time to the first PGTC seizure during the Treatment Period
REDACTED
ures, h
ures, 
ost by
ost by
a care
a care
COPY
analo
analo
or subj
or sub
This document
r
•
cannot
toric
oric
The 
The 
be
ment P
ment 
used 
dary
ary
nt ch
nt ch
to 
y efef
y
support 
PGTC
PGTC
alylysis
sis
any 
ariabl
ariab
marketing
egive
giv
ry effi
y ef
authorization
bject
ect
hospit
hospit
y subje
subj
y
ver
ver
application 
-Level
Leve
gue sc
gue s
s ≥
and
eds
ds
hool
hoo
any
18 y
8 ye
sQL
sQL
extensions 
ory
ry-F
-F
ng,g,
ionin
onin
or 
p
variations 
er 
er 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 210 of 267
Sections 4.1.3 and 9.3, Other efficacy variables
Other efficacy variables are:
•
Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline
•
Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Prospective Baseline
•
Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline
•
Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Prospective Baseline
•
Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline
•
Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline
•
Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period 
•
Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period 
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
first 12 weeks of the Treatment Period compared to Combined Baseline 
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Treatment Period compared to Combined Baseline 
•
Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period 
•
Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period 
•
Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory 
form 31 (QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or 
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age
•
Change from Baseline to end of treatment or ET in the 3-Level EuroQol-5 Dimension 
Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age)
REDACTED 
C seiz
C seiz
PGTC
PGTC
COPY 
ductio
ducti
This document
Q
cannot
nge 
ge 
rm 31
31
Ener
Ener
Q
be 
e fro
e fro
used
e statu
stat
to 
d 
support
ared
ared
(yes, n
es, n
any
h at le
at l
ed to
ed t
marketing
C se
se
st a 50%
st a 50
t Perio
Perio
ea
authorization
on in
on in
zures 
ures 
eizu
eizu
application
e Bas
e Bas
ay
ays du
s d
and 
ing th
ng th
any 
en
extensions 
ompar
mpar
nt Pe
t Pe
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 211 of 267
•
Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits
•
Number of working or school days lost by subject due to epilepsy
•
Number of days with help from a caregiver due to epilepsy
Change #7
Section 4.2, Safety variables
New bullet points
•
Incidence of new seizure types during the Treatment Period
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
Change #8
Section 5.1, Study description
Paragraph 2
Approximately 200 subjects across approximately 150 sites in the US, Canada, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized 
in this study.
Paragraph 4
Eligibility to enter SP0982 will be based on a 12-week Historical Baseline prior to screening at 
Visit 1. Subjects with a confirmed diagnosis of IGE with uncontrolled PGTC seizures, who had 
≥2 documented PGTC seizures in the 12-week Historical Baseline, with ≥1 PGTC seizure during 
the first 8 weeks of the Historical Baseline will enter a 4-week Prospective Baseline. In addition, 
to be eligible for randomization, the subject must have ≥1 PGTC seizure during the last 4 weeks 
of the Historical Baseline or the 4-week Prospective Baseline. Thus, a total of ≥3 PGTC seizures 
in the 16-week Combined Baseline Period (12-week Historical and 4-week Prospective Baseline) 
are required for study randomization to treatment (see Section 6.1, Inclusion Criterion 5). 
A schematic diagram for the Combined Baseline Period seizure eligibility is provided in 
Figure 5-1.
Have been changed to:
Paragraph 2
Approximately 200 subjects across approximately 150 sites in the US, Asia, and Australia, with 
possible extension to other countries and regions, are planned to be randomized in this study.
REDACTED 
mately
mately
er coun
r cou
COPY 
This document
Para
ara
Ap
A
cannot 
1.1.
e be
be
ag
be 
c di
used
om
om
r stud
stud
diagr
iagr
to
mbin
mbi
support 
toric
oric
mizatio
mizati
line o
line o
any
s in th
s in t
cal
marketing 
based o
ased 
d diag
ia
authorization 
y 150 
150 
y
ntries 
ntries
application and
relat
rela
any 
, and 
 and
tiv
ti
extensions 
% in t
% in t
he Pro
e Pro
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 212 of 267
Paragraph 4
Eligibility to enter SP0982 will be based on a 12-week Historical Baseline prior to screening at 
Visit 1. In rare cases where there is a gap between consenting and Visit 1 procedures, the 
12-week Historical Baseline will be calculated from the date of Informed Consent/Assent. 
Prior to randomization, the following 3 criteria concerning PGTC seizure frequency must be met: 
•
The subject must have experienced at least 3 PGTC seizures during the 16-week Combined 
Baseline Period, 
•
The subject must have experienced at least 2 PGTC seizures during the 12-week Historical 
Baseline Period, 
•
Of the above seizures, at least 1 PGTC seizure should have occurred during the first 8 weeks 
and at least 1 PGTC seizure should have occurred during the second 8 weeks of the 16-week 
Combined Baseline Period. 
Examples of different scenarios and the subjects´ eligibility in terms of Baseline Period seizures 
are presented in a table in Inclusion Criterion 5. A schematic diagram for the Combined Baseline
Period seizure eligibility is provided in Figure 5-1.
Change #9
Section 5.1.4, Anticipated sites and regions
The study is planned to be conducted in the US, Canada, Asia, and Australia, with possible 
extension to other countries and regions.
Has been changed to:
The study is planned to be conducted in the US, Asia, and Australia, with possible extension to 
other countries and regions.
Change #10
Table 5‒1: Schedule of study assessments for SP0982 (Prospective Baseline, Titration 
Period, Maintenance Period, ET Visit, and Unscheduled Visits)
The following footnote has been added to Visit 1
bb
Participation in the study starts from the time of signing the approved Informed 
Consent/Assent form. However, sites may conduct prescreening EEGs and prior to this,
subjects will read and sign a separate Informed Consent form that has been approved by an 
IRB/IEC and the Sponsor, and which complies with regulatory requirements.
Change #11
Table 5‒1: Schedule of study assessments for SP0982 (Prospective Baseline, Titration 
Period, Maintenance Period, ET Visit, and Unscheduled Visits)
Footnote o
o
Urinalysis will be required for subjects ≥5 years of age only.
REDACTED
US, C
US, C
d in
d in
COPY 
Ca
C
This document
Tabl
Tabl
Pe
Pe
cannot
IEC
IEC
ange
ange
be
s wi
wi
C
used
in t
n t
Assent
ssent
ill
ill
to 
the
the
support 
dy
dy
eriod, 
iod,
e has 
e has
any 
y ass
y ass
marketing 
n the U
the U
authorization 
anada,
nada,
application 
ram
and
of Ba
f Ba
m fo
m fo
any 
ase
extensions 
i
the fi
the f
eeks o
eks o
or
tori
tor
variations 
d 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 213 of 267
Table 5‒2: Schedule of study assessments for SP0982 (Transition Period)
Footnote i
i
Urinalysis will be required for subjects ≥5 years of age only.
Table 5‒3: Schedule of study assessments for SP0982 (Taper Period and Safety Follow-up 
Period)
Footnote f
f
Urinalysis will be required for subjects ≥5 years of age only.
Table 10-2: Laboratory tests
Footnote b
b
Urinalysis will be required for subjects ≥5 years of age only.
Have been changed to:
Table 5‒1: Schedule of study assessments for SP0982 (Prospective Baseline, Titration 
Period, Maintenance Period, ET Visit, and Unscheduled Visits)
Footnote o
o
Urinalysis will be required for all subjects.
Table 5‒2: Schedule of study assessments for SP0982 (Transition Period)
Footnote i
i
Urinalysis will be required for all subjects.
Table 5‒3: Schedule of study assessments for SP0982 (Taper Period and Safety Follow-up 
Period)
Footnote f
f
Urinalysis will be required for all subjects.
Table 10‒2: Laboratory measurements
Footnote b
b
Urinalysis will be required for all subjects.
REDACTED 
r S
r S
ubject
ubjec
ssme
ssme
COPY 
SP0
SP0
This document cannot be used
will b
ll b
to 
be
be
support 
y meas
mea
any 
d for a
d for 
marketing
ents f
ents f
authorization 
0982 (
982 (
ts.s.
application 
ts)
ts)
and 
ve Ba
e Ba
any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 214 of 267
Change #12
Figure 5‒1: Combined Baseline Period seizure eligibility for SP0982
Has been changed to:
Figure 5‒1: Combined Baseline Period seizure eligibility for SP0982
Change #13
Section 5.4.1, Rationale for dose
Paragraph 2
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, as 
well as on information available in the medical literature, the pediatric dosing recommendations 
for SP0982 are to achieve LCM plasma concentrations similar to the average steady-state LCM 
plasma concentration reached after a LCM 400mg/day dose administration in adult studies, 
which is approximately 8μg/mL.
Has been changed to:
Paragraph 2
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, as 
well as on information available in the medical literature, the pediatric dosing recommendations 
REDACTED COPY 
This document
whic
hic
Ha
Ha
cannot
982 
982 
ma co
ma co
ch
ch
be
infor
info
used 
curre
curre
to support 
nale fo
ale fo
an
any marketing authorization 
cation 
r SP09
SP0
applica
and any 
ions 
xtension
ext
r
or 
ations 
tio
variatio
v
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 215 of 267
for SP0982 are to achieve LCM plasma concentrations similar to the average steady-state LCM 
plasma concentration reached after a LCM 400mg/day dose administration in adult studies.
Paragraphs 3 and 4 have been added: 
A population PK model (CL0177) was developed using plasma concentration data and 
demographic information from all pediatric subjects in SP847 and SP1047. The data consisted of 
402 LCM plasma concentration-time records obtained in 79 children, with a balanced 
distribution of 14, 22, 25, and 18 subjects in the age groups 6 months to <2 years, 2 to <6 years, 
6 to <12 years, and 12 to <18 years, respectively. Body weights ranged from 6kg to 76kg. 
Different pediatric dosing adaptation schemes were simulated with the aim of reaching the range 
of average steady-state plasma concentration (CSS,ave) obtained in adults receiving LCM 
400mg/day, which is approximately 8μg/mL (90% prediction interval: 5μg/mL to 12μg/mL). 
This was achieved with a dosing scheme of 12mg/kg/day in children weighing <30kg, 
8mg/kg/day in children weighing from 30 to <50kg, and 400mg/day in children weighing ≥50kg. 
The proportional pediatric dose adaptation corresponding to 300mg/day in adults and in children 
weighing ≥50 kg, are 8mg/kg/day in children weighing <30kg, and 6mg/kg/day in children 
weighing from 30 to <50kg.
Change #14
Section 6.1, Inclusion criteria
5. Subject has ≥3 PGTC seizures during the 16-week Combined Baseline (12-week Historical 
Baseline plus 4-week Prospective Baseline) distributed as described below:
•
≥2 PGTC seizures during the 12-week Historical Baseline with ≥1 PGTC seizure during first 
8 weeks of the Historical Baseline, and
•
≥1 PGTC seizure during the second 8 weeks of the Combined Baseline (ie, during the last 
4 weeks of the Historical Baseline or during the 4-week Prospective Baseline) 
7. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with at least 1 AED identified as a benzodiazepine) for at least 
28 days prior to Visit 1 with or without additional concurrent stable VNS (see Section 7.8).
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline and 
Treatment Period.
Have been changed to:
5. Subject has ≥3 PGTC seizures during the 16-week Combined Baseline (12-week Historical 
Baseline plus 4-week Prospective Baseline) distributed as described below: 
−
at least 3 PGTC seizures should have occurred during the 16-week Combined Baseline 
Period, 
−
at least 2 PGTC seizures should have occurred during the 12-week Historical Baseline 
Period, 
REDACTED 
6-w
ine) d
ine) d
ek Hi
ek Hi
ne, and
ne, and
COPY 
wee
we
This document cannot 
ubject 
bject 
Basel
Base
be
en c
en c
used
ng
Period
eriod
ch
to
gs fo
s fo
support 
(w
(w
t 1 with
1 wi
ulatio
ulatio
any
d on
d on
with a
with
marketing 
d
nd 8 we
nd 8 w
line or 
ne or
n a
n
authorization 
ek Co
k Co
distribu
stribu
storic
toric
application and 
ay i
y
6mg/k
mg/k
any
ildre
ldre
in ad
n a
extensions
ng th
g th
LCM 
LCM
to 12
to 12
ng <30
g <30
en
or 
he
he
variations 
ars, 
ars, 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 216 of 267
−
of the above seizures, at least 1 PGTC seizure should have occurred during the first 
8 weeks and at least 1 PGTC seizure should have occurred during the second 8 weeks of 
the 16-week Combined Baseline Period. 
The schematic diagram for the Combined Baseline Period eligibility is provided in Figure 5‒1. 
Examples of PGTC seizure frequency and eligibility are provided in the table below: 
Number of PGTC seizures
Is subject eligible?
(In terms of 
Inclusion Criterion 5)
Historical Baseline
Weeks -16 to -8 
Historical Baseline
Weeks -8 to -4 
Prospective Baseline
Weeks -4 to 0
(Visit 1 to Visit 2)
2
1
0
Yes
3
0
0
No*
1
1
1
Yes
0
2
1
No
1
2
0
Yes
2
0
1
Yes
1
0
2
No
1
1
0
No*
Screening Visit
*Eligible to roll over to EP0012 if all other inclusion criteria are also met.
PGTC=primary generalized tonic-clonic
7. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine, see examples in the 
table below) for at least 28 days prior to Visit 1 with or without additional concurrent stable 
VNS (see Section 7.8).
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline and 
Treatment Period.
REDACTED 
D 
er inc
er inc
COPY 
Y
O
CO
This document cannot be used
ings
ngs
Perio
Peri
to
mul
mu
s f
s f
support 
t 28
28
8).).
ulati
ulat
any
with 1 
with 1
da
d
marketing 
clusion c
lusion 
on a s
n a 
autho
Scree
Scree
rization 
n
at
horiza
application 
1
tio
2
pli
a
and 
a
any 
a
extensions 
r
Y
on
en
e
or
terio
terio
variations 
ble?
e?
f f
n
on thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 217 of 267
Benzodiazepine AEDs
Non-Benzodiazepine AEDs
Total AEDs
Is subject eligible?
(In terms of 
Inclusion Criterion 7)
0
1
1
Yes
0
2
2
Yes
1
1
2
Yes
1
2
3
Yes
1
0
1
No
0
3
3
No
2
1
3
No
AED=antiepileptic drug
Change #15
Section 6.2, Exclusion criteria
1. Subject has previously participated in this study or subject has previously been assigned to 
treatment in a study of LCM.
12. Subject has any history of alcohol or drug abuse within the previous 2 years. 
15. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥2x the upper limit of normal (ULN) or has alkaline phosphatase levels 
≥3xULN at Visit 1.
17. Subject has a known sodium channelopathy, such as Brugada syndrome.
22. Subject has been taking 1 or more of the following medications on a regular basis within 
28 days prior to Visit 1: neuroleptics, monoamine oxidase (MAO) inhibitors, barbiturates (for 
indications other than epilepsy), or narcotic analgesics.
23. Subject with concomitant treatment of felbamate or previous felbamate therapy within the 
last 6 months prior to Visit 1.
25. Subject is on a ketogenic diet. 
If the investigator has any doubts concerning the subject’s eligibility, he/she should consult the 
UCB Study Physician or representative for clarification.
Have been changed to:
1. Subject has previously been randomized in this study or subject has previously been assigned 
to treatment in a clinical study of LCM.
12. Subject has any history of alcohol, opioid, or other drug use disorder, as per Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), within the previous 2 years. 
Note: previous sporadic cannabis use is not exclusionary as long as subject is requested and 
agrees not to use cannabis during the study.
15. At Visit 1, subject has ≥2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
REDACTED
T), a
T), a
ormal
ormal
annelo
annelo
COPY 
se with
e with
asp
asp
This document 
12.
12.
cannot 
ee
ee
Subjec
ubjec
to tr
to t
be 
en c
en c
used
or ha
r ha
hy
hysic
sic
to 
et
as
support
nt t
nt t
o Visit 
Visi
togen
ogen
any 
sy
sy)
trea
trea
marketing
opath
pat
e of the
e of th
leptics,
eptic
), or
) o
authorization 
thi
partat
artat
l (ULN
(ULN
athth
application 
has pre
as pr
in the
n the
and any extensions 
N
N
s
si
xt
or 
o
variations 
n
on
at
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 218 of 267
>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 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. This includes re-screening.
17. Subject has a known cardiac channelopathy, such as Brugada syndrome.
22. Subject has been taking 1 or more of the following medications on a regular basis within 
28 days prior to Visit 1: monoamine oxidase A (MAO-A) inhibitors, barbiturates (for 
indications other than epilepsy), or clozapine.
23. 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.
25. 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. 
Subjects may be rescreened with prior consultation and permission of the Medical Monitor. If 
the investigator has any doubts concerning the subject’s eligibility, he/she should consult the 
UCB Study Physician or representative for clarification.
Change #16
Section 6.3, Exit criteria
Last paragraph
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure.
Has been changed to:
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure, 
with the following exception: if the 2 PGTC seizures occur during the first 6 weeks of the 
Treatment Period (after randomization), the subject should continue the Titration Period visits 
and wait for the end of the first 6 weeks of the Treatment Period to complete the ET Visit.
REDACTED 
ted
ted
oxicity
oxicity
as
as eith
eith
udy
udy.
COPY
expe
exp
this tr
this 
d wi
d w
This document
Once
nce
to c
to c
a
cannot 
been
been
ce t
e t
be
wh
have
hav
used
ct has
has
hethe
ethe
to support 
ia
any marketing 
r consu
consu
ncernin
ernin
tative
tativ
authorization 
trea
ea
th fel
th fe
y issue
issu
y
her 
er ch
ch
application 
hibito
bito
ien
enced
ce
atme
atm
and
on a r
n a r
or
any 
me.
me.
extensions 
mu
may
may b
y
or
ust b
ust 
variations 
ing,
ng,
alllly y 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 219 of 267
Change #17
Section 6.4, Withdrawal criteria 
Bullet point 15
•
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 drug.
Investigators should attempt to obtain information on subjects, in the case of withdrawal or 
discontinuation. For subjects considered lost to follow-up the investigator should make an effort 
(at least 1 telephone call and 1 written message to the subject), and document his/her effort (date 
and summary of the telephone call and copy of the written message in the source documents), to 
complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The electronic case report form (eCRF) must document the primary reason for 
withdrawal or discontinuation.
Has been changed to:
•
Discontinuation criteria for potential drug-induced liver injury (PDILI) are described in 
Section 6.4.1.
Investigators should attempt to obtain information on subjects in the case of withdrawal. For 
subjects considered as lost to follow up, the investigator should make an effort (at least 1 phone 
call and 1 written message to the subject), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The 
electronic Case Report form (eCRF) must document the primary reason for withdrawal.
Change #18
A new section has been added:
Section 6.4.1, Potential drug-induced liver injury IMP discontinuation criteria
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. 
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 
The PDILI criterion below requires immediate discontinuation of IMP:
REDACTED 
ormati
rmati
, the i
the i
bject),
bject),
es
es
COPY 
duced 
duced
This document 
•
S
cannot
dical
ical
e PDIL
PDI
be
scon
scon
l
used 
oten
ten
poten
poten
to
entia
nti
support 
n add
n add
any
CRF
CRF
marketing
, and
an
ssage in
sage in
uations
ation
subjec
subje
)
authorization
live
ive
ion on
on on
invest
nvest
nd d
nd
application 
nt th
t t
er in
er i
and
be re
e re
the
he
any 
ou
ou
ations
ation
co
extensions
rawal 
awal 
make
make
his/he
his/h
urce
urce
or variations 
ng 
ng 
ator is
tor is
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 220 of 267
•
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).
Evaluation of PDILI must be initiated as described in Section 10.2.1. 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.
Change #19
Section 7.2, Treatments to be administered
Paragraph 2
At Visit 2, subjects will be randomized to receive either LCM (oral solution for pediatric subjects 
[≥4 to <18 years of age] weighing <50kg or tablets for adult subjects [≥18 years of age] and 
pediatric subjects weighing ≥50kg) or matching placebo. At the end of Visit 2, subjects should 
take the first dose of study drug while in the clinic.
Has been changed to:
At Visit 2, subjects will be randomized to receive either LCM (oral solution for pediatric subjects 
[≥4 to <18 years of age] weighing <50kg or tablets for adult subjects [≥18 years of age] and 
pediatric subjects weighing ≥50kg) or matching placebo. At the end of Visit 2, subjects should 
take the first dose of study drug while in the clinic. Treatment assigned will be determined by the 
subject’s weight at Visit 2.
Paragraph 3
The following text has been added: 
Tablets are 50mg and must not be broken; instead unequal dosing is allowed – if subjects are 
taking an odd number of tablets per day (eg, 7 tablets totaling 350mg), they should take the 
lower dose in the morning (eg, 150mg [3 tablets]) and the higher dose in the evening (eg, 200mg 
[4 tablets]).
d to re
d to re
50kg
50kg
COPY 
This document
ab
takin
takin
lolo
cannot 
llowin
llowin
blets 
lets 
be 
 3 3
used 
e of
o
ht at V
t at V
o
ei
of st
f st
support
e rand
ran
] weigh
weig
ghing
ghing
any 
do
d
marketing
g or ta
g or t
r match
r matc
hile in t
ile in
authorization 
eceive
ceive
application 
sub
sub
RF mu
RF m
and
evalu
valu
ubje
bje
any 
f I
drawn
draw
at
extensions 
re una
e una
mmedia
media
IMP
MP
or 
(
variations 
(eg, 
(eg, 
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 221 of 267
Change #20
Section 7.2.3, Transition Period (for subjects who enter EP0012)
Paragraph 1
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period, or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24) respectively, choose to continue in EP0012. 
Subjects completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded 
transition followed by a Final Clinic Visit. Two weeks after Visit 10 (Week 24) or the ET Visit, a 
Transition telephone contact is required; a subsequent Clinic Visit is at the discretion of the 
investigator (Table 5‒2). The Final Clinic Visit is the same as Visit 1 of EP0012.
Has been changed to:
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24) respectively, choose to continue in EP0012. 
Subjects completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded 
transition followed by a Final Clinic Visit. Two weeks after Visit 10 (Week 24) or the ET Visit, a 
Transition telephone contact is required; a subsequent Clinic Visit is at the discretion of the 
investigator (Table 5‒2). The background AED may be adjusted during the Transition Period at 
the discretion of the investigator. The Final Clinic Visit is the same as Visit 1 of EP0012.
Change #21
Section 7.5, Handling and storage requirements
Paragraphs 1 to 3
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.
Appropriate storage conditions must be ensured by controlled room temperature and by 
completion of a temperature log (showing minimum and maximum temperatures reached over 
the time interval) in accordance with local requirements on a regular basis.
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Clinical Project Manager (CPM) (or designee) before further use of the IMP and communicated 
to the sponsor’s designee in accordance with the pharmacy manual.
Have been changed to:
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 (eg, room, 
refrigeration unit) or by completion of a temperature log (showing actual and 
minimum/maximum temperatures reached over the time interval) in accordance with local 
requirements on a regular basis.
quirem
quirem
COPY 
t Cl
t C
ay
ay be a
be 
y
c Vis
c Vi
This document 
he 
he
Inve
Inve
lim
li
annot
e bee
bee
e inv
inv
be
nsor’
nsor’
used
f-ran
ran
ct Ma
ct Ma
to 
ng
ng
support
tions 
ions
ature lo
ture 
ccord
ccord
any 
s m
marketing 
ponsibl
onsib
stored
store
authorization
sit is 
sit is 
ments
ment
application
mplet
mple
Visit 10
isit 10
ic Visi
c Vis
djuste
djust
h
and 
com
om
oose t
ose t
t
any
ring
ring
mes f
mes
extensions
of t
of t
g t
or
T V
T V
the
th
variations 
2. 
2. 
Vis
Vis
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 222 of 267
In case an out-of-range temperature is noted, it must be immediately reported as per the 
instructions contained in the IMP Handling Manual.
Change #22
Section 7.6, Drug accountability
Paragraph 1 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost (due to breakage or wastage), not used, disposed of at the study site, or returned to 
the sponsor’s 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.
Paragraph 5
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. Investigational medicinal product intended for the study 
cannot be used for any other purpose than that described in this protocol.
Have been changed to:
Paragraph 1
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’s 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.
Paragraph 5
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 (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol.
Change #23
Section 7.8.1, Permitted concomitant treatments (medications and therapies)
Paragraph 1
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with at least 1 AED identified as a benzodiazepine) for at least 28 days 
prior to Visit 1 and during the Prospective Baseline and Treatment Period with or without 
additional concurrent stable VNS.
REDACTED 
o reco
reco
e docu
e docu
age or
age or
r’s d
r’s d
COPY 
This document
Para
ara
Su
Su
cannot 
 
on 
n 7.8
7.8
agr
ag
be
#23
23
used
tigat
iga
that d
hat d
to
e ac
e ac
atio
atio
support
comp
comp
sed, un
ed, u
ccor
cco
any marketing 
r w
design
esign
tation m
ation
authorization 
rd I
d IM
ument
ment
wast
wast
application 
urn
roduct
roduc
his pro
his pro
nd
y, all
 all
ned 
ned 
any 
l us
l u
extensions 
and 
and 
(or de
or de
or
urne
urn
variations 
n a
n a
etails 
tails
d
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 223 of 267
Bullet point 2
•
The chronic (daily dose) use of benzodiazepines is allowed regardless of indication and will 
be counted as 1 of the 3 allowed AEDs.
Paragraph 2
Contraceptive treatment is allowed as described in in Section 6.2 (Exclusion Criterion 21). 
Have been changed to:
Paragraph 1
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to 
Visit 1 and during the Prospective Baseline and Treatment Period with or without additional 
concurrent stable VNS.
Bullet point 2
•
The chronic (daily dose) use of a benzodiazepine is allowed regardless of indication and will 
be counted as 1 of the 3 allowed AEDs.
Paragraph 2
Contraceptive treatment is allowed as described in in Section 6.2 (Exclusion Criterion 21). 
Recommended contraception methods for subjects on enzyme-inducing antiepileptic drugs 
(EI-AEDs) or not on EI-AEDs are detailed in Section 17.8.
The following paragraph has been added (Paragraph 4): 
Neuroleptics (except for clozapine) are allowed during the study but the investigator should 
make every effort to keep the dose stable. 
Change #24
Section 7.8.2, Prohibited concomitant treatments (medications and therapies)
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics.
•
MAO inhibitors.
•
Barbiturates (except as antiepileptic medications).
•
Narcotic analgesics.
•
Only stable, low doses (<50% of the maximum daily dose recommended by the 
country-specific product label) of non-benzodiazepine anxiolytics or once-daily hypnotics 
are allowed for nonepilepsy indications.
Has been changed to:
The following medications/therapies are prohibited during the course of this study:
•
Clozapine.
•
MAO-A inhibitors.
REDACTED
ect
n Sect
n Sec
d (Par
d (Pa
are all
are all
ab
ab
COPY 
n in Se
n S
ts on
ts on
This document 
c
cannot
otic
otic
Only
Only s
y
cou
cou
be 
ic a
ic a
used 
orsrs
es (e
es (e
to 
s
support
ns/ther
/the
any
comi
com
marketing
lowe
ow
ble.
le.
t
authorization 
ect
n enzy
n enzy
tion 1
ion 1
ragrap
ragra
wed
wed
application 
ga
tion 6
ion 6
and 
ardle
rdle
any extensions
mark
mark
28 day
8 day
out ad
out ad
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 224 of 267
•
Barbiturates (except as antiepileptic medications).
•
Patients taking non-benzodiazepine anxiolytics or once-daily hypnotics must remain on 
stable doses of these medications throughout the study.
Change #25
Section 7.10, Randomization and numbering of subjects
First paragraph
An IVRS/IWRS will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by UCB. The 
randomization schedule will be produced by the UCB Clinical Trial Supply Officer who is 
otherwise not involved in this study. The IVRS/IWRS will generate individual assignments for 
subject kits of IMP, as appropriate, according to the visit schedule.
Last paragraph
To randomize a subject (Visit 2), the investigator (or designee) will contact the IVRS/IWRS and 
provide brief details about the subject to be randomized. The IVRS/IWRS will automatically 
inform the investigator (or designee) of the subject’s randomization number. The IVRS/IWRS 
will allocate kit numbers to the subject based on the subject number during the course of the 
study. 
Has been changed to:
First paragraph
An IRT will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by UCB. The 
randomization schedule will be produced by the IRT Vendor who is otherwise not involved in 
this study. The IRT will generate individual assignments for subject kits of IMP, as appropriate, 
according to the visit schedule.
Last paragraph
To randomize a subject (Visit 2), the investigator (or designee) will contact the IRT and provide 
brief details about the subject to be randomized. The IRT will automatically inform the 
investigator (or designee) of the subject’s randomization number. The IRT will allocate kit 
numbers to the subject based on the subject number during the course of the study. The 
randomization number must be incorporated into the eCRF.
Change #26
Section 8.1.1, Visit 1 (Week -4) 
Paragraph 2
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 and the subject’s 
parent/legal guardian (for subjects <18 years of age) by the investigator (or designee). The 
IRB-approved Informed Consent/Assent Form must be signed and dated by the subject, or 
his/her legal representative, and by the person who conducted the informed consent/assent 
discussion (investigator or designee).
REDACTED 
ible su
ible su
ation 
ation 
c
COPY 
ub
This document
P
t
ara
ara
P
cannot
ge #
e #
tion 8
on 8
be 
on
#2
#26
used
subje
ubje
n num
n nu
to
igne
ign
support 
(Visit 2
Visit
subje
subje
ee
any marketing
and/
and
ced b
ed by
ndividu
dividu
authorization 
ubject
ubjec
d/o
d/o
application 
S/I/IW
zation n
ation 
numb
numb
and
conta
onta
W
any extensions 
B. T
. T
er r who
who
assign
ssign
or
on
o
Th
Th
variations 
on a
n a
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 225 of 267
Has been changed to:
Paragraph 3
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 and the subject’s 
parent/legal guardian (for subjects <18 years of age) by the investigator (or designee). The 
IRB/IEC-approved Informed Consent/Assent form must be signed and dated by the subject, or 
his/her legal representative, and by the person who conducted the informed consent/assent 
discussion (investigator or designee). Participation in the study starts from the time of signing the 
IRB/IEC-approved Informed Consent/Assent form. 
Paragraph 4
The following text has been added:
Sites may conduct prescreening EEGs and prior to this, subjects will read and sign a separate 
Informed Consent form that has been approved by an IRB/IEC and the Sponsor, and which 
complies with regulatory requirements.
Change #27
Section 9.3.1, Seizure frequency
During the study, subjects will keep a diary to record daily seizure activity from Visit 1 until the 
end of study participation. The subject should be reminded to bring the diary to each clinic visit. 
The following information will be recorded on a daily basis as applicable:
•
Seizure type
•
Number of seizures 
Investigators should advise subjects and/or caregivers about the importance of reporting 
non-PGTC seizures. Subjects should be reminded that diaries must include daily entries even if 
no seizures have occurred.
Has been changed to:
Section 9.3.1, Seizure variables
Subjects will keep a diary to record daily seizure activity from Visit 1 until the end of study 
participation. Efficacy and safety variables will be assessed using the seizure count information 
recorded on the subject diaries. Subjects should be reminded that diaries must include daily 
entries even if no seizures have occurred. The subject should be reminded to bring the diary to 
each clinic visit. 
9.3.1.1 PGTC seizures
The following information will be recorded on a daily basis as applicable:
•
Seizure type
•
Number of PGTC seizures
If more than one PGTC seizure occurs on a single day, each seizure should be counted 
separately, provided there is a complete recovery of consciousness between seizures.
REDACTED 
be 
be 
on a d
on a d
COPY 
ord da
rd d
rem
rem
This document 
3
The
The
cannot
e
inic v
nic v
1.1 P
1.1 P
be
th
n if n
n if 
sed
p
Efficac
ffica
he su
he su
to
a di
a di
support 
o:
e varia
vari
ar
any marketing 
and/or 
and/o
uld be 
uld be
authorization 
aily
minded
inded
daily
aily b
y
application 
ly sei
se
y
and 
Sp
S
any
and 
and
pons
pons
extensions 
d s
d
or variations 
ning t
ing t
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 226 of 267
9.3.1.2 Absence and myoclonic seizures
In the subject diary, the following information will be recorded on a daily basis:
•
Seizure type
•
Number of seizures to be recorded although for the purpose of data analysis, only the number 
of days with seizure will be analyzed.
Investigators should advise subjects and/or caregivers about the importance of reporting absence 
and myoclonic seizures.
Change #28
Section 9.3.6, Number of working or school days lost 
The number of working or school days lost by the subject will be recorded, as applicable.
Section 9.3.7, Number of days with help from a caregiver
The number of days with help from a caregiver will be recorded, as applicable.
Have been changed to:
Section 9.3.6, Number of working or school days lost due to epilepsy
The number of working or school days lost due to epilepsy by the subject will be recorded, as 
applicable.
Section 9.3.7, Number of days with help from a caregiver due to epilepsy
The number of days with help from a caregiver due to epilepsy will be recorded, as applicable.
Working or school days lost and days of help from a caregiver are further specified as “due to 
epilepsy” throughout the protocol, eg, Table 5‒1, Table 5‒2, and Table 5‒3 Schedules of study 
assessments, Section 8 STUDY PROCEDURES BY VISIT, etc.
Change #29
Section 10, ASSESSMENT OF SAFETY
A new section 10.1.1 Definitions has been added and 10.2.1 Definition of serious adverse event 
has been moved up to Section 10.1.1.2 Serious adverse event, following 10.1.1.1 Adverse event.
Section 10.5 Anticipated serious adverse events has been moved up to Section 10.1.1.2.1.
Section 10.3 Adverse events of special interest has been moved up to Section 10.1.1.3.
Section 10.1.5 Rule for repetition of an adverse event has been moved up to Section 10.1.2.2.
Section 10.2.2 Procedures for reporting serious adverse events has been moved up to Section 
10.1.2.3 Additional procedures for reporting serious adverse events.
REDACTED 
from a
from a
aregiv
aregiv
ys of 
ys of 
COPY 
epilep
epilep
This document
10.1.
10.1.
cannot
n 10.1
10.1
tion 
ion 
be
3 Ad
A
used
nticip
ticip
dv
d
to
to S
to 
support
NT O
T O
Definit
efini
Sec
Se
any 
OF
OF
marketing
f help f
f help
g,g, Table
Tab
OCED
CED
authorization 
ps
a care
 car
ver du
er du
f
application 
e to ep
to ep
sy by
by
y
and
applic
pplic
any extensions 
s appl
s app
or variations 
ence
nce
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 227 of 267
Change #30
Section 10.1.1.3, Adverse events of special interest
New bullet point added:
•
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.
Change #31
Section 10.1.4, Follow-up of adverse events
Paragraph 1 
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. 
Has been changed to:
Section 10.1.3, Follow-up of adverse events
Paragraphs 1 and 3
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. 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 10.2.1.4.
Information on SAEs obtained after clinical database lock will be captured through the PS 
database without limitation of time.
Change #32
The following section has been added:
Section 10.1.5, 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.
Change #33
Section 10.6.1, Liver function tests
Refer to Section 6.4 for LFT withdrawal criteria.
Transaminases (AST, ALT, or both) ≥3x but <5xULN, in the presence of total bilirubin 
≥2xULN, or transaminases (AST, ALT, or both) ≥5xULN will result in immediate 
REDACTED 
lved, h
lved, h
or the
or th
nd AE
nd AE
Sect
Sect
COPY 
This document
Cha
Cha
S
cannot
e (eg,
(eg,
pathog
atho
be
dule
dule
used
s of r
of r
d be 
d be 
to 
pe
p
support 
as been
s bee
ected
cted
any marketing
Es 
ion 10
ion 1
r clinic
clini
me.e.
authorization 
has a 
has a 
e subj
subj
of s
of s
application 
ollow
llow
and
e, the 
, the
w
any extensions or variations 
l
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 228 of 267
discontinuation of study drug and withdrawal of the subject from the study. The LFTs will be 
repeated as soon as possible, and in no case more than 1 week later.
Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality (ie, 
transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring of LFTs 
should continue until resolved (ie, <3xULN or stable condition). The investigator is to decide 
whether or not to stop the study drug. 
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C will 
be done.
Referral to a specialist (ie, hepatologist or gastroenterologist) is at the discretion of the 
investigator. This is recommended especially if the transaminase abnormalities >3xULN persist 
after discontinuation of the study drug.
Has been changed to:
Section 10.2.1, Evaluation of PDILI
The PDILI IMP discontinuation criteria for this study are provided in Section 6.4.1, 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 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.1.2). 
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1). 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 
10.2.1.4). 
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 
REDACTED 
on 
on 
gnosti
gnosti
on lab
on la
st (i
st (i
COPY
site 
site
he cri
he cr
n 10.
10
This document
most
most
2 lala
cannot 
are d
are d
tral la
ral la
t r
t
be
e me
e me
used 
ud
u
s resu
s resu
d
to
o
dy s
y s
support 
ause
us
nitorin
itorin
any
nves
nve
se of
e o
marketing 
bo
bo
if appli
f appl
nsulted
sulte
disease
diseas
sti
authorization 
iteri
ter
.1.1.3
1.1.3
ic test
c test
orato
rato
application 
ded in 
ed in
ing det
ng de
nd spo
nd spo
rion 
ion
and any extensions 
f the
the
>3xU
>3xU
or variations 
C w
C w
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 229 of 267
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative.
When IMP is stopped due to PDILI (as described in Section 6.4.1), IMP must be permanently 
discontinued. 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.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 230 of 267
Table 10‒3: Required investigations and follow up for PDILI
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptomsa 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 10.2.1.3); 
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
≥8xULN
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 
10.2.1.2).
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator).
≥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
10.2.1.3).
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, 
stabilize, or return to within 
Baseline values.d
REDACTED 
T
r 
e
llo
ll
F
TE
CT
COPY 
ry y
anent,
anent
contin
conti
This document t cannot 
c
be used to 
o support 
dical
ica
require
equir
s
any 
sion w
sion w
al M
l M
y marketing 
ows 
ws 
nuation
uatio
g
m
authorization
nuatio
uati
Furthe
Furthe
– im
im
d
riz
a
application 
a
tes
te
o
IMP 
MP 
on
ioioio
and
hemis
emi
and 
nd
any 
l: M
l: 
repeat
repea
t
extensions 
on
Mu
Mu
xt
o
Follo
oll
o variations 
on
ow
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 231 of 267
Table 10‒3: Required investigations and follow up for PDILI
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptomsa of 
hepatitis or 
hypersensitivity
Consultation 
requirements
Actions
Testing
Evaluation
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 10.2.1.1. 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.
REDACTED COPY
pons
pon
sible p
sible p
O
This document cannot be used to support any marketing authorization 
h
n application 
e disc
dis
e treatin
treati
st.
st.
ble phys
e phy
ysicia
ysicia
a
and 
rsen
en
scu
cu
any
ns
n
N=upp
N=up
nsitiv
nsit
extensions 
on
sfera
fer
xt
o
Follo
oll
o variations 
on
ow
va
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 232 of 267
10.2.1.1 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 10.2.1.3) and SAE report (if applicable).
10.2.1.2 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 6.4.1 and Table 10‒3 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.
10.2.1.3 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 
10‒4 (laboratory measurements) and Table 10‒5 (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.
The following measurements are to be assessed:
REDACTED
n req
n req
may
may ha
ha
y
able 10
able 1
ation 
ation 
hist
hist
COPY 
ox
o
ernati
ernat
qui
This document cannot be used to support
so be
o b
ements
ment
any
tored
tored
e s
marketing 
co
story
tory o
y
se addi
e add
authorization 
ive 
ve
uired f
red f
ave be
ve be
0‒5 (a
‒5 (a
ollec
ollec
application 
r sho
r sho
d consi
cons
to a sui
o a su
e etio
eti
and
supple
uppl
ou
any
0‒3 fo
‒3 f
extensions 
hepat
hepat
te in
e in
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 233 of 267
Table 10-4 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
Eosinophil count
Urinalysis
Toxicology screen
Chemistry
Amylase
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation
Additional
Prothrombin time/INR
a
Serum pregnancy test
PK sample
ALT=alanine aminotransferase; CPK=creatine phosphokinase; 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; RNA=ribonucleic acid; 
ULN=upper limit of normal
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).
RED
tine ph
tine ph
=im
=im
EDACTED 
ED
AC
ED
COPY 
nate
nat
sible m
ible m
PY
CO
This document cannot be used to support
mpto
mpto
any 
>
ms inc
ms in
tom
om
marketing
hosph
sph
mmunogl
munog
uced liv
ced li
>8xU
>8xU
au
hok
hok
authorization 
musc
usc
on
za
ho
au
application 
ion
bilirubi
ilirub
ica
scle in
cle i
pp
and 
an
any
quantit
quant
y
a
extensions 
ile a
e a
sio
te
e
or 
ant
ant
r variations 
on
tio
ari
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 234 of 267
The following additional information is to be collected:
Table 10‒5: 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:
•
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)
•
Adverse reactions to drugs
•
Allergies
•
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
•
Recent travel 
•
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
Alcohol and illicit drug use
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
10.2.1.4 Follow-up evaluation
Potential drug-induced liver injury events require follow-up monitoring as described in
Table 10-3. 
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.
Change #34
A new section has been added:
Section 10.3.3, New seizure types 
Incidence of new seizure types, and increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period will be assessed using the seizure count 
information recorded on the subject diaries (see Section 9.3.1).
REDACTED 
oxemi
oxemi
D
CTE
, if don
, if don
DA
R
COPY 
atiti
ati
eased a
eased 
C
This document
A new
ne
Se
Se
cannot 
hep
he
ange 
nge 
ew
be 
ete
epato
epato
used
ould c
uld c
ermi
ermi
to support
ation
tion
d liver 
liver
any
=aspa
=asp
marketing 
ne
onsult, 
onsult,
ng
rk
m
authorization 
a with
a with
tio
ori
ut
application
c dise
dis
d/or AL
/or AL
or hype
hyp
ppetite
ppetit
ca
and 
sea
sea
any 
p
extensions 
pha
ha
or
fat
fa
variations 
on
atty
atty
tio
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 235 of 267
Change #35
Section 11, ASSESSMENT OF PHARMACOKINETICS
Paragraph 2
Each blood sample drawn for LCM plasma concentration determination will be centrifuged and 
split into 2 duplicate samples prior to freezing. The samples will be stored at -20°C until shipped 
to a central laboratory. The central laboratory will store the plasma samples at -70°C until 
analysis.
Has been changed to:
Each blood sample drawn for LCM plasma concentration determination will be centrifuged and 
split into 2 duplicate samples prior to freezing. The samples will be stored at -20°C until shipped 
to a central laboratory. The central laboratory will store the plasma samples at -20°C until 
analysis. 
Change #36
Section 13.3.2, Secondary efficacy analyses
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 
24-week Treatment Period, will be analyzed in the same manner as the primary endpoint using 
the FAS. The percentage of seizure-free subjects at the end of the 24-week Treatment Period will 
be estimated from the KM estimates of time to first seizure using 2-sided 95% confidence 
intervals.  A gatekeeping strategy will be employed to control the Type I error (Marcus et al, 
1976). If the primary endpoint is statistically significant at the 5% level, then the key secondary 
efficacy endpoint will also be assessed at the 5% significance level. If the primary endpoint fails 
to reach statistical significance, then the key secondary efficacy endpoint will be exploratory 
only.
Analyses of the secondary efficacy variables will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1 13.3.1) and the analysis 
of the key secondary efficacy variable (as described above) will be exploratory only. 
Time to the first PGTC seizure for the 24 week Treatment Period will be analyzed in the same 
manner as the primary endpoint using the FAS.
The percent change in log-transformed PGTC seizure frequency during the first 6 weeks of the 
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure 
frequency. The percent change in log-transformed PGTC seizure frequency during the 24-week 
Treatment Period will be analyzed in a similar manner. Further approaches for the analysis of the 
secondary variable will be described in a detailed SAP.
Has been changed to:
13.3.2.1 Key secondary efficacy variable
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 
24-week Treatment Period, will be analyzed in the same manner as the primary endpoint using 
the FAS. The percentage of seizure-free subjects at 24 weeks will be estimated from the KM 
estimates of time to first seizure using 2-sided 95% confidence intervals. A gatekeeping strategy 
REDACTED 
fir
fir
mploy
mploy
ally
ally sis
y
d at th
d at th
n the k
n the 
COPY
ame 
ame
at the 
at the
rst s
rst
This document 
eco
co
Ha
Ha
cannot
cy. T
. T
ment
ment
onda
onda
be
Peri
eri
Th
Th
used 
ma
m
hange
hange
to
ary
ary
support 
marar
cacy
cacy v
y
C seiz
C sei
any
y p-v
p-
y
ry va
v
y
marketing
key
key s
y
y varia
var
y
va
authorization 
end
en
seizur
eizur
ed to 
ed to 
ignific
ignifi
e 5% 
5% 
application 
dom fo
dom f
manner
anne
nd of
d o
and any extensions 
ntrifu
ntrifu
0°C u
°C u
at -20°
20
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 236 of 267
will be employed to control the Type I error (Marcus et al, 1976). If the primary endpoint is 
statistically significant at the 5% level, then the key secondary efficacy endpoint will also be 
assessed at the 5% significance level. If the primary endpoint fails to reach statistical 
significance, then the key secondary efficacy endpoint will be exploratory only.
Section 13.3.2.2, Other secondary efficacy variables
Analyses of the other secondary efficacy variables will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described in Section 13.3.2.1) will be exploratory only. 
Time to the first PGTC seizure for the Treatment Period will be analyzed in the same manner as 
the primary endpoint using the FAS.
The percent change in log-transformed PGTC seizure frequency during the first 6 weeks of the 
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline PGTC 
seizure frequency. The percent change in log-transformed PGTC seizure frequency during the 
Treatment Period will be analyzed in a similar manner. Further approaches for the analysis of the 
secondary variable will be described in a detailed SAP.
Change #37
Section 13.4, Planned safety and other analyses
Paragraph 3
Observed values and changes from Baseline in vital signs, body weight, continuous laboratory 
parameters, and 12 lead ECG measurements will be summarized using continuous descriptive 
statistics. The number and percentage of subjects in each category will be summarized for 
categorical outcomes. The incidence of clinically relevant laboratory values will be summarized 
and shift tables summarizing the number and percentage of subjects having a different status (eg, 
abnormal laboratory result) post-Baseline compared to Baseline will be provided.
Has been changed to:
Observed values and changes from Baseline in vital signs, body weight, continuous laboratory 
parameters, and 12 lead ECG measurements will be summarized using continuous descriptive 
statistics. The number and percentage of subjects in each category will be summarized for the 
categorical outcomes. Shift tables summarizing the number and percentage of subjects having a 
different status (eg, abnormal laboratory result) post-Baseline compared to Baseline will be 
provided.
New last paragraph:
Incidence of new seizure types, and increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period will be summarized for each treatment 
group.
REDACTED 
ine in 
ne in 
ments
ments
ge of s
ge of s
COPY 
This document
ncid
cid
seiz
seiz
g
cannot 
last pa
ast pa
iden
den
be 
tu
used
come
ome
s (eg
s (e
to
ber 
ber 
support 
anges f
anges
ad EC
ad EC
an
any marketing 
subje
ubj
of clinic
f clinic
umber a
mber 
Baseli
Base
authorization 
vital 
vital 
s will b
will 
jec
jec
application 
pro
and
ure f
ure f
oach
oac
any
ng fo
ng fo
fre
f
extensions 
on
me m
me m
irst 6
rst 6
or 
nlyly
variations 
the
he
of the
f the
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 237 of 267
Change #38
Section 13.5, 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. 
Has been changed to:
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on outcomes for an individual subject. 
Change #39
Section 13.7, Planned interim analysis and data monitoring
Paragraph 2, last sentence:
Analysis of the primary endpoint (time to second PGTC seizure) will only be examined at the 
planned futility assessment; an unblinded, descriptive review of safety and seizure frequency 
data will be provided for all IDMC meetings. 
Has been changed to:
Analysis of the primary endpoint (time to second PGTC seizure) will only be examined at the 
planned futility assessment; an unblinded, descriptive review of safety, PGTC seizure frequency,
and changes in days with absence and/or myoclonic seizures will be provided for all IDMC 
meetings. 
Change #40
Section 13.8, Determination of sample size
Paragraph 1
Observing 125 events (subjects who had a second PGTC seizure during the 24-week Treatment 
Period) will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, 
assuming a nominal dropout rate of <10%. The observed hazard ratio was based on a 25.4% 
survival rate for placebo and 48.2% for lamotrigine from a previous study comparing lamotrigine 
and placebo (French et al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; 
however, to provide a conservative margin, the hazard ratio was increased to 0.56 for estimating 
a sample size for the study. The rationale for the increase in the hazard ratio was 2-fold: different 
active compounds (LCM and lamotrigine) and a choice of time to second seizure as the primary 
efficacy endpoint (in the lamotrigine study, percent change in seizure frequency was the primary 
endpoint).
Has been changed to:
Observing 125 events (subjects who had a second PGTC seizure during the 24-week Treatment 
Period) will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, 
assuming a dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate 
for placebo and 48.2% for lamotrigine from a previous study comparing lamotrigine and placebo 
(French et al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in 
order to account for the possibility of an increased placebo response, as has been documented in 
REDACTED 
rip
yoclon
yoclon
COPY 
PGTC
PGT
ptive
ptive
This document
Has
Has
O
cannot
mp
cy end
end
y
point)
point)
be
e f
poun
pou
sed
ovide 
vide
for t
for 
to
h et
h et
support
powe
owe
pout ra
pout r
ebo an
bo an
a
any
s who
s wh
wer t
er
marketing 
ple size
le siz
authorization 
C s
ve revi
e revi
nic sei
ic sei
application 
fet
seizu
eizu
and
only
only
tyty an
an
y
any 
y b
y
extensions or variations 
ve a
ve a
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 238 of 267
recent clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a 
sample size for this study. The rationale for the increase in the hazard ratio included the 
following considerations: different active compounds (LCM and lamotrigine) and a choice of 
time to second seizure as the primary efficacy endpoint (in the lamotrigine study, percent change 
in PGTC seizure frequency was the primary endpoint) (see rationale for second PGTC seizure in 
Section 5.4.2).
Change #41
Section 14.1, Informed consent/assent
Paragraph 3, first sentence
Prior to participation in the study, the written Informed Consent/Assent Form should be signed 
and personally dated by the subject, or his/her legal representative, and by the person who 
conducted the Informed Consent/Assent discussion (investigator or designee). 
Has been changed to:
Prior to participation in the study (and prior to prescreening EEG, if applicable), the written 
Informed Consent/Assent form should be signed and personally dated by the subject, or his/her 
legal representative, and by the person who conducted the Informed Consent/Assent discussion 
(investigator or designee). 
Change #42
Section 14.2, Subject identification cards
Upon signing the Informed Consent/Assent Form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with them at all times.
Has been changed to:
Prior to study participation at Visit 2, upon signing the Informed Consent/Assent form (as 
applicable), the subject or legal representative will be provided with a subject identification card 
in the language of the subject. The investigator will fill in the subject identifying information and 
medical emergency contact information. The investigator will instruct the subject to keep the 
card with them at all times.
Change #43
Section 14.3, Institutional Review Boards and Independent Ethics Committees
Paragraph 2
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/Assent 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.
REDACTED 
sent F
sent F
a subj
a subj
ect i
ect i
COPY 
This document
The 
The 
thth
cannot
14.3
14.3
ragrap
agrap
be 
43
43
3
used
at all
all
3
to
y con
co
y
l t
l t
support 
at V
t 
r legal
r lega
subjec
subje
onta
ont
any 
Visit
Vis
marketing 
jec
ec
identif
dentif
nstruct t
struct
authorization 
Form (
orm (
ct id
ct id
application 
if a
y dated
dated
formed
forme
and 
app
app
any 
e)e)
extensions 
ould b
uld b
perso
perso
). . 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 239 of 267
Has been changed to:
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/Assent form (including Informed Consent/Assent form for prescreening EEG, if 
applicable), 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.
Change #44
Section 16, REFERENCES
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 1999;Feb:9-11.
Has been changed to:
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of 
epilepsy: a systematic review and meta-analysis. Neurology. 2011;77(10):1005-12.
The following reference has been added:
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.
REDACTED 
man
ma
and Re
and Re
COPY 
ustry
ustry
an S
an S
This document cannot be used to support any marketing authorization 
Dr
Dr
Servic
ervic
esearc
searc
application 
, N
011;77(
11;77
rug
rug
and 
New
New
any 
in
extensions 
ne. 1
e.
or variations 
udy
dy toto
y
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 240 of 267
17.7
Protocol Amendment 5
Rationale for the amendment
The primary purpose of this substantial amendment is to stop the subjects’ study participation 
once 125 events have been observed to avoid exposing subjects to placebo unnecessarily and 
allow for flexible dosing of the treatment in the open-label follow-up study EP0012.
In addition, the following changes have been made:
•
The initial plan was to enroll 20% pediatric subjects out of a total sample size of 
approximately 200 subjects, which would have resulted in 40 pediatric subjects enrolled in 
the study. Due to a fluctuating event rate, the study has now been changed to enroll subjects
until the 125th event has occurred (defined as a subject experiencing the second primary 
generalized tonic-clonic [PGTC] seizure). Changing the number of pediatric subjects from 
20% to 40 absolute ensures that at least 40 pediatric subjects are recruited while also limiting 
the number of required pediatric subjects in case more than 200 subjects will have to be 
enrolled. This is considered appropriate in light of the extremely challenging recruitment of 
pediatric subjects in this study. Additionally, from the biostatistical point of view, increasing 
the number of pediatric subjects from 40 to 45 or 50 is very unlikely to yield significantly 
new or different safety information. 
•
To update the introduction with regulatory information on the marketing authorization of 
Vimpat and to provide an update on the lacosamide clinical program.
•
To appropriately align the Inclusion Criterion 7.a with the examples given in the supportive 
table.
•
To clarify that Visit 5 is the beginning of the Maintenance Period (18 weeks). 
•
To remove some blood sampling details from the protocol and refer to the laboratory manual. 
•
To clarify the potential drug-induced liver injury (PDILI) criteria requiring immediate and 
permanent discontinuation of the investigational medicinal product (IMP). 
•
To clarify that if the monitor has no direct access to the source electronic medical records, 
certified copies should be generated by the investigator and verified by the monitor against 
the original medical record.
•
To make a minor clarification to the sentence about pooling strategies for age strata for 
consistency with the Statistical Analysis Plan (SAP). Furthermore, title page and study 
physician contact details have been updated and minor editorial and formatting changes have 
been made throughout the protocol.
Modifications and changes
Specific changes
Change #1
Title page:
The title was updated from “Protocol SP0982 Amendment 4” to “Protocol SP0982 
Amendment 5.”
REDACTED 
os
iterion
iterion
inning
nning
COPY 
ormati
ormati
samid
amid
This document 
o
Spe
Sp
cannot
ci
en ma
n ma
odifi
difi
be
nc
an c
an c
used
minor
mino
cy wi
w
y
to 
ic
support
monito
onito
ould be
uld b
cal re
al r
any
of th
of th
marketing
g of t
of 
details
detail
nduce
nduc
authorization
io
de cli
de cli
n 7.a w
7.a w
f th
f th
application
stica
tic
y unlike
unlik
on on 
n on 
and
j
chall
hall
cal
cal
any 
ed 
ed
ects
cts w
extensions
ro
nroll
nroll su
s
nd 
nd pri
pri
ricic sub
su
d wh
w
or
lled
lled
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 241 of 267
The information below was revised to include Protocol Amendment 5 and the type of protocol 
amendment:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
5 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
09 Jan 2015
Non-substantial
Protocol Amendment 4
08 Jun 2016
Substantial
Has been changed to:
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
05 Aug 2011
N/A
Protocol Amendment 1
25 Sep 2012
Substantial
Protocol Amendment 2
11 Jul 2014
Substantial
Protocol Amendment 3
09 Jan 2015
Non-substantial
Protocol Amendment 4
08 Jun 2016
Substantial
Protocol Amendment 5
07 Nov 2017
Substantial
Change #2
STUDY CONTACT INFORMATION
Sponsor Study Physician
Name:
, MD
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Email:
REDACTED
07 No
07 N
TE
ION
ION
COPY 
015
015
un 201
un 20
PY
C
This document cannot be 
be used 
se
to 
to support 
fre
fr
4078
4078
G
u
any
ed
ed-
ny
N
ny marketing 
ar
ma
authorization 
16
v v 201
201
io
riz
application 
on
ca
app
and 
N
n
S
nd
an
any 
e o
e 
N/A
/A
ny extensions 
on
of a
of a
xt
or 
or variations 
on
io
ar
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 242 of 267
Has been changed to:
Sponsor Study Physician
Name:
, MD
Address:
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Phone:
Email:
Change #3
Section 1 SUMMARY
Paragraph 2
Approximately 200 subjects across approximately 150 sites in the US, Europe, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized 
in this study.
Paragraph 6
The primary efficacy variable is the time to the second PGTC seizure (also defined as an event) 
during the 24 week Treatment Period.
Paragraph 8
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs); 
withdrawal due to AEs; changes in hematology, chemistry, endocrinology, and urinalysis 
parameters; changes in 12-lead electrocardiograms (ECGs); changes in vital sign measurements; 
incidence of new seizure types, increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period; and changes in physical and neurological 
examination findings. In addition, for pediatric subjects <18 years of age, safety will be 
evaluated using a behavioral assessment (Achenbach Child Behavior Checklist [CBCL]) and a 
cognitive function assessment (Behavior Rating Inventory of Executive Function®
[BRIEF®]/Behavior Rating Inventory of Executive Function Preschool Version [BRIEF-P]).
PPD
PPD
REDACTED
he se
he se
the 
the 
COPY 
co
This document cannot be used
on as
n a
havio
havio
to
eha
eha
assss
support 
pes
e
during
during
In add
n add
avio
avi
any
elec
ele
s, inc
s, inc
marketing 
 safet
safety
variabl
variab
n hema
n hem
ctr
ct
authorization 
ond P
ond P
application
e US
US
ns, are
ns, are
and 
S
any extensions s
sio
or 
o variations 
on
va
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 243 of 267
Has been changed to:
Paragraph 2
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study. 
Paragraph 6
The primary efficacy variable is the time to the second PGTC seizure (also defined as an event) 
during the 24-week Treatment Period. Once the 125th event occurs, the study will have met its 
protocol-defined endpoint or milestone; all subjects will transition into EP0012 or taper off study 
medication.
Paragraph 8
The secondary objective is to assess the safety and tolerability of LCM in subjects with IGE with 
uncontrolled PGTC seizures. Safety variables to be assessed are adverse events (AEs) as reported 
spontaneously by the subject and/or caregiver or observed by the investigator. Other safety 
variables are; withdrawal due to AEs; incidence of new seizure types, increase in absence seizure 
days per 28 days or myoclonic seizure days per 28 days during the Treatment Period; changes in 
physical and neurological examination findings; changes in hematology, chemistry, 
endocrinology, and urinalysis parameters; changes in 12-lead electrocardiograms (ECGs); 
changes in vital sign measurements; for pediatric subjects <18 years of age, safety will be 
evaluated using a behavioral assessment (Achenbach Child Behavior Checklist [CBCL]) and a 
cognitive function assessment (Behavior Rating Inventory of Executive Function®
[BRIEF®]/Behavior Rating Inventory of Executive Function Preschool Version [BRIEF-P]).
Change #4
Section 2 INTRODUCTION
Paragraph 7
Lacosamide has been approved in the European Union (oral tablets, oral solution [syrup], and 
solution for intravenous [iv] infusion) as adjunctive therapy in the treatment of partial-onset 
seizures with or without secondary generalization in patients 16 years of age and older. 
Lacosamide has also been approved in the US (oral tablets, oral solution [syrup], and solution for 
iv infusion) as adjunctive therapy in the treatment of partial-onset seizures in patients 17 years of 
age and older. The approved indication of LCM as adjunctive treatment for partial-onset seizures 
was based on 1327 subjects who received LCM in the pooled Phase 2 or Phase 3 studies during 
the development program. With the completion of the 3 open-label studies, the cumulative 
exposure to LCM during the clinical studies was 3297.4 subject-years. Further information on 
LCM nonclinical results, as well as the PK, efficacy, and safety profiles, can be obtained from 
the current version of the LCM Investigator’s Brochure.
In addition, lacosamide is being evaluated in the following ongoing pediatric efficacy and safety 
studies: 
•
SP0967 (ages ≥1 month to <4 years) as adjunctive therapy in partial-onset seizures
•
SP0969 (ages ≥4 to <17 years) as adjunctive therapy in partial-onset seizures 
REDACTED 
enb
enb
ating I
ating I
Execu
Execu
COPY
n 12
n 12
subjec
subje
bach
bac
This document
the c
he c
In
In
cannot 
lop
op
ure to
ure to
M no
M no
be 
n 1
n 
pme
pme
used 
jun
un
The a
The a
132
132
o
o b
ncti
nct
support
v] inf
v] in
t secon
seco
been 
been 
any 
d in t
d in 
fu
f
marketing authorization 
cts 
cts 
h Chil
h Chi
Invent
nvent
utive F
utive 
application 
pes
the Tre
he Tr
hemato
hemat
ead ele
ad el
s <18
<1
and
estiga
stig
s, in
, in
any
event
even
gato
at
extensions 
e
bject
ject
or
off 
off
variations 
ent)
nt)
t its
t its
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 244 of 267
•
EP0034, open-label extension study to SP0967 and SP0969
•
SP0966 (ages ≥1 month to <18 years) as adjunctive therapy, exploratory study in subjects 
with epilepsy syndromes associated with generalized seizures
Has been changed to:
Paragraph 7
Lacosamide has been approved in the European Union (oral tablets, oral solution [syrup], and 
solution for intravenous [iv] infusion) as monotherapy or adjunctive therapy in the treatment of 
partial-onset seizures with or without secondary generalization in patients 4 years of age and 
older. Lacosamide has also been approved in the US (oral tablets, oral solution [syrup], and 
solution for iv infusion) as monotherapy or adjunctive therapy in the treatment of partial-onset 
seizures in patients 17 years of age and older. The safety and efficacy of LCM has been 
evaluated in Phase 2/3 studies as adjunctive oral therapy in over 1300 adult subjects with 
partial-onset seizures. Excluding blinded ongoing studies and indications not currently pursued, 
as of the data cutoff of 31 Aug 2016, 4938 subjects have been exposed to LCM in the clinical 
development program.
New paragraph
Preliminary recent safety and PK data suggest that the exposure-response in pediatric and adult 
subjects treated with LCM will be similar. Lacosamide has been evaluated in 3 completed 
pediatric studies; 2 studies in subjects aged 1 month to 17 years, and in subjects with epilepsy 
≥4 years to <17 years of age with uncontrolled partial-onset seizures. Subjects who completed 
the Maintenance Period were offered to participate in the open-label extension study.
In addition, LCM is being evaluated in the following ongoing pediatric efficacy and safety 
studies: 
•
SP0967 (ages ≥1 month to <4 years) as adjunctive therapy in partial-onset seizures
•
EP0034, open-label extension study to SP0967 and SP0969
•
SP0966 (ages ≥1 month to <18 years) as adjunctive therapy, exploratory study in subjects 
with epilepsy syndromes associated with generalized seizures
Further information on LCM nonclinical results, as well as the PK, efficacy, and safety profiles, 
can be obtained from the current version of the LCM Investigator’s Brochure.
Change #5
Section 4.1.2 Secondary efficacy variables
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures during the 24-week Treatment Period, estimated using 
Kaplan-Meier analysis
The other secondary efficacy variables are:
•
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline) 
mon
mon
led pa
led pa
partici
partici
in the
in the
COPY
he
he ex
ex
amide
amide
nth
nth
This document 
•
S
cannot
on 4
n 4
e ke
e ke
be 
#5
used
from
from
to
n on
n on
m
support
th to <
h to 
romes a
omes
n LC
n L
any
ion s
on 
<
marketing 
e fo
fo
years) 
ears)
stut
authorization
e has
ha
h to 17
to 17
artial
rtial
ipate 
pate 
follo
ollo
application 
posure
osur
as be
as b
and
ed to 
d to 
any 
su
su
not c
not 
L
extensions
ge
up], a
up], a
f parti
parti
M has b
has 
subje
ubj
or
 and
an
variations 
nd d 
ent of
nt of
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 245 of 267
•
The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline
•
Time to the first PGTC seizure during the Treatment Period
Has been changed to:
The key secondary efficacy variable is:
•
Seizure freedom for PGTC seizures during the 24-week Treatment Period, estimated using 
Kaplan-Meier analysis
The other secondary efficacy variable is:
•
Time to the first PGTC seizure during the Treatment Period
Change #6
Section 4.1.3 Other efficacy variables
The following variables have been added as the first three bullets (Note that the first and third 
variable have been moved from Secondary to Other and the second variable has been added):
•
The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Phase) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline) 
•
The percent change in PGTC seizure frequency per 28 days during the first 12 weeks of the 
Treatment Period relative to the Combined Baseline
•
The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline
The following variable has been added as bullet 14:
•
Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Titration Period compared to Combined Baseline
Change #7
Section 4.2 Safety variables
The safety variables are:
•
AEs as reported spontaneously by the subject and/or caregiver or observed by the 
investigator.
•
Subject withdrawal due to AE
•
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
•
Changes in 12-lead ECGs
•
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings
•
Incidence of new seizure types during the Treatment Period
REDACTED
quenc
uenc
ined B
ined B
ure fre
ure fr
ne
ne
COPY
e Co
e Co
This document
C
•
cannot 
stigig
Subjec
ubjec
Ch
Ch
be 
repo
ep
gato
gato
used
ables 
bles
port
port
to 
ety
a
support 
y v
y
a
any 
at l
at 
d to Co
to C
marketing 
ed as b
d as
least
lea
authorization 
y per 2
per 
y
Baseli
aseli
quen
quen
application
nd va
nd v
ay
ays dur
s du
mbined
bined
and 
ote th
ote th
any extensions or variations 
ng g
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 246 of 267
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Subjects with an increase of up to25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
Other safety variables are:
•
Behavioral assessment (Achenbach CBCL/1½-5 or CBCL/6-18)
•
Cognitive function assessment (BRIEF-P or BRIEF)
Has been changed to:
The safety variable is:
•
AEs as reported spontaneously by the subject and/or caregiver or observed by the 
investigator.
Other safety variables are:
•
Subject withdrawal due to AE
•
Incidence of new seizure types during the Treatment Period
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline
•
Changes in hematology, chemistry, endocrinology, and urinalysis parameters
•
Changes in 12-lead ECGs
•
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings
•
Behavioral assessment (Achenbach CBCL/1½-5 or CBCL/6-18) for pediatric subjects only
•
Cognitive function assessment (BRIEF-P or BRIEF) for pediatric subjects only
Change #8
Section 5.1 Study description
Paragraph 2 
Approximately 200 subjects across approximately 150 sites in the US, Europe, Asia, and 
Australia, with possible extension to other countries and regions, are planned to be randomized 
in this study. 
Paragraph 12
25%
25%
ng the
ng the
to 25
25
COPY 
atmen
atme
t
This document 
Sec
ec
Pa
Pa
cannot 
nge #
ge #
ctio
ctio
be
ive f
ive f
used 
l asses
asses
to
ght) 
ght)
support 
CGs
Gs
ign me
gn me
an
a
any
emis
emi
marketing
5%, >
%, >
ay
ays dur
s du
str
authorization
nt P
t P
to 50%
o 50
e Trea
Trea
2
application 
Perio
Peri
and 
obse
bs
any 
erve
erv
extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 247 of 267
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
Paragraph 14
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24) respectively, choose to continue in EP0012.
Subjects completing Visit 10 (Week 24) or the ET Visit must complete a 4-week blinded 
transition followed by a Final Clinic Visit.
Paragraph 15
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24), and an up to 4-week 
blinded taper followed by an End of Taper Visit. Following the End of Taper Visit, there will be 
a 30-day Safety Follow up Period (see Section 7.2.4).
Has been changed to:
Paragraph 2 
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study.
Paragraph 12
The Treatment Period continues until 1 of the following occurs (whichever occurs first):
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
•
The 125th event occurs in the study. A second PGTC seizure is defined as an event.
Paragraph 14
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period or if the 125th event occurs in the study 
(whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012. Subjects completing Visit 10 (Week 24) or the ET 
Visit must complete a 4-week blinded transition followed by a Final Clinic Visit. The Final 
Clinic Visit is the same as Visit 1 of EP0012 (see Section 7.2.3). During the 4-week blinded 
transition, subjects receiving placebo during SP0982 will have their dose titrated to LCM (see 
Table 7-4).
Paragraph 15
If the subject discontinues from the study at any time and is not eligible or chooses not to enter 
EP0012, the subject must complete the ET Visit or Visit 10 (Week 24), and an up to 4-week 
blinded taper followed by an End of Taper Visit. Following the End of Taper Visit, there will be 
a 30-day Safety Follow up Period (see Section 7.2.4). In case the 125th event occurs in the study, 
the subjects discontinuing treatment will complete the ET Visit or Visit 10 (Week 24), and an up 
REDACTED
plann
plann
1 of t
1 of 
rere
COPY 
US, E
US, E
ne
This document 
abl
ab
Pa
Pa
cannot
Visit 
Visit 
sition
ition
lele 7
be
c
com
com
used
mes fi
es fi
choo
hoo
to
mplet
ple
support 
weeks 
weeks 
tin
ti
any
he stu
he st
marketing 
th
eatmen
atmen
e Treat
Trea
authorization
Europ
Euro
ed to b
d to b
he fo
e fo
application 
pe
and
of Ta
f Ta
any
nd an
nd an
ape
extensions 
e
hoos
oos
or 
d d 
variations 
0012
0012
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 248 of 267
to 4-week blinded taper followed by an End of Taper Visit. However, the End of Taper Visit will 
be the same as Visit 1 of EP0012. The 30-day Safety Follow up Period will be done as part of 
EP0012, except if the subject refuses to sign the EP0012 informed consent form. If the subject 
signs the informed consent form for a short Safety Follow-up as part of EP0012, the 30-day 
Safety Follow-up will be performed as part of EP0012; otherwise, the Safety Follow-up will be 
performed in SP0982.
Change #9
Section 5.1.1 Study duration per subject
The following paragraphs were added:
Titration Period
In case the 125th event occurs in the study while subjects are still in their 6-week Titration 
Period, these subjects will not have to proceed to Week 6 prior to initiating the Transition/Taper 
Period; these subjects will also be invited for their ET Visit at the next scheduled visit.
Maintenance Period
In case the 125th event occurs in the study while subjects are in their Maintenance Period, these 
subjects will also be invited for their ET Visit at the next scheduled visit and enter the 
Transition/Taper Period.
Transition Period
In case the subject is in the Transition/Taper Period, these subjects will proceed to their 
scheduled completion visit.
Screening Period
In case the 125th event occurs while a subject is in screening, the subject may proceed to the 
scheduled Baseline Visit if they are eligible or are a Baseline failure; these subjects will be able 
to enter EP0012 and will not proceed to randomization in SP0982 but will enter EP0012. For the 
subjects entering EP0012, their next visit will be Visit 1. 
Change #10
Section 5.1.2 Study completers
The following subjects will be considered study completers:
•
Subjects who meet any of the predetermined exit criteria (Section 6.3)
•
Subjects who experience <2 PGTC seizures within the 24-week Treatment Period
Has been changed to:
The following subjects will be considered study completers:
•
Subjects who meet any of the predetermined exit criteria (Section 6.3)
•
Subjects who experience <2 PGTC seizures within the 24-week Treatment Period
Further information is provided in Section 6.3.
REDACTED 
er 
er Perer
COPY 
ex
This document 
as
The
The
cannot
bjects
jects
s be
s be
be
ts wh
ts w
used
subje
ubje
ho
ho
to
tud
tud
support 
he
dy c
dy
any
ocee
oce
ir nex
ir nex
marketing 
a subje
subje
re eligi
e elig
eed
eed
authorization 
iod
od, tht
application 
n their 
their
hedule
edul
and 
sc
sc
any
g the
g th
hedu
hed
extensions 
week T
eek T
e
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 249 of 267
Change #11
Section 5.1.3 Planned number of subjects and sites
The number of screened subjects may vary according to the observed screen failure rate. 
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a total of 
125 events, where an event is defined as the occurrence of the second PGTC seizure. 
Subjects will be randomized in the following age categories:
•
≥4 years of age to <12 years of age (approximately 50 subjects)
•
≥12 years of age to <18 years of age (approximately 50 subjects)
•
≥18 years of age (approximately 100 subjects)
There will be approximately 150 sites 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 <18 years of age. Of these 100 subjects, 50% will be enrolled in each 
of the 2 age categories <18 years of age.
Has been changed to:
The number of screened subjects may vary according to the observed screen failure rate. Up to 
250 subjects (100 to 125 per treatment arm) will be randomized to achieve a total of 125 events, 
where an event is defined as the occurrence of the second PGTC seizure. 
Subjects will be randomized in the following age categories:
•
(a) ≥4 years of age to <12 years of age 
•
(b) ≥12 years of age to <18 years of age 
•
(c) ≥18 years of age category 
There will be approximately 150 to 200 sites in order to recruit the required subjects; additional 
sites will be added if deemed necessary. A target of at least 40 of the randomized subjects should 
consist of subjects <18 years of age.
REDACTED 
g age 
g age 
age
age
s of a
s of a
COPY 
to o
e rando
e rand
e sec
e sec
This document cannot be used to support
ars of
rs o
any 
t
neces
nece
f a
f
marketing 
age
age
to 20
o 20
authorization
ond 
ond 
categ
categ
application 
e obser
obse
omized
mize
PG
and 
% w
any
rand
rand
will b
will
extensions 
s; add
; add
do
d
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 250 of 267
Change #12
Section 5.2 Schedule of study assessments
Table 5‒1: the line in front of the Maintenance Period (18 weeks) has been shifted one box to the 
left, so that V5 is the start of the Maintenance Period.
Table 5-1: Schedule of study assessments for SP0982 (Prospective 
Baseline, Titration Period, Maintenance Period, ET Visit, and 
Unscheduled Visits)
Assessments
Prospective
Baseline
4 weeks
Treatment Perioda
Unsched
uledb
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period 
(18 weeks)
Visitc
V1bb
TC
V2d
TCe V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/
ETf
Visit
Study week
-4
-2
1
2
3
4
5
6
8
12
16
20
24
NA
Has been changed to:
Table 5-1: Schedule of study assessments for SP0982 (Prospective 
Baseline, Titration Period, Maintenance Period, ET Visit, and 
Unscheduled Visits)
Assessments
Prospective 
Baseline
4 weeks
Treatment Perioda
Unschedu
ledb
6 to 24 weeks (maximum)
NA
Titration Period (6 weeks)e
Maintenance Period (18 weeks)
Visitc
V1bb
TC
V2d
TCe
V3
TC
V4
TC
V5
V6
V7
V8
V9
V10/
ETf
Visit
Study week
-4
-2
1
2
3
4
5
6
8
12
16
20
24
NA
Change #13
Section 5.2 Schedule of study assessments
Table 5‒3: Footnote c has been updated.
c There will be a 30-day (-1/+3 days) Safety Follow-up Period for subjects who complete the End of Taper Visit. 
The Safety Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by 
a TC. 
REDACTED 
TE
DA
ratio
ratio
RE
COPY
sme
sme
, Ma
Ma
This document cannot be used
0-day 
day 
w-up 
up 
to
te c 
e c
support 
ule of
ule o
c has
ha
any y marketing 
on Perio
n Peri
g
V3
V3
tininin
ma
in
1
ma
ma
ma
authorization
aint
nt
riz
au
application 
nts 
ts f
ten
ten
and 
12
12
nd
a
any 
we
we
V8
V8
y
a
extensions 
sio
ce Per
Per
eeks
eks
en
or 
o variations 
ve 
ve 
and
and
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 251 of 267
Has been changed to: 
c There will be a 30-day (-1/+3 days) Safety Follow-up Period for subjects who complete the End of Taper Visit. 
The Safety Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by 
a TC. After the 125th event occurs, the 30-day Safety Follow up Period will be done as part of EP0012, except if the 
subject refuses to sign the EP0012 informed consent form. If the subject signs the informed consent form for a short 
Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part of EP0012; otherwise, 
the Safety Follow-up will be performed in SP0982.
Change #14
Section 5.3 Schematic diagrams for SP0982
Figure 5-2: Footnote b has been updated and footnote c has been added.
b If the subject discontinues from the study at any time and is not eligible or chooses not to enter EP0012, the 
subject must complete the ET Visit or Visit 10 (Week 24) and an up to 4-week blinded taper followed by an End 
of Taper Visit. There will be a 30-day Safety Follow-up Period for subjects who complete the End of Taper Visit. 
Has been changed to:
b If the subject discontinues from the study at any time and is not eligible or chooses not to enter EP0012, the 
subject must complete the ET Visit or Visit 10 (Week 24) and an up to 4-week blinded taper followed by an End 
of Taper Visit. There will be a 30-day Safety Follow-up Period for subjects who complete the End of Taper Visit. 
After the 125th event occurs, the 30-day Safety Follow up Period will be done as part of EP0012, except if the 
subject refuses to sign the EP0012 informed consent form. If the subject signs the informed consent form for a 
short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part of EP0012; 
otherwise, the Safety Follow-up will be performed in SP0982.
c If the subject is in the Titration Period when the 125th event occurs, the subject will proceed to the 
Transition/Taper Period directly after their ET/V10 Visit.
Figure 5-3: Footnote a has been added.
a If a subject is in the Titration period and the next scheduled visit after the 125th event is not until Week 6, the 
subject will enter the Transition/Taper Period, and the escalation will be adapted accordingly.
REDACTED
P0
even
eve
10 
10 Visis
d.d.
he ne
he ne
COPY
f the su
f the s
ety Fol
ety Fo
0982
0982
This document cannot be used to support any marketing
ext sch
ext sch
od, and 
od, and
authorization 
llow
ow
.
t occu
occu
t.
application
o
ek bli
ek bl
cts w
s who
ho
w
be done
e don
ubject si
bject s
w-up
up
and 
ses no
es n
any 
e e 
extensions 
r EP00
EP00
er follo
r follo
the E
the 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 252 of 267
Change #15
Section 6.1 Inclusion criteria
Inclusion Criterion 7 has been updated
7. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine, see examples in the table 
below) for at least 28 days prior to Visit 1 with or without additional concurrent stable VNS (see 
Section 7.8).
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline and 
Treatment Period.
Benzodiazepine AEDs
Non-Benzodiazepine AEDs
Total AEDs
Is subject eligible?
(In terms of 
Inclusion Criterion 7)
0
1
1
Yes
0
2
2
Yes
1
1
2
Yes
1
2
3
Yes
1
0
1
No
0
3
3
No
2
1
3
No
AED=antiepileptic drug
REDACTED 
3
TE
AC
RE
COPY 
PY
CO
This document cannot be used to support any marketing 
1
g authorization 
on
iz
th
application 
2
n
ca
pp
ap
and 
1
d any y extensions
w
eline 
line 
Is 
Is 
te
e
or 
ith
ith
variations 
see
see
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 253 of 267
Has been changed to:
7a. Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs with no benzodiazepine AEDs OR 1 benzodiazepine marketed AED with 1 to 2 
non-benzodiazepine marketed AEDs (see examples in the table below) for at least 28 days prior 
to Visit 1 with or without additional concurrent stable VNS (see Section 7.8)
Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and during the Prospective Baseline and 
Treatment Period.
Benzodiazepine AEDs
Non-Benzodiazepine AEDs
Total AEDs
Is subject eligible?
(In terms of 
Inclusion Criterion 7)
0
1
1
Yes
0
2
2
Yes
1
1
2
Yes
1
2
3
Yes
1
0
1
No
0
3
3
No
2
1
3
No
AED=antiepileptic drug
Change #16
Section 6.2 Exclusion Criteria
Criterion 4 has been updated.
4.  Subject has symptomatic generalized epilepsy ([ILAE, 1989] eg, Lennox Gastaut Syndrome) 
or evidence of both focal and generalized epilepsy.
Has been changed to:
4a. Subject has symptomatic generalized epilepsy ([ILAE, 1989] (eg, Lennox Gastaut Syndrome 
typically presenting with seizures including tonic seizures), some other related syndrome like 
Doose’s syndrome (typically presenting with myoclonic-atonic seizures), or evidence of both 
focal and generalized epilepsy.
Change #17
Section 6.3 Exit Criteria
Subjects will be required to exit the study if either of the following events occurs:
•
Subject completes the first 6 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTC seizures during that time
•
Subject experiences a second PGTC seizure after the first 6 weeks of the Treatment Period
REDACTED 
ED
ia
ia
COPY 
PY
CO
This document 
e
Sub
Sub
cannot
nge #
ge #
ctio
ctio
be
gener
gene
used
ing 
ng 
rom
ome
ra
to 
mpto
pto
g w
g w
support 
d d 
 to:
to:
toma
om
any
nera
ner
gene
gene
marketing 
aliz
ali
authorization 
on
iza
application 
3
n
at
pp
ap
and 
2
d
a
any y extensions
bject 
ect 
(In t
(In 
Inclus
nclus
te
e
or 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 254 of 267
Has been changed to:
Subjects will be required to exit the study if either of the following events occurs:
•
Subject completes the first 6 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTC seizures during that time
•
Subject experiences a second PGTC seizure after the first 6 weeks of the Treatment Period
•
The 125th event occurs in the study
Change #18
Section 6.4.1
Potential drug-induced liver injury IMP discontinuation 
criteria
Subjects with 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. 
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 
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).
Evaluation of PDILI must be initiated as described in Section 10.2.1. 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.
REDACTED 
ate di
ate di
N who
N who
patitis 
patitis
s H
s H
COPY 
al bil
al bil
This document 
ntil
ti
obse
obse
ap
ap
cannot
gator
ator
omplet
mple
il in
l in
be
h thth
used 
PDILI
DILI
he a
he a
to
 vom
vo
support 
r AST
AST
eosinop
osino
omi
m
any 
ws 
ws 
marketing
 sy
sy
Hy
Hyper
per
y
ophi
ophilia
l
 for 
for
authorization
lirubi
lirubi
iscont
scont
o exhi
exh
mp
mp
application 
ntin
tin
and 
nua
nua
any
ecess
eces
extensions
ontin
ntin
nued. 
ued. 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 255 of 267
Has been changed to:
Subjects with PDILI must be assessed to determine if IMP must be immediately and permanently 
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: 
•
ALT or AST ≥5xULN
•
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
•
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).
Evaluation of PDILI must be initiated as described in Section 10.2.1. 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.
Change #19
Section 7.2.3 Transition Period (for subjects who enter EP0012)
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24) respectively, choose to continue in EP0012.
Has been changed to:
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period or when the 125th event occurs in the 
study (whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012.
Table 7-4: A note has been added.
Note: If a subject is in the Titration Period and the next scheduled visit after the 125th event occurs, dosing will 
be adapted to reach the target dosing at Week 4.
REDACTED 
le, I
le, 
rmatio
rmatio
cts wit
cts wit
re com
e com
) fo
) fo
COPY 
in 
in
d in S
in 
IM
IM
This document
study
tudy
res
res
cannot 
comp
comp
iod or
od or
be
n ch
n c
used 
mp
mp
at the 
t the 
h
to
w
mplet
ple
support 
sition 
tion
weeks
week
any marketing 
mple
pl
or IMP
r IMP
source
ourc
authorization 
ect
ec
MP mu
P mu
on on
n on
th PD
h PD
lete
ete
application
<5xU
<5xU
sh, or s
h, or 
tendern
ende
ction
tion
and 
U
any 
discre
discr
extensions
ms of
s of
iting, 
ting, 
r (wit
r (wit
or 
f
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 256 of 267
Change #20
Section 7.2.4 Taper Period
Paragraph 3
Following the End of Taper Visit, there will be a 30-day Safety Follow up Period. The Safety 
Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed by a 
Safety Follow-up telephone contact 30 days after the last dose of study drug.
The following schematic displays the scenario for subject dispensation:
Visit 10 or 
ET Visit
0-4 week 
taper
End of 
Taper Visit
Final Clinic 
Visit 
Safety 
Follow-up 
TC
2 weeks after 
last dose of 
study drug
(±2 days)
30 days after last 
dose of study 
drug
(-1/+3 days)
Has been changed to:
Paragraph 3
Following the End of Taper Visit, there will be a 30-day Safety Follow up Period. The Safety 
Follow-up Period consists of a clinic visit 2 weeks after the End of Taper Visit followed by a 
Safety Follow-up telephone contact 30 days after the last dose of study drug. In case the 125th
event occurs in the study, the subjects discontinuing treatment will complete the ET Visit or Visit 
10 (Week 24), and an up to 4-week blinded taper followed by an End of Taper Visit. However, 
the End of Taper Visit will be the same as Visit 1 of EP0012. The 30-day Safety Follow up 
Period will be done as part of EP0012, except if the subject refuses to sign the EP0012 informed 
consent form. If the subject signs the informed consent form for a short Safety Follow-up as part 
of EP0012, the 30-day Safety Follow-up will be performed as part of EP0012; otherwise, the 
Safety Follow-up will be performed in SP0982.
The following schematic displays the scenario for subject dispensation:
Visit 10 or 
ET Visit
0-4 week 
taper
End of 
Taper Visit
Final Clinic 
Visit 
Safety 
Follow-up 
TC
2 weeks after 
last dose of 
study drug
(±2 days)
30 days after last 
dose of study 
drug
(-1/+3 days)
After the 125th event 
occurs
Table 7-5: A note has been added.
Note: Dosing for the Taper Period will be adapted depending on the dose subjects reached during the Titration 
Period when the 125th event occurs.
EP0012 
Visit 1
REDACTED 
nui
nui
taper 
taper 
s Visi
s Vis
, excep
, exce
e info
e info
COPY
fter t
fter 
the las
he l
ing 
ing
This document 
Ta
Ta
cannot be used to sup
upport 
E
T
up
any 
ys th
s t
an marketing
orme
orme
up wil
up w
d in SP
in S
the
th
authorization 
st d
treatm
treatm
follow
follow
it 1 of
t 1 of
pt if t
pt if t
d
application 
ty y Foll
Fo
he End 
e End
dose
dos
and any extensions 
dy y
days)
days)
si
or 
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 257 of 267
Change #21
Section 
7.8.1 
Permitted 
concomitant 
treatments 
(medications 
and 
therapies) 
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to 
Visit 1 and during the Prospective Baseline and Treatment Period with or without additional 
concurrent stable VNS. 
Has been changed to:
Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed 
AEDs OR 2 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to 
Visit 1 and during the Prospective Baseline and Treatment Period with or without additional 
concurrent stable VNS. 
Change #22
Section 7.8.2 Prohibited concomitant treatments (medications and 
therapies) 
•
MAO-A inhibitors
Has been changed to:
•
Any MAO inhibitors
Herbal medicines for epilepsy has been added.
•
Herbal medicines for epilepsy
Change #23
Section 8.2 Treatment Period
The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
Has been changed to:
The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
•
Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTC seizures
•
Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTC seizures
•
The 125th event occurs in the study
REDACTED 
added
dded
COPY 
This document cannot
Com
Com
•
C
be
ment 
ment
used
hang
ang
t P
t P
to 
of 
of 
support 
nu
6 week
6 we
f 24 w
24
any 
es un
es un
marketing 
od
od
authorization 
.
application 
nts
nt
and 
ts
any extensions 
e mark
e mark
28 da
28 da
hout a
hout a
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 258 of 267
Change #24
Section 8.2.2.1.4 Visit 5 (end of Week 6)
The 
entire 
section 
has 
been 
moved 
from 
Section 
8.2.2 
Titration 
Period 
to
Section 8.2.3 Maintenance Period as Section 8.2.3.1. The remainding subsections under 
Section 8.2.3 have been renumbered accordingly.
Change #25
Section 8.2.3.6 Visit 10/ET Visit (end of Week 24)
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure 
(see Section 6.3).
Has been changed to: 
Once the subject has experienced 2 PGTC seizures, the site should contact the Medical Monitor 
to confirm whether the subject has met the exit criteria. If the exit criteria are met, sites will be 
advised to have subjects return for their ET Visit within 1 week of the subject’s second seizure. 
Once the 125th event occurs subjects will return to the site at the next scheduled visit and the 
ET/Visit 10 will be performed (see Section 6.3).
Change #26
Section 8.3.1.2 Final Clinic Visit
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period (whichever comes first), eligible 
subjects may, at the ET Visit or Visit 10 (Week 24) respectively, choose to continue in EP0012.
Has been changed to:
After completing ≥6 weeks and experiencing the second PGTC seizure during the Treatment 
Period or after completing the 24-week Treatment Period or the 125th event occurs in the study
(whichever comes first), eligible subjects may, at the ET Visit or Visit 10 (Week 24) 
respectively, choose to continue in EP0012.
Change #27
Section 8.3.2.2 Safety Follow-up Visit
Following the End of Taper Visit, the subject will return 2 weeks (±2 days) after the last dose of 
study drug for a Safety Follow-up Visit.
Has been changed to:
Following the End of Taper Visit, the subject will return 2 weeks (±2 days) after the last dose of 
study drug for a Safety Follow-up Visit. In case the 125th event occurs in the study, the subjects 
discontinuing treatment will complete a 30-day Safety Follow-up Period in the EP0012 study.
The 30-day Safety Follow up Period will be done as part of EP0012, except if the subject refuses 
to sign the EP0012 informed consent form. If the subject signs the informed consent form for a 
REDACTED 
iencin
ienci
eek T
eek T
COPY 
e sit
e s
This document
Has
Has
F
cannot
ing th
ng th
y drug
drug
y
be 
8.3.
3
h
used 
2
to 
t
support
g the 2
the 
), eligi
, elig
o con
o con
any 
nd exp
d ex
24
marketing
Treatm
Treat
10 (W
10 (W
authorization 
g the
g the
application
t crit
t crit
ek of th
k of t
at the n
t the 
and 
ontac
ontac
any extensions
cal M
al M
sites 
sites 
s secon
 seco
or 
Mo
Mo
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 259 of 267
short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part 
of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
Change #28
Section 8.3.2.3 Safety Follow-up telephone contact
Thirty days (-1/+3 days) after the last dose of study drug, the subject will receive a Safety 
Follow-up telephone contact.
Has been changed to:
Thirty days (-1/+3 days) after the last dose of study drug, the subject will receive a Safety 
Follow-up telephone contact. In case the 125th event occurs in the study, the subjects 
discontinuing treatment will complete a 30-day Safety Follow-up Period in the EP0012 study. 
The 30-day Safety Follow up Period will be done as part of EP0012, except if the subject refuses 
to sign the EP0012 informed consent form. If the subject signs the informed consent form for a 
short Safety Follow-up as part of EP0012, the 30-day Safety Follow-up will be performed as part 
of EP0012; otherwise, the Safety Follow-up will be performed in SP0982.
Change #29
Section 10.2.1 Evaluation of PDILI
Paragraph 7
When IMP is stopped due to PDILI (as described in Section 6.4.1), IMP must be permanently 
discontinued.
Has been changed to:
Paragraph 7
When IMP is stopped due to PDILI (as described in Section 6.4.1), IMP must be permanently 
discontinued. Rechallenge with a substance potentially causing drug-induced liver injury is 
dangerous, may be fatal, and must not occur.
Change #30
Section 10.2.1 Evaluation of PDILI
Table 10-3 Required investigations and follow up for PDILI, text under Actions column for the 
ALT or AST ≥3xULN WITH Symptoms of hepatitis or hypersensitivity row
Immediate, temporary or permanent, IMP discontinuation.
Has been changed to:
Immediate, permanent IMP discontinuation.
Change #31
Section 11 ASSESSMENT OF PHARMACOKINETICS
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 
2 successive bid doses, according to the schedule of study assessments in Table 5-1. The time the 
REDACTED
ibed 
ibed
COPY 
i
This document
mm
mm
Ch
Ch
cannot 
te,
been
been
med
med
be
, tem
, tem
used
uired
red
3xUL
xUL
to 
d i
d i
support 
valua
alua
any
must n
must 
marketing 
I (as de
(as d
subst
subs
authorization 
n Sect
n Sect
application and 
p w
 w
P0982
0982
any 
me
med d
will b
will 
extensions 
ve
y, the
the
he EP
EP
if the 
f the 
d
or 
a
variations 
y y
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 260 of 267
subject took the most recent dose of IMP and the time of blood sampling must be recorded. 
Actual dosing and sampling times will be recorded in the eCRF to the minute.
Each blood sample drawn for LCM plasma concentration determination will be centrifuged and 
split into 2 duplicate samples prior to freezing. The samples will be stored at -20°C until shipped 
to a central laboratory. The central laboratory will store the plasma samples at -20°C until 
analysis.
Blood draws for these assessments will coincide with the blood collection times for assessment 
of the hematology and clinical chemistry parameters. Time and date of each blood draw will be 
documented on the eCRF. 
Instructions on blood sample collection, processing, storage, and labeling/shipping will be 
provided in the laboratory manual for this study.
Has been changed to:
Blood samples for analysis of LCM plasma concentrations will be collected at any time between 
2 successive bid doses, according to the schedule of study assessments in Table 5-1. The time the 
subject took the most recent dose of IMP and the time of blood sampling must be recorded. 
Actual dosing and sampling times will be recorded in the eCRF to the minute.
The central laboratory will store the plasma samples at -20°C until analysis. Blood draws for 
these assessments will coincide with the blood collection times for assessment of the hematology 
and clinical chemistry parameters. Time and date of each blood draw will be documented on the 
eCRF. 
Instructions on blood sample collection, processing, storage, and labeling/shipping are provided 
in the laboratory manual for this study.
Change #32
Section 12.2.1 Definition of source data
Paragraph 3
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.
Has been changed to:
Paragraph 3
If the source documents are maintained by the investigator in a computerized system, the 
monitor should ensure that electronic records are ALCOA (attributable, legible, 
contemporaneous, original, and accurate) compliant and that there is proper access control, 
validation, and audit trail available upon request. If the monitor has no direct access to the 
original electronic medical records, the certified copies should be generated by the investigator 
and used for the study purposes. Accuracy and completeness of data on the certified copies 
should be verified by the monitor to maintain ongoing compliance.
REDACTED 
ate 
ate
, proc
, proc
dy
dy.
COPY
at 
at -2
lec
ectio
ti
e of 
of
This document
f the
the
mo
mo
cannot 
en
en
agraph
graph
e s
e
be 
n ch
n c
used
 faci
fac
he da
he da
to
and
and
cili
il
support 
re com
e com
r (eg, E
(eg, E
d be
d b
any marketing 
f sou
so
authorization 
on t
n t
f each 
each 
cessing
essing
application
ampl
ampl
RF to th
F to th
0°C un
°C u
time
tim
and 
ect
ec
nts in
ts in
lili
any 
ted a
ted a
extensions 
g will 
will 
or variations 
ent 
nt 
ill be
ill be
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 261 of 267
Change #33
Section 13.3.1 Analysis of the primary efficacy variable
Paragraph 1, second sentence
Pooling strategies for strata with no events (ie, no subjects who had a second PGTC seizure) will 
be defined in the SAP prior to unblinding.
Has been changed to:
Paragraph 1, second sentence
Pooling strategies for strata with a low number of events will be defined in the SAP prior to 
unblinding.
Change #34
Section 13.3.2.2 Other secondary efficacy variables
Analyses of the other secondary efficacy variables will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described in Section 13.3.2.1) will be exploratory only. 
Time to the first PGTC seizure for the Treatment Period will be analyzed in the same manner as 
the primary endpoint using the FAS.
The percent change in log-transformed PGTC seizure frequency during the first 6 weeks of the 
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline PGTC 
seizure frequency. The percent change in log-transformed PGTC seizure frequency during the 
Treatment Period will be analyzed in a similar manner. Further approaches for the analysis of the 
secondary variable will be described in a detailed SAP.
Has been changed to:
Analyses of the other secondary efficacy variables will be performed using the FAS and will be 
descriptive in manner only. Any p-values or confidence limits provided other than those for the 
primary analysis of the primary variable (as described in Section 13.3.1) and the analysis of the 
key secondary efficacy variable (as described in Section 13.3.2.1) will be exploratory only. 
Time to the first PGTC seizure for the Treatment Period will be analyzed in the same manner as 
the primary endpoint using the FAS.
Further approaches for the analysis of the secondary variable will be described in a detailed SAP.
Change #35
Section 13.4 Planned safety and other analyses
Analyses of other variables, eg, safety or plasma concentration data, will be descriptive in 
manner only. Lacosamide plasma concentrations will be summarized and evaluated by 
population PK; details will be provided in a separate analysis plan.
The incidence and frequency of TEAEs will be summarized for each treatment group and study 
period. The incidence of SAEs and TEAEs leading to premature discontinuation from study drug 
REDACTED 
GTC se
TC se
g anal
g anal
ge in l
ge in l
n a
n a
COPY 
on
on
Period
Perio
This document
Sec
Sec
A
cannot
appr
ppr
a
ange
ange
be 
en
ro
ro
used
st PGT
PG
ndpo
ndpo
to
cacy
acy
support 
dar
da
ly. An
y. An
e prim
e prim
y va
v
y
any 
ry
ry ef
y
marketing 
log
og
simila
simila
in a d
in a d
authorization 
d w
eizure
izure
ys
ysis o
is o
g-tra
tra
application
ovide
ovid
on
on 13.
13
.3.2.1
3.2.1)
will b
will
and 
d usin
usin
d
any extensions
prior
prior
or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 262 of 267
will also be summarized for each treatment group and study period. Additional summaries will 
be provided by maximum intensity and relationship to study drug. All tables for AEs will be 
displayed by MedDRA® primary System Organ Class and Preferred Term. Further details on the 
analysis of AE data will be given in the SAP.
Observed values and changes from Baseline in vital signs, body weight, continuous laboratory 
parameters, and 12 lead ECG measurements will be summarized using continuous descriptive 
statistics. The number and percentage of subjects in each category will be summarized for the 
categorical outcomes. Shift tables summarizing the number and percentage of subjects having a 
different status (eg, abnormal laboratory result) post-Baseline compared to Baseline will be 
provided.
Incidence of new seizure types, and increase in absence seizure days per 28 days or myoclonic 
seizure days per 28 days during the Treatment Period will be summarized for each treatment 
group.
Has been changed to:
All safety analyses will be described in the SAP. Analyses of other variables, eg, safety or 
plasma concentration data, will be descriptive in manner only. Lacosamide plasma 
concentrations will be summarized and evaluated by population PK; details will be provided in a 
separate analysis plan.
The incidence and frequency of TEAEs will be summarized for each treatment group and study 
period. The incidence of SAEs and TEAEs leading to premature discontinuation from study drug
will also be summarized for each treatment group and study period. Additional summaries will 
be provided by maximum intensity and relationship to study drug. All tables for AEs will be 
displayed by MedDRA® primary System Organ Class and Preferred Term. Further details on the 
analysis of AE data will be given in the SAP.
Change #36
Section 13.4.1 Other safety analysis
This section has been removed for consistency with the variables section
Change #37
Section 13.8 Determination of sample size
Paragraph 2
This is an event-driven study. The study will be closed to enrollment once 125 events have been 
observed. If 125 events are observed prior 200 randomized subjects, then enrollment will stop 
and fewer than 200 subjects will be randomized. However, if 125 events are not observed after 
200 subjects are randomized, then the study will continue to enroll up to a maximum of 
250 subjects randomized or 125 events, whichever occurs first.
REDACTED
eadin
eadin
nt grou
t grou
relati
relati
stem O
stem O
the
th
COPY 
umm
umm
This document 
200
00
25
25
cannot 
n e
ved. If
ed. I
fewe
fewe
be 
even
even
used 
De
De
to
eter
ete
support
moved 
ved
any
ety
ety
f
marketing
Org
Org
e SAP.
SAP.
a
authorization
marize
marize
g to pr
g to pr
up and
p and
ionshi
onsh
rgan
gan
application 
r va
v
Lacosa
Lacos
tion PK
ion P
d
and 
varia
ari
any extensions 
 or m
or m
each t
each 
or 
be
be
variations 
ving a
ng a
thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 263 of 267
Has been changed to:
Paragraph 2
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring 
or a maximum of 250 subjects randomizing, whichever comes first.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 264 of 267
17.8
International Classification of Epileptic Seizures (1981)
Adapted from the International Classification of Epileptic Seizures (1981)
Clinical seizure types
I.
Partial seizures (focal, local)
A. Simple partial seizures (consciousness not impaired)
1. With motor signs
2. With somatosensory or special sensory symptoms (simple hallucinations, eg, 
tingling, light flashes, buzzing)
3. With autonomic symptoms or signs (including epigastric sensation, pallor, 
sweating, flushing, piloerection, and pupillary dilatation)
4. With psychic symptoms (disturbance of higher cerebral function). These 
symptoms rarely occur without impairment of consciousness and are much more 
commonly experienced as complex partial seizures.
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
with simple symptomatology)
C. Partial seizures evolving to secondarily generalized seizures (this may be generalized 
tonic-clonic, tonic, or clonic)
II. Generalized seizures (convulsive or non-convulsive)
A. Absence seizures
B. Myoclonic seizures - Myoclonic jerks (single or multiple)
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures - (Astatic)
III.Unclassified epileptic seizures
Includes all seizures that cannot be classified because of inadequate or incomplete data and some 
that defy classification in hitherto described categories. This includes some neonatal seizures, eg,
rhythmic eye movements, chewing, and swimming movements. 
Status epilepticus
Prolonged partial or generalized seizures without recovery between attacks.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised 
clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981;22:489-501.
REDACTED 
non
non-co
co
onic
onic
COPY 
eneral
ner
This documen
Prolo
rolo
Co
C
cannot 
ey
ey
us epi
s ep
on
on
be 
assi
ye m
e m
used
izures
zures
sific
ific
to
pilep
pile
support 
es
- (Asta
(As
epti
pt
any marketing
c jerks
jerks
authorization 
alize
iz
onvul
nvul
application 
ousness
usnes
zed s
ed s
and
usne
usne
any
unctio
nctio
ess
extensions 
ns
on, pa
n, pa
or
 eg
eg
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 265 of 267
17.9
Contraception table
Method
Abbreviation
no EI-AEDs
EI-AEDs
combined injectable contraceptives
CIC
ok
ok
combined patch
P
ok
needs barrier
combined vaginal ring
R
ok
needs second method
low-dose combined oral contraceptives
COC
ok
needs barrier
etonogestrel implant
ETG
ok
ok
levonorgestrel implant
LNG
ok
ok
depot medroxyprogesterone acetate
DMPA
ok
ok
norethisterone enantate
NET-EN
ok
ok
progestogen-only pills
POP
ok
needs barrier
emergency contraceptive pills
ECP
NA
NA
copper-bearing intrauterine devices
Cu-IUDs
ok
ok
levonorgestrel-releasing IUDs
LNG-IUDs
ok
ok
barrier methods
BARR
not eligible 
not eligible 
fertility awareness-based methods
FAB
not eligible 
not eligible 
lactational amenorrhoea method
LAM
not eligible 
not eligible 
coitus interruptus
CI
not eligible 
not eligible 
female and male sterilization
STER
ok
ok
REDACTED 
CT
CTED
RED
REDA
Cu-
L
COPY 
CO
COP
This document cannot be used
ed to
to sup
up ort 
uppo
any
any marketing 
g
U
LNG
NG-IU
IU
ar
arket
rket
uthorization
on
on 
hor
oriza
au
Ds
application 
n
lic
licati
ok
ok
ap
ap
nd 
and an
any
any extensions
ns s
eds b
eds b
tens
tensio
need
n
e
or
or 
or
or variations 
on
ar
thereof. 
07
07


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 266 of 267
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 
__
__
This document cannot be used to support any marketing authorization 
___
__
Date/
Date
application 
__
and any extensions
be 
ation 
ation
ents w
nts w
or
trea
tre
variations thereof. 


UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 267 of 267
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.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Approval Date 
(dd-mon-yyyy
(HH:mm))
633URWRFRO$PHQGPHQW
&OLQLFDO$SSURYDO
1RY*07
&OLQLFDO$SSURYDO
1RY*07
REDACTED COPY 
DO
This document cannot be used to support any marketing authorization application and 
an
a
y
any 
erve
a y extensions or variations thereof. 

SAP_000.pdf: 
UCB 
28 Mar 2019 
Statistical Analysis Plan 
SP0982 
STATISTICAL ANALYSIS PLAN 
Study: SP0982 
Product: Lacosamide 
A double-blind, randomized, placebo-controlled, parallel-group, multicenter study to evaluate 
the efficacy and safety of lacosamide as adjunctive therapy for uncontrolled primary generalized 
tonic-clonic seizures in subjects with idiopathic generalized epilepsy 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Amendment #2 
14 Mar 2017 
Amendment #3 
4 Jan 2019 
Amendment #4 
28 Mar 2019 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
REDACTED COPY 
16
AC
16
017
DAC
017
ar 201
RED
ar 201
20
R
20
keting authorization application and any extensions or variations thereof.
icenter
nd a
icenter
ntrolle
n and
ntrolle
neralize
tion 
neralize
17
ng
17
not be used to support any mar
01
e
019
eti
9
Mar 201
arke
Mar 201
This document canno
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 8 
1 
INTRODUCTION ........................................................................................................... 10 
2 
PROTOCOL SUMMARY ............................................................................................... 10 
2.1 
Study objectives ........................................................................................................... 10 
2.1.1 
Primary objective ................................................................................................. 10 
2.1.2 
Secondary objective ............................................................................................. 10 
2.2 
Study variables ............................................................................................................. 10 
2.2.1 
Efficacy variables ................................................................................................ 10 
2.2.1.1 
Primary efficacy variable .......................................................................... 10 
2.2.1.2 
Secondary efficacy variables ..................................................................... 10 
2.2.1.3 
Other efficacy variables ............................................................................. 10 
2.2.2 
Safety variables .................................................................................................... 12 
2.2.2.1 
Other safety variables ................................................................................ 12 
2.2.3 
Pharmacokinetic variables ................................................................................... 12 
2.3 
Study design and conduct ............................................................................................ 12 
2.3.1 
Study description ................................................................................................. 12 
2.3.2 
Rationale for study design ................................................................................... 14 
2.4 
Determination of sample size ....................................................................................... 15 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 15 
3.1 
General presentation of summaries and analyses ........................................................ 15 
3.2 
General study level definitions .................................................................................... 16 
3.2.1 
Analysis time points ............................................................................................ 16 
3.2.2 
Seizure cluster ...................................................................................................... 17 
3.2.3 
Event .................................................................................................................... 17 
3.2.4 
Censoring ............................................................................................................. 17 
3.2.5 
AEDs and benzodiazepines ................................................................................. 18 
3.2.5.1 
Prohibited concomitant treatments (medications and therapies) ............... 18 
3.2.6 
Relative day ......................................................................................................... 19 
3.2.7 
Last Visit .............................................................................................................. 19 
3.2.8 
Month ................................................................................................................... 19 
3.3 
Definition of Baseline values ....................................................................................... 19 
3.4 
Protocol deviations....................................................................................................... 19 
3.5 
Analysis sets................................................................................................................. 20 
3.5.1 
Screened Set ......................................................................................................... 20 
3.5.2 
Randomized Set ................................................................................................... 20 
3.5.3 
Safety Set ............................................................................................................. 20 
3.5.4 
Full Analysis Set .................................................................................................. 20 
REDACTED COPY 
.
Y
.
......
OP
......
.......
D C
.......
......
TE
......
ONS
ACT
ONS
aries a
REDA
aries a
s
R
s
ment cannot be used to support any marketing authorization application and any extensions or variations thereof.
0
v
0
...
o
...10
or v
10
........
on
........ 1
....
ns
.......
ns
...
........
ext
........
.......
ny
.......
........
d
........
........
n a
........
.......
atio
.......
........
plic
........
.......
ap
.......
........
tio
........
........
iz
........
.......
th
.......
and ana
g au
and ana
.......
tin
.......
........
ark
........
........
m
........
.......
an
.......
........
o
........
d benzo
supp
d benzo
Prohib
to s
Prohib
lative d
sed 
lative d
Last V
e us
Last V
Mo
be
Mo
Defi
anno
Defi
4
t
4
P
a
P
This documen
3.5
men
3.5


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
3.5.5 
Per Protocol Set ................................................................................................... 20 
3.6 
Treatment assignment and treatment groups ............................................................... 20 
3.7 
Center pooling strategy ................................................................................................ 21 
3.8 
Coding dictionaries ...................................................................................................... 21 
3.9 
Changes to protocol-defined analyses ......................................................................... 21 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 
4.1 
Adjustments for covariates .......................................................................................... 21 
4.2 
Handling of dropouts or missing data .......................................................................... 21 
4.2.1 
Missing seizure diary days ................................................................................... 21 
4.2.2 
Incomplete dates for first epilepsy diagnosis ....................................................... 22 
4.2.3 
Incomplete dates for adverse events and concomitant medications .................... 22 
4.2.4 
Incomplete date for the last administration of study medication ......................... 23 
4.2.5 
Missing adverse event intensity ........................................................................... 24 
4.2.6 
Missing adverse event relationship to study medication ..................................... 24 
4.3 
Interim analyses and data monitoring .......................................................................... 24 
4.4 
Multicenter studies ....................................................................................................... 24 
4.5 
Multiple comparisons/multiplicity ............................................................................... 24 
4.6 
Use of an efficacy subset of subjects ........................................................................... 24 
4.7 
Active-control studies intended to show equivalence .................................................. 25 
4.8 
Examination of subgroups ........................................................................................... 25 
4.9 
Stratum Pooling ........................................................................................................... 26 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 26 
5.1 
Subject disposition ....................................................................................................... 26 
5.2 
Protocol deviations....................................................................................................... 27 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 27 
6.1 
Demographics .............................................................................................................. 27 
6.1.1 
Derivation of demographics variables ................................................................. 27 
6.1.1.1 
BMI ........................................................................................................... 27 
6.1.2 
Analysis of demographics variables .................................................................... 28 
6.2 
Other Baseline characteristics ...................................................................................... 28 
6.2.1 
Derivation of other Baseline characteristics ........................................................ 28 
6.2.1.1 
Time since first diagnosis .......................................................................... 28 
6.2.1.2 
Age at diagnosis ........................................................................................ 28 
6.2.2 
Analysis of other Baseline characteristics ........................................................... 28 
6.3 
Subgroups .................................................................................................................... 28 
6.4 
Medical history and concomitant diseases ................................................................... 29 
6.5 
Procedure history ......................................................................................................... 29 
6.6 
Prior and concomitant medications .............................................................................. 29 
REDACTED COPY 
......
PY
......
......
CO
......
w equi
ED C
w equi
......
CT
......
.......
ED
.......
RACT
RE
RACT
to support any marketing authorization application and any extensions or variations thereof.
.21
r v
21
.......
ns
.......2
o
2
.......
si
.......
........
xte
........
........
y
........
.......
d a
.......
........
an
........
.......
tio
.......
.......
ica
........
a
.
.....
app
........
pp
...
.......
on
.......
ivalenc
izatio
ivalenc
.......
ho
.......
........
au
........
TERIS
ing 
TERIS
.......
ke
.......
........
ma
........
OTH
ny 
OTHE
........
ort
........
of dem
uppo
of dem
MI
o s
MI .
s
.
This document cannot be used
alysis o
ed to
alysis o
Baseli
use
Baseli
Der
be
Der
6.2.1.1
nnot
6.2.1.1
6.2
can
6.2
6.2
ent
6.2
6.3
m
6.3


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 29 
8 
EFFICACY ANALYSES ................................................................................................ 30 
8.1 
Statistical analysis of the primary efficacy variable .................................................... 30 
8.1.1 
Derivations of primary efficacy variable ............................................................. 30 
8.1.2 
Primary analysis of the primary efficacy variable ............................................... 30 
8.1.3 
Secondary analyses of the primary efficacy variable .......................................... 31 
8.1.4 
Supportive and sensitivity analyses of the primary efficacy variable ................. 31 
8.2 
Statistical analysis of the secondary efficacy variables ............................................... 31 
8.2.1 
Derivations of secondary efficacy variables ........................................................ 32 
8.2.1.1 
Variable: Seizure freedom for PGTCS for the 166-day Treatment Period 32 
8.2.1.2 
Variable: Time to first PGTCS during the 166-day Treatment Period ..... 32 
8.2.2 
Analysis of secondary efficacy variables............................................................. 32 
8.2.2.1 
Analysis: Seizure freedom for PGTCS for the 166-day Treatment Period32 
8.2.2.2 
Analysis: Time to first PGTCS during the 166-day Treatment Period ..... 33 
8.3 
Analysis of seizure related other efficacy variables .................................................... 34 
8.3.1 
Derivations of seizure related other efficacy variables ........................................ 34 
8.3.1.1 
Variable: PGTCS frequency per 28 days .................................................. 34 
8.3.1.2 
Variable: Days with seizures per 28 days ................................................. 35 
8.3.1.3 
Variable: Seizure-free status ..................................................................... 35 
8.3.1.4 
Variable: Responder status – reduction in PGTCS frequency .................. 35 
8.3.1.5 
Variable: PGTCS frequency - worsening .................................................. 36 
8.3.1.6 
Variable: Responder status – reduction in days with absence seizures ..... 36 
8.3.1.7 
Variable: Responder status – reduction in days with myoclonic seizures 36 
8.3.1.8 
Variable: Days with absence and myoclonic seizures – worsening .......... 36 
8.3.1.9 
Variable: Absence and myoclonic seizure frequencies per 28 days ......... 36 
8.3.1.10 
Variable: Responder status – reduction in absence and myoclonic seizure 
frequencies ................................................................................................. 37 
8.3.1.11 
Variable: Absence and myoclonic seizure frequency - worsening ........... 37 
8.3.2 
Analysis of seizure related other efficacy variables ............................................ 37 
8.3.2.1 
Analysis: Percent change in PGTCS frequency per 28 days from 
Combined Baseline .................................................................................... 37 
8.3.2.2 
Analysis: Reduction in days with seizures per 28 days ............................. 37 
8.3.2.3 
Analysis: Seizure-free status ..................................................................... 38 
8.3.2.4 
Analysis: Responder status – reduction in PGTCS frequency .................. 38 
8.3.2.5 
Analysis: Responder status – reduction in days with absence seizures..... 39 
8.3.2.6 
Analysis: Responder status – reduction in days with myoclonic seizures 39 
8.3.2.7 
Analysis: Percent change in absence and myoclonic seizure frequency per 
28 days from Prospective Baseline............................................................ 40 
REDACTED COPY
8 day
PY 
8 day
er 28 
COP
er 28 
s
E
s ....
ED
....
atus
ACT
atus –
T
–
equen
EDA
equen
der st
RE
der st
y marketing authorization application and any extensions or variations thereof.
.31
r v
31
.......
ns
.......32
o
32
nt Perio
nsion
nt Perio
nt Perio
xten
nt Perio
........
y
........
y Treat
d any
y Treat
y Treatm
and
y Treatm
.......
tio
.......
bles
licat
bles..
a
..
s
a
s ......
app
......
days
ion a
days
........
za
........
reduct
horiz
reduct
ncy 
au
ncy -
u
- w
th
w
status
ting
status
der statu
rket
der statu
with a
mar
with a
This document cannot be used to support an
Absence
any 
Absence
e: Resp
ort a
e: Resp
uencies
ppo
uencies
Variable
o sup
Variable
lysis of
ed to
lysis of
A
e
A
.3.2.2
not b
.3.2.2
8.3.2
ann
8.3.2
8
c
8


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
8.3.2.8 
Analysis: Responder status – reduction in absence and myoclonic seizure 
frequency ................................................................................................... 40 
8.4 
Analysis of health outcome other efficacy variables ................................................... 41 
8.4.1 
Derivations of health outcome other efficacy variables ...................................... 41 
8.4.1.1 
QOLIE-31-P variables ............................................................................... 41 
8.4.1.2 
PedsQL variables ....................................................................................... 42 
8.4.1.3 
EQ-5D-3L quality of life variables ........................................................... 42 
8.4.1.4 
Hospital stays ............................................................................................ 42 
8.4.2 
Analysis of health outcome other efficacy variables ........................................... 43 
8.4.2.1 
QOLIE-31-P variables ............................................................................... 43 
8.4.2.2 
PedsQL variables ....................................................................................... 43 
8.4.2.3 
EQ-5D-3L quality of life variables ........................................................... 43 
8.4.2.4 
Concomitant medical procedures .............................................................. 44 
8.4.2.5 
Healthcare provider consultations ............................................................. 44 
8.4.2.6 
Hospital stays ............................................................................................ 44 
8.4.2.7 
Number of working or school days lost due to epilepsy ........................... 44 
8.4.2.8 
Number of days with help from a paid caregiver due to epilepsy ............. 44 
8.4.2.9 
Socio-professional data ............................................................................. 44 
9 
PHARMACOKINETICS ................................................................................................. 44 
10 SAFETY ANALYSES ..................................................................................................... 45 
10.1 
Extent of exposure ....................................................................................................... 45 
10.1.1 
Derivation of exposure variables ......................................................................... 45 
10.1.2 
Analysis of exposure variables ............................................................................ 45 
10.2 
Adverse events ............................................................................................................. 45 
10.3 
Clinical laboratory evaluations .................................................................................... 47 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 48 
10.4.1 
Vital signs ............................................................................................................ 48 
10.4.2 
Electrocardiograms .............................................................................................. 48 
10.4.2.1 
Derivation of corrected QT values ............................................................ 48 
10.4.2.2 
Analysis of ECG parameters ..................................................................... 49 
10.4.3 
Physical examination ........................................................................................... 49 
10.4.4 
Safety Seizure Information .................................................................................. 49 
10.4.4.1 
New Seizure Type ..................................................................................... 49 
10.4.4.2 
Increase in days with absence seizures ...................................................... 50 
10.4.4.3 
Increase in days with myoclonic seizures ................................................. 50 
10.4.4.4 
Increase in absence seizure frequency ....................................................... 50 
10.4.4.5 
Increase in myoclonic seizure frequency .................................................. 50 
10.4.5 
Tanner stage assessment ...................................................................................... 50 
REDACTED COPY
paid c
PY 
paid c
......
CO
......
.....
ED
......
D
.
......
CT
......
.......
DA
.......
variab
RED
variab
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
42
r v
42
......
s
......43
o
43
.......
sio
.......
........
te
........
........
y e
........
.......
an
.......
.....
an
........
n
...
.......
on
.......
to epil
icati
to epil
aregive
ppli
aregive
.......
n
.......
........
at
........
.......
or
.......
..........
ut
......
bles
ng
bles..
g
..
ables
ketin
ables
........
ma
........
uations
ny m
uations
l findin
ort a
l findin
........
pp
........
cardiog
o sup
cardiog
Deriv
d to
Deriv
2
A
e
A
Phys
be 
Phys
.4
n
.4
S
10.4
an
10.4


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
10.4.6 
Neurological examination .................................................................................... 51 
10.4.7 
Assessment of suicidality .................................................................................... 51 
10.4.8 
Achenbach Child Behavior Checklist .................................................................. 51 
10.4.8.1 
Derivation of Achenbach variables ........................................................... 51 
10.4.8.2 
Analysis of Achenbach variables .............................................................. 52 
10.4.9 
BRIEF-P and BRIEF assessment ......................................................................... 53 
10.4.9.1 
BRIEF-P scores ......................................................................................... 53 
10.4.9.2 
BRIEF scores ............................................................................................. 54 
10.4.10 
Vagus nerve stimulation ...................................................................................... 55 
10.4.11 
Ketogenic diet ...................................................................................................... 56 
11 REFERENCES ................................................................................................................ 57 
12 APPENDICES ................................................................................................................. 58 
12.1 
Appendix 1: QOLIE-31-P total and subscale score calculations ................................. 58 
12.2 
Appendix 2: Adverse Events ....................................................................................... 62 
12.2.1 
Other Significant AEs .......................................................................................... 62 
12.2.2 
List of AEs for Potentially Drug Induced Liver Injury (PDILI).......................... 64 
12.3 
Appendix 3: Markedly abnormal values ...................................................................... 67 
12.3.1 
Hematology .......................................................................................................... 67 
12.3.2 
Chemistry ............................................................................................................. 68 
12.3.3 
Vital signs ............................................................................................................ 70 
12.3.4 
ECGs .................................................................................................................... 72 
12.4 
Appendix 4: NCI CTC ................................................................................................. 73 
12.5 
Appendix 5: Registry Required Tables ........................................................................ 75 
12.6 
Additional Subgroups to be programmed in ADSL .................................................... 76 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 77 
13.1 
Amendment 1 ............................................................................................................... 77 
13.1.1 
Rationale for the amendment ............................................................................... 77 
13.1.2 
Modification and changes .................................................................................... 77 
13.1.2.1 
Specific changes ........................................................................................ 77 
13.2 
Amendment 2 ............................................................................................................... 80 
13.2.1 
Rationale for the amendment ............................................................................... 80 
13.2.2 
Modification and changes .................................................................................... 81 
13.2.2.1 
Specific changes ........................................................................................ 81 
13.3 
Amendment 3 ............................................................................................................... 82 
13.3.1 
Rationale for the amendment ............................................................................... 82 
13.3.2 
Modification and changes .................................................................................... 82 
13.3.2.1 
Specific changes ........................................................................................ 82 
13.4 
Amendment 4 ............................................................................................................. 114 
REDACTED COPY 
......
PY
......
......
CO
......
......
ED
......
.
C
......
CT
.....
.......
ED
.......
....
R
....
sed to support any marketing authorization application and any extensions or variations thereof.
.54
r v
54
.......
ns
.......55
o
55
......
si
.......
..
xt
........
xte
......
.......
y
........
.......
d a
.......
........
an
........
.......
tio
.......
njury (P
licat
njury (P
........
app
........
.......
on
.......
........
za
........
.......
ho
.......
........
au
........
........
ing
........
d Table
rket
d Table
e progr
mar
e progr
HE
any
HE ST
y 
ST
........
ort
........
or the a
ppo
or the a
cation a
to su
cation a
Spec
ed to
Spec
ent cannot be u
dment
use
dment
Rat
be
Rat
2.2
nn
2.2
13
an
13
This documen
13.3
ent
13.3


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
13.4.1 
Rationale for the amendment ............................................................................. 114 
13.4.2 
Modification and changes .................................................................................. 114 
13.4.2.1 
Specific changes ...................................................................................... 115 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 126 
 
LIST OF TABLES 
Table 1: 
Number of PGTC Seizures for Study Entry .................................................... 13 
Table 2: 
CBCL/1½-5 ...................................................................................................... 51 
Table 3:  
CBCL/6-18 ....................................................................................................... 52 
Table 4: 
BRIEF-P questionnaire scoring ....................................................................... 53 
Table 5: 
BRIEF questionnaire scoring ........................................................................... 54 
Table 6:  
Other Significant AEs ...................................................................................... 62 
Table 7:  
AEs for PDILI .................................................................................................. 64 
Table 8:  
Hematology - Markedly Abnormal Values ...................................................... 67 
Table 9:  
Chemistry: Markedly Abnormal Values .......................................................... 68 
Table 10:  
Vital Signs - Abnormality Criteria ................................................................... 70 
Table 11:  
ECGs - Abnormality Criteria ........................................................................... 72 
Table 12:  
NCI CTC .......................................................................................................... 73 
 
 
REDACTED COPY 
ues
OP
ues...
PY
...
a
D
a.....
D C
.....
......
CTE
......
......
DA
......
ication and any extensions or variations thereof.
13
v
13
......
s 
......51
o
51
......
nsi
........
i
..
.......
ext
.......
.......
ny
.......
........
nd
........
.....
on
.......
n
..
uthorization applic
.......
lica
.......
........
ap
........
.......
tio
.......
.......
oriz
.......
This document cannot be used to support any marketing au
........
ut
........


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
BMI 
body mass index 
BP 
Blood pressure 
BRI 
Behavioral Regulation index 
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive 
Function®-Preschool version 
CB 
combined baseline 
CBCL 
Child Behavior Checklist 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
ET 
Early Termination 
EQ-5D-3L 
3-Level EuroQol-5 Dimension Quality of Life 
Assessment 
FAS 
Full Analysis Set 
GEC 
Global Executive Composite 
GGT 
Gamma glutamyl transferase 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IDMC 
independent data monitoring committee 
IGE 
idiopathic generalized epilepsy 
II 
Generalized seizures 
IIA 
Absence seizures 
IIB 
Myoclonic seizures 
IIC 
Clonic seizures 
IID 
Tonic seizures 
IIE 
(primary generalized) tonic-clonic seizures 
IIF 
Atonic seizures 
REDACTED COPY 
icide S
CO
icide S
ardiogr
TED 
ardiogr
y Term
ACT
y Term
-
E
-Leve
RED
Leve
Ass
RE
Ass
keting authorization application and any extensions or variations thereof.
nction
y ex
nction®
t
®
e 
d
e 
Severity
ion a
Severity
ram
iza
ram
mination
thor
mination
l
g
l EuroQ
g au
EuroQ
essmen
ting
essmen
This document cannot be used to support any mark
Full A
arke
Full A
Gl
ma
Gl
A
IIB
t ca
IIB
I
n
I


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
III 
Unclassified seizures 
ILAE 
International League Against Epilepsy 
IRT 
Interactive response technology 
KM 
Kaplan-Meier 
LCM 
Lacosamide 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Metacognition Index 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
PCH 
percent change 
PedsQL 
Pediatric Quality of Life Inventory  
PGTC 
primary generalized tonic-clonic 
PGTCS 
Primary generalized tonic-clonic seizure 
PH 
proportional hazard 
PHREG 
proportional hazards regression 
PPS 
Per-Protocol Set 
PT 
preferred term 
QOLIE-31-P 
Patient-Weighted Quality of Life in Epilepsy 
Inventory-Form 31 
QTcB 
Bazett corrected QT 
QTcF 
Fridericia corrected QT 
RS 
Randomized Set 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical analysis software 
ScS 
Screened Set 
SF 
seizure frequency 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
treatment emergent adverse event 
TEMA 
treatment emergent markedly abnormal 
ULN 
upper limit of normal 
VAS 
visual analog scale 
VNS 
vagus nerve stimulation 
WHO-DD 
World Health Organization Drug Dictionary 
REDACTED COPY 
zards r
OPY
zards r
l Set
D CO
l Set
ed term
CTE
ed term
ient
DAC
ient-
A
-W
AC
W
Invent
RED
Invent
B
R
B
ting authorization application and any extensions or variations thereof.
Criteria
nsio
Criteria
nic seiz
tion
nic seiz
regressi
n app
regressi
m
o
m
Weighte
auth
Weighte
tory
g a
tory-
a
-Fo
au
Fo
This document cannot be used to support any marke
azett co
keting
azett co
Fride
mark
Fride
R
m
R
EAE
nno
EAE
TEM
nt ca
TEM
U


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
1 
INTRODUCTION 
The purpose of the statistical analysis plan (SAP) is to describe the analyses of study SP0982. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary study objective is to demonstrate the efficacy of oral lacosamide (LCM) vs placebo 
as adjunctive therapy for uncontrolled primary generalized tonic-clonic seizures (PGTCS) in 
subjects with idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant 
antiepileptic drugs (AEDs) independent of the number of prior failed AEDs. 
2.1.2 
Secondary objective 
The secondary study objective is to assess the safety and tolerability of LCM in subjects with 
IGE with uncontrolled PGTCS. 
2.2 
Study variables 
2.2.1 
Efficacy variables 
2.2.1.1 
Primary efficacy variable 
The primary efficacy variable is the time to the second PGTCS during the 24-week Treatment 
Period. 
2.2.1.2 
Secondary efficacy variables 
The key secondary efficacy variable is: 
 Seizure freedom for PGTCS during the 24-week Treatment Period, estimated using Kaplan-
Meier analysis 
The other secondary efficacy variable is: 
  Time to first seizure during the 24-week Treatment Period 
2.2.1.3 
Other efficacy variables 
Other efficacy variables are: 
 The percent change in PGTCS frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Combined Baseline Period (combined 12-
week Historical and 4-week Prospective Baseline Periods) 
 The percent change in PGTCS frequency per 28 days during the first 12 weeks of the 
Treatment Period relative to the Combined Baseline Period 
 The percent change in PGTCS frequency per 28 days during the Treatment Period relative to 
the Combined Baseline Period 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline Period 
REDACTED COPY 
cond P
COP
cond P
ables
CTE
ables
ng th
RE
ng th
d to support any marketing authorization application and any extensions or variations thereof.
ebo 
vari
ebo 
) in
or
) in
M in su
ny e
M in su
PGTCS
on ap
PGTCS
h
the 24
ting
the 24
iable is
y ma
iable is
ing the 
t any
ing the 
ficacy
ppor
ficacy
bles are
o sup
bles are
This document cannot be used
change
ed to
change
t Period
use
t Period
Historic
be u
Historic
he perce
nnot
he perce
Treatm
can
Treatm

e

Th
nt
Th


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline Period 
 Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline Period 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline Period 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline Period 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline Period 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline Period 
 Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Titration Period compared to Combined Baseline Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 
weeks of the Treatment Period compared to Combined Baseline Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Treatment Period compared to Combined Baseline Period 
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
 Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or 
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age 
 Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 
Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and 
change in utility as converted from the 5 dimensions (for subjects ≥12 years of age) 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
 Number of working or school days lost by subject due to epilepsy 
REDACTED COPY 
wee
Y
wee
uction
COP
uction
aseline
ED C
aseline
0% re
ACTE
0% re
pared 
EDAC
pared 
st a 
RE
st a 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
e to
var
e to
eks of th
ons 
eks of th
eatment
exte
eatment
eizure 
nd a
eizure 
ks of th
atio
ks of th
Treatm
pplic
Treatm
n in PG
on a
n in PG
e Perio
zatio
e Perio
ductio
horiz
ductio
to Com
auth
to Com
50% re
ting 
50% re
mbined
rketi
mbined
or all 
ma
or all g
a
g
s, no) f
port 
s, no) f
aseline
to s
aseline
P) subs
ed t
P) subs
atigue, 
use
atigue, 
y of Lif
be u
y of Lif
nge fro
not b
nge fro
Functio
ann
Functio
score
nt ca
score

me



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Number of days with help from a caregiver due to epilepsy 
2.2.2 
Safety variables 
The safety variable is: 
 Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed 
by the investigator 
2.2.2.1 
Other safety variables 
Other safety variables are: 
 Subject withdrawal due to AEs 
 Incidence of new seizure types during the Treatment Period 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
 Changes in hematology, chemistry, endocrinology, and urinalysis parameters 
 Changes in 12-lead electrocardiograms (ECGs) 
 Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings 
 Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18) 
 Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool 
Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF]) for 
pediatric subjects only 
2.2.3 
Pharmacokinetic variables 
The plasma concentrations of LCM will be assessed. 
2.3 
Study design and conduct 
2.3.1 
Study description 
SP0982 is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy of oral LCM vs placebo as adjunctive therapy for uncontrolled 
PGTCS in subjects ≥4 years of age with IGE currently taking 1 to 3 concomitant AEDs 
independent of the number of prior failed AEDs.  
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study to see 125 
events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of 
study medication administration is 28 weeks. The study will last a maximum of 36 weeks per 
subject.  
REDACTED COPY 
gy, an
OPY
gy, an
Gs)
D C
Gs)
 blood
CTE
 blood
neuro
DAC
neuro
ch Ch
RE
ch Ch
port any marketing authorization application and any extensions or variations thereof.
>75% 
exte
>75% 
to the 
any e
to the 
75%, a
n an
75%, a
eriod re
ation
eriod re
nd urina
app
nd urina
d press
horiz
d press
ological
utho
ological
hild Be
ing a
hild Be
ehavio
rket
ehavio
or Ratin
mar
or Ratin
kinetic
rt a
kinetic
This document cannot be used to sup
ions of 
uppo
ions of 
udy de
d to s
udy de
Study
used
Study
a doub
be u
a doub
d to as
not b
d to as
CS in s
ann
CS in s
ndepend
nt ca
ndepend
Up t
men
Up t
ex
m
ex


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Eligibility to enter SP0982 will be based on a 12-week Historical Baseline prior to screening at 
Visit 1. In rare cases where there is a gap between consenting and Visit 1 procedures, the 12-
week Historical Baseline will be calculated from the date of Informed Consent/Assent.  
Prior to randomization, the following 3 criteria concerning PGTCS frequency must be met: 
 The subject must have experience at least 3 PGTCS during the 16-week Combined Baseline 
Period, 
 The subject must have experienced at least 2 PGTCS during the 12-week Historical Baseline 
Period, 
 Of the above seizures, at least 1 PGTCS should have occurred during the first 8 weeks and at 
least 1 PGTC seizure should have occurred during the second 8 weeks of the 16-week 
Combined Baseline Period. 
Examples of different scenarios and the subjects’ eligibility in terms of Baseline Period PGTCS 
are presented in Table 1 . Seizures reported on the Historical Seizure Count CRF with 
incomplete dates will be assumed to have occurred with the 12-week Historical Baseline Period 
when checking eligibility for the study and inclusion in baseline PGTCS frequency per 28 days. 
Table 1: 
Number of PGTC Seizures for Study Entry 
Number of PGTCS for Study Entry 
Subject Eligible for 
Study? 
Historical Baseline 
Weeks -16 to -9 
Historical Baseline 
Weeks -8 to -5 
Prospective Baseline 
Weeks -4 to 0 
(Visit 1 to Visit 2) 
2 
1 
0 
Yes 
3 
0 
0 
No 
1 
1 
1 
Yes 
0 
2 
1 
No 
1 
2 
0 
Yes 
2 
0 
1 
Yes 
1 
0 
2 
No 
1 
1 
0 
No 
The study consists of a 4-week Prospective Baseline Period and a 6-week (minimum) to 24-week 
(maximum) Treatment Period, which includes a 6-week Titration Period and an 18-week 
(maximum) Maintenance Period. Eligible subjects who choose to enter the open-label extension 
study (EP0012) after the completion of Visit 10 (Week 24) or the ET Visit will complete a 4-
week blinded transition. Subjects who choose not to continue in EP0012 must complete an up to 
4-week blinded taper followed by a 30-day Safety Follow-up Period. 
At the end of the 4-week Prospective Baseline (Visit 2), eligible subjects will be randomized to 
receive LCM or placebo in a 1:1 fashion (active:placebo) and stratified by Baseline PGTCS 
frequency (≤2 per 28 days vs >2 per 28 days for the 16 week Combined Baseline Period prior to 
randomization) and by age at informed consent (≥4 to <12 years of age vs ≥12 to <18 years of 
REDACTED COPY 
y
OP
y
Y
Pro
CO
Pro
OP
ED
DA
RE
d to support any marketing authorization application and any extensions or variations thereof.
ine
ari
ine 
eeks an
ons 
eeks an
6
n
6-week
sio
week
eline Pe
ny e
eline Pe
unt CR
d any
unt CR
Histori
and 
Histori
GTCS f
on a
GTCS f
ry
ic
ry
pli
ospectiv
tion
ospectiv
We
at
We
(V
r
(V
a
th
uth
uth
uth
uth
g
1
ke
2
y m
2
ma
any
o
s
cannot be used to su
sup
s
d t
us
consist
be u
consist
mum) Tr
not b
mum) Tr
ximum)
ann
ximum)
This document 
udy (E
nt ca
udy (E
week
ment
week
4
m
4


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
age, and ≥18 years of age). The Treatment Period starts at the time of the Randomization Visit 
(Visit 2). 
The Treatment Period continues until 1 of the following occurs (whichever occurs first): 
 Completion of ≥6 weeks of the Treatment Period and occurrence of ≥2 PGTCS 
 Completion of 24 weeks of the Treatment Period without occurrence of 2 PGTCS 
 Occurrence of the 125th event (an event is each subject’s 2nd second PGTCS). 
Subjects will be required to exit the study and complete the ET Visit if either of the following 
events occur: 
 Subject completes the first 6 weeks of the Treatment Period (after randomization) and 
experiences ≥2 PGTCS during that time 
 Subject experiences a second PGTCS after the first 6 weeks of the Treatment Period 
If the 125th event occurs while the subject is still participating in the study, the subject can: 
 Complete the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and 
choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic 
Visit. 
 Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next 
scheduled visit is not Visit 10) and an up to 4-week blinded taper followed by an End of 
Taper visit.  
The study design is discussed in more detail in Section 5 of the protocol. 
2.3.2 
Rationale for study design 
Clinical experience has shown that up to 30% of patients with PGTCS who are treated with 
currently available AEDs have insufficient PGTCS control or unacceptable drug tolerability.  
Thus, there is a significant unmet medical need for new treatment options in this patient 
population.  
The primary efficacy variable, the time to the second PGTCS, has several advantages from a 
clinical and methodological perspective. In traditional adjunctive study designs, the primary 
endpoint is percent reduction in PGTCS frequency over the entire Treatment Period; which 
requires a higher frequency of PGTCS at entry. Using the time to second PGTCS, the frequency 
of Baseline PGTCS and the duration of the Prospective Baseline can be reduced as the endpoint 
is time to reach an event (second PGTCS), rather than a percentage decrease in the number of 
events (PGTCS). This expands the patient population under study and allows for enrollment of 
subjects more representative of the broader PGTCS population. Furthermore, subjects are treated 
for up to 24 weeks in a traditional adjunctive design, depending upon the titration schedule of the 
active treatment. Subjects must remain on treatment as they continue to experience PGTCS. In 
the time to nth seizure design, subjects are required to remain in the study for a minimum of 6 
weeks. If a subject experiences ≥2 PGTCS while on treatment, then after 6 weeks the subject 
exits the study, rather than continuing to have PGTCS, while remaining eligible to receive LCM 
in the open-label extension study (EP0012). 
REDACTED COPY 
Visit 10
OPY
Visit 10
week
D CO
week
ail in S
ACT
ail in S
desig
REDA
desig
t
R
t
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
ing
or v
ing
on) and 
nsion
on) and 
ment P
ny ex
ment P
dy, the 
d an
dy, the 
uled vis
n an
uled vis
tion fo
ation
tion fo
0 (Wee
app
0 (Wee
k blind
tion 
k blind
Section
thor
Section
gn
g a
gn
to 30%
keting
to 30%
fficient
arke
fficient
t medic
y ma
t medic
able, th
port 
able, th
gical pe
uppo
gical pe
reductio
o su
reductio
frequen
d to
frequen
GTCS a
used
GTCS a
each an
be us
each an
PGTCS
ot be
PGTCS
cts mor
nno
cts mor
r up to 2
t can
r up to 2
This documen
active 
ent c
active 
the 
me
the 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The rationale for time to second PGTCS was established by using data from an adjunctive study 
in subjects with PGTCS, using an 8-week Baseline, 7-week Titration, and 12-week Maintenance 
Period comparing lamotrigine and placebo (French et al, 2007). This post-hoc analysis using a 
Cox proportional hazards model revealed that time to third PGTCS was statistically significant 
with a hazard ratio of 0.533 (lamotrigine 48.2%, placebo 25.4%). Lamotrigine requires a long 
Titration Period, where a minimally effective dose is not reached until the fifth week of the 
Titration Period (100mg/day). Lacosamide, by comparison, reaches a minimally effective dose in 
the second week (200mg/day) for a majority of trial subjects. Since a majority of the events in 
the lamotrigine study occurred before Day 21, it is likely that fewer events would occur using 
LCM as it reaches an effective dose earlier; therefore, time to second PGTCS was chosen as a 
reasonable endpoint from a clinical and statistical perspective. 
2.4 
Determination of sample size 
Observing 125 events (subjects who had a second PGTCS during the 24-week Treatment Period) 
will provide 90% power to observe a hazard ratio of 0.56 at the 2-sided 5% level, assuming a 
dropout rate of 15%. The observed hazard ratio was based on a 25.4% survival rate for placebo 
and 48.2% for lamotrigine from a previous study comparing lamotrigine and placebo (French et 
al, 2007). The observed hazard ratio in the lamotrigine study was 0.533; however, in order to 
account for the possibility of an increased placebo response, as has been documented in recent 
clinical studies of AEDs, the hazard ratio was increased by 5% to 0.56 for estimating a sample 
size for this study. The rationale for the increase in the hazard ratio included the following 
considerations: different active compounds (LCM and lamotrigine) and a choice of time to 
second PGTCS as the primary efficacy endpoint (in the lamotrigine study, percent change in 
PGTCS frequency was the primary endpoint).  
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring 
or a maximum of 250 subjects randomized, whichever comes first.  
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier 
New font size 9. 
Descriptive statistics will be used to provide an overview of the primary, secondary, and other 
variable results. For categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based on the number of 
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will 
be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal 
will be presented when the percentage is 100%. For continuous parameters, descriptive statistics 
will include number of subjects, mean, standard deviation, median, minimum, and maximum.  
Decimal places for descriptive statistics will always apply the following rules: 
 “n” will be an integer 
 Mean, SD and median will use 1 additional decimal place compared to the original data. 
 Minimum and maximum will have the same number of decimal places as the original value. 
REDACTED COPY
ed by
PY 
ed by
the ha
COPY
the ha
M and
D CO
M and
oint (in
TED
oint (in
int).
ACT
int).
ment in
REDA
ment in
mize
RE
mize
annot be used to support any marketing authorization application and any extensions or variations thereof.
ng 
r v
ng 
n as a 
s or 
n as a 
ek Trea
y ex
ek Trea
% level
any 
% level
surviva
nd a
surviva
gine an
n an
gine an
0.533;
tion
0.533;
s has be
licat
s has be
5% to 
ppli
5% to 
azard r
n ap
azard r
d lamot
ation
d lamot
n the la
rizat
n the la
n the st
g au
n the st
ed, whi
ting 
ed, whi
S CO
arke
S CO
entati
ny m
entati
eration 
ort a
eration 
SAS® 
ppor
SAS® 
tics wil
d to
tics wil
s. For c
used
s. For c
ll be pr
be us
ll be pr
approp
ot be
approp
played
nno
played
This document c
ll be pr
t can
ll be pr
will in
ent c
will in
De
m
De


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. 
Data provided at these visits will be included in subject data listings. A complete set of data 
listings containing all documented data and all calculated data (eg, change from Baseline) will be 
generated. 
3.2 
General study level definitions 
3.2.1 
Analysis time points 
The following study periods will be defined for analyses:  
 Historical Baseline Period: This period starts 84 days prior to Visit 1 and ends the day before 
Visit 1. This is expected to be 12 weeks in duration. 
 Prospective Baseline Period: This period starts the date of Visit 1 and ends the day before 
Visit 2. This is expected to be 4 weeks in duration. 
 Combined Baseline Period: combined Historical and Prospective Baseline Periods. This 
Period starts 84 days prior to Visit 1 and ends the day before Visit 2. This is expected to be 
16 weeks in duration. 
 Treatment Period: 24-week period following the 4-week Prospective Baseline. The 
Treatment Period is composed of the Titration Period and the Maintenance Period. 
 Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration 
Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before 
Visit 5 (or the date of the Early Termination (ET) visit in the situation where a subject 
discontinues prior to the last visit in the Titration Period). 
 Maintenance Period: 18-week period following the 6-week Titration Period. The 
Maintenance Period starts on the day of Visit 5 and continues until 1 of the following 
occurs (whichever occurs first): 
◦ 
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures 
and completion of the ET Visit 
◦ 
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 
2 PGTC seizures. 
 First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the 
Maintenance Period. 
 Transition Period: up to 4-week period after the completion of Visit 10 (Week 24) or the ET 
Visit for subjects who choose to enter EP0012. The Transition Period starts the day after 
Visit 10 (Week 24) or the ET Visit and continues until 1 of the following occurs (whichever 
occurs first): 
◦ 
On the day before the first date that there is a dose decrease (subject enters Taper 
period) 
◦ 
On the date of the Final Clinic Visit (also date of EP0012 Visit 1). 
 Taper Period: up to 4-week period following either the Treatment Period for subjects who 
discontinue from the study at any time and are not eligible or choose not to enter EP0012 or 
DACTED COPY 
Y
he 4
OPY
he 4-
P
-w
PY
w
ation 
D CO
ation 
nation
TED 
nation
n the T
ACTE
n the T
RED
period
EDA
period
the
RE
the d
E
d
uthorization application and any extensions or variations thereof.
y befor
or v
y befor
e day b
ensi
e day b
line Pe
any 
line Pe
. This i
nd a
. This i
spectiv
ation
spectiv
the M
plica
the M
week Pr
n app
week Pr
Visit (
tion 
Visit (
n (ET) v
izati
n (ET) v
Titratio
horiz
Titratio
support any marketing a
d follow
aut
d follow
day of 
ting 
day of 
):
k
):
ks of th
mar
ks of th
he ET V
ny m
he ET V
18 wee
ort a
18 wee
ures.
ppo
ures.
ot be used to 
ks: this
o su
ks: this
nce Pe
d to
nce Pe
on Perio
e us
on Perio
for subj
t be
for subj
This document cann
sit 10 (
nnot 
sit 10 (
occurs
cann
occurs


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
following the Transition Period for subjects that discontinue from the study during the 
Transition Period. The Taper Period starts the first date that there is a dose decrease or the 
day after the ET Visit for subjects that choose not to enter EP0012 and continues until the 
date of last dose of study medication.  
 Safety Follow-up Period: period following the Taper Period for subjects who complete the 
Taper Period. The Safety Follow-up Period starts the day after the last dose of study 
medication and continues until the Final Clinic Visit date or the Safety Follow-up telephone 
contact date, whichever is later. 
3.2.2 
Seizure cluster 
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy 
(ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters 
reported. 
3.2.3 
Event 
In the primary efficacy analysis, an event for analysis purposes is: 
 The 2nd PGTCS 
While keeping in mind the definition of seizure clusters in Section 3.2.2. 
For the primary and secondary efficacy analyses, these endpoints will be assessed using the at 
most the first 166 days, which is the 24-week Treatment Period minus a protocol-allowed 2 day 
window.  For all other efficacy parameters, all data reported during the Treatment Period will be 
used in the analysis. 
The primary efficacy endpoint, time to event, is defined as the “stop date” - the date of first dose 
of study drug + 1 day where the “stop date” is the first of the following to occur: 
 date of the event,  
 date of the premature discontinuation,  
 date of last dose of study medication in the Treatment Period, 
 date of the completion of the Treatment Period,  
 date of the 125th event,  
 Day 166 
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by 
time to 1st PGTCS. 
3.2.4 
Censoring 
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized. 
The censoring for the primary efficacy analysis will be as follows: 
 Subjects who complete the Treatment Period without having an event during the Treatment 
Period will be censored as of Day 167.  
REDACTED COPY 
ese end
OPY
ese end
atmen
CO
atmen
data r
ED C
data r
event,
EDAC
event,
p date
RED
p date
used to support any marketing authorization application and any extensions or variations thereof.
t Epilep
sions
t Epilep
of clus
ensi
of clus
ction
licat
ction 3
at
3
ndpoint
app
ndpoint
nt Perio
tion a
nt Perio
report
zatio
reporte
o
e
, is def
auth
, is def
e” is th
ng a
e” is th
inuatio
y ma
inuatio
medic
t any
medic
on of th
ppor
on of th
event, 
o su
event, 
t cannot be
lgorithm
be us
lgorithm
PGT
t be
PGT
4
a
4
This documen
For the 
nt c
For the 
The 
men
The 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 If the subject’s Treatment Period participation is less than or equal to 166 days (premature 
discontinuation), their PGTCS information will be censored on the date after the last dose of 
study drug.  
 If the subject’s Treatment Period participation is greater than 166 days, their PGTCS 
information will be censored as of Day 167.  
 For the subjects who are ongoing in the study when the 125th event occurs, their PGTCS 
information for the primary efficacy endpoint analysis will be censored as of the day after the 
125th event, even if the subjects experience an event after the date of the 125th event but 
before 166 days of treatment is completed. 
 Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on 
the same date in reporting the 125th event, the first event reported to IRT will be deemed the 
125th event.  Data after the 125th event will be censored. 
Censoring for time to 1st PGTCS will be calculated in a similar manner, except using the date of 
the 1st PGTCS instead of the date of the event. For subjects who are ongoing in the study when 
the 125th event occurs, the time to 1st PGTCS information will be censored in the same manner 
as the time to event information (ie., censor all PGTCS information beyond the date of the 125th 
event). 
3.2.5 
AEDs and benzodiazepines 
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant 
and prior medication case report form (CRF) for AEDs. At study entry, a subject should be 
taking a stable dose of 1 to 2 non-benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 
of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at least 28 
days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the 
Prospective Baseline and the Treatment Period with or without additional concurrent stable 
VNS. Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the 
Treatment Period. 
AEDs at study entry are defined as AEDs where the start date is on or before 28 days prior to 
Visit 1 and the medication was still ongoing on the date of Visit 1. Lifetime AEDs are defined as 
AEDs taken in the subject’s history and stopped at least 28 days prior to Visit 1. 
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the 
CRF, although rescue AEDs will also be identified programmatically as any AED taken 
intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication. 
Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 
28 days) for epilepsy indications if established at least 28 days prior to Visit 1.  Lifetime 
benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at 
least 28 days prior to Visit 1. 
3.2.5.1 
Prohibited concomitant treatments (medications and therapies) 
The following medications/therapies are prohibited during the Treatment Period: 
 Clozapine 
REDACTED COPY 
or resc
D CO
or resc
for AE
TED 
for AE
azepine
ACTE
azepine
zepine
EDAC
zepine
st mai
RED
st mai
nt
R
nt
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
the 
aria
the 
ase of t
sion
ase of t
be dee
tens
be dee
xcept u
any 
xcept u
going i
nd a
going i
nsored 
an
nsored 
on beyo
tion
on beyo
cue) wi
tion 
cue) wi
EDs. A
izati
EDs. A
nes mar
horiz
nes mar
e). This
auth
e). This
intain t
ng a
intain t
t Period
eting
t Period
have b
arke
have b
ays prio
ma
ays prio
efined a
ort a
efined a
ion was
uppo
ion was
ubject’s
o sup
ubject’s
taken 
ed to
taken 
h rescu
use
h rescu
ntly for 
be u
ntly for 
medica
not b
medica
ays) for
anno
ays) for
enzodia
t ca
enzodia
least 2
ment
least 2
3
m
3


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Any MAO inhibitors 
 Barbiturates (except as antiepileptic medications) 
 Unstable dosing of non-benzodiazepine anxiolytics or once-daily hypnotics 
 Herbal medicines for epilepsy 
The study physician will review the concomitant medications and flag prohibited medications. 
3.2.6 
Relative day 
Relative day will be presented in most subject data listings. Relative day will be calculated as 
follows: 
 If the start/stop date occurred prior to the first dose of study medication, the relative day is 
calculated as start/stop date minus first study medication dose date. In subject data listings, 
relative days based on this situation will be preceded by a ‘-’. 
 If the start/stop date occurred on or after the first dose of study medication but prior to the 
last dose of study medication, the relative day is calculated as start/stop date minus first study 
medication dose date + 1. 
 If the start/stop date occurred after the date of last dose of study medication, the relative day 
is calculated as start/stop date minus date of last dose of study medication. In subject data 
listings, relative days based on this situation will be preceded by a ‘+’. 
Subjects with missing or incomplete dates will also have a missing relative day. 
3.2.7 
Last Visit 
Last Visit is defined as the last post-Baseline non-missing visit (including unscheduled visits) 
during the Treatment Period.  
3.2.8 
Month 
A month is defined as 28 days. 
3.3 
Definition of Baseline values 
Data collected at Visit 2 prior to the first dose of study medication (physical examination, 
neurological examination, ECG, vital signs, laboratory tests) will be used as Baseline values. 
Data collected on the date of first dose of study medication will be assumed to be prior to the 
first dose. For quantitative ECG assessments, if repeat measurements pre-dose, then the average 
value is used as the Baseline value. For data not collected at Visit 2 prior to the first dose of 
study medication, the last data collected prior to the first dose of study medication will be used as 
Baseline values.  
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined 
Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline 
calculations come from the Prospective Baseline Period only.  
3.4 
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 
REDACTED COPY
dose o
PY 
dose o
ill be p
COP
ill be p
l also 
ED C
l also 
aselin
REDA
aselin
to support any marketing authorization application and any extensions or variations thereof.
ed as
or v
ed as
elative d
ensio
elative d
ect data
exte
ect data
ication 
nd a
ication 
rt/stop 
and
rt/stop 
f study 
plica
f study 
of study
appl
of study
preced
on ap
preced
have a
izatio
have a
e non
g au
e non
of
rt a
of Ba
an
Ba
2 prior 
uppo
2 prior 
ation, E
o sup
ation, E
nt cannot be used 
the dat
d to 
the dat
quantit
sed
quantit
d as the
be us
d as the
edicatio
ot be
edicatio
ne valu
nnot
ne valu
or PGT
t ca
or PGT
This documen
Basel
ment
Basel
cal
m
cal


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
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, 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 in a blinded manner as part of the ongoing data 
cleaning process prior to database lock to confirm exclusion from the Per Protocol Set (PPS). 
3.5 
Analysis sets 
The Safety Set (SS) will serve as the primary population for assessing safety endpoints. The Full 
Analysis Set (FAS) will serve as the primary population for assessing efficacy endpoints. 
3.5.1 
Screened Set 
The Screened Set (ScS) consists of all subjects who have entered screening at Visit 1, have a 
signed Informed Consent/Assent Form, and have at least basic demographic data available. 
3.5.2 
Randomized Set 
The Randomized Set (RS) is a subset of the ScS and consists of all subjects who were 
randomized at the Randomization Visit (Visit 2). 
3.5.3 
Safety Set 
The SS is a subset of the RS and consists of all subjects who have been treated with at least 1 
dose of study drug, either LCM or placebo. This population will serve as the primary population 
for assessing safety endpoints. 
3.5.4 
Full Analysis Set 
The FAS is a subset of the SS consisting of all subjects with at least 1 seizure diary assessment 
during the Treatment Period. This population will serve as the primary population for assessing 
efficacy endpoints. 
3.5.5 
Per Protocol Set 
The PPS is a subset of the FAS excluding subjects who completed fewer than 6 weeks of 
treatment or subjects with important protocol deviations affecting the interpretation of the 
primary efficacy analysis. Important protocol deviations will be determined prior to database 
lock and unblinding. 
3.6 
Treatment assignment and treatment groups 
Safety data summaries will be presented by randomized treatment and sometimes by overall, 
while efficacy data summaries will be presented by randomized treatment. Treatments will be 
reported as LCM and placebo, and in some cases, by all subjects.  
If a subject receives a treatment other than the randomized treatment, an evaluation of the 
mis-treatment will be made to determine if the subject should be summarized under a different 
treatment arm for safety assessments. Data obtained from subjects who receive an incorrect kit 
REDACTED COPY
consi
PY 
consi
of all s
ACT
of all s
ebo. T
EDAC
ebo. T
to support any marketing authorization application and any extensions or variations thereof.
ta
va
ta
PS).
or v
PS).
points. 
ensi
points. 
endpoi
exte
endpoi
ening a
and 
ening a
ograph
on a
ograph
sts of a
appli
sts of al
subject
thori
subject
This pop
auth
This pop
nsisting
ma
nsisting
This pop
any m
This pop
tocol 
ppo
tocol 
of the 
to su
of the 
This document cannot be used
jects w
ed to
jects w
acy ana
use
acy ana
nblindi
be u
nblindi
afety da
t can
afety da
while 
ent 
while 
rep
me
rep


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
will be reviewed and the study team will determine how to handle such cases in the statistical 
analyses prior to database lock and unblinding. 
3.7 
Center pooling strategy 
Refer to Section 4.4. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 16.1. Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD, SEP/2013). All coding will be completed prior to 
database lock and unblinding. 
3.9 
Changes to protocol-defined analyses 
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for 
PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. 
Also, Protocol Section 13.3.2.1 states that the key secondary efficacy variable will be analyzed in 
the same manner as the primary endpoint using the FAS and that the percentage of seizure-free 
subjects at 24 weeks will be estimated from the KM estimates of time to first seizure. The 
analysis of the key secondary endpoint has been clarified to assess the seizure-free rate at 24 
weeks using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates 
within each stratum. The extended Mantel-Haenszel technique is a randomization-based 
nonparametric method that provides a more robust method to assess seizure freedom. Thus, the 
key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy 
endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the 
same manner as the primary efficacy endpoint. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Analyses of the primary efficacy variable and several other efficacy variables will be adjusted for 
the stratification variables Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 
16 week Combined Baseline Period prior to randomization) and age at informed consent (≥4 to 
<12 years of age vs ≥12 to <18 years of age, and ≥18 years of age). Stratification factors 
recorded at randomization in the interactive response technology (IRT) will be used. 
4.2 
Handling of dropouts or missing data 
4.2.1 
Missing seizure diary days 
For evaluations based on seizure diary data, imputation for missing data will not be performed. 
For the purpose of the derivation of the primary efficacy endpoint, secondary efficacy endpoints 
and for PGTC seizure-free status, if there are PGTCS counts reported as “not done” on a specific 
day, then the PGTCS count will be assumed to be zero on that date.  
The calculation of average 28-day PGTCS frequency accounts for missing data by only 
evaluating days for which data are available.  
REDACTED COPY
whic
PY 
whic
l techn
OPY
l techn
ust met
D CO
ust met
nalyze
TED 
nalyze
able, t
ACTE
able, t
dpoin
EDAC
dpoin
NAL
RE
NAL
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
y
or to
or
or to
seizure 
y ext
seizure 
plan
any
plan-
ny
-M
y 
M
ariable 
nd a
ariable 
percen
n and
percen
ime to
tion 
ime to
sess the
icati
sess the
combi
pplic
combi
hnique i
n app
hnique i
ethod to
tion 
ethod to
ed in th
izat
ed in th
time to
horiz
time to
nt.
a
nt.
LYTIC
ting 
LYTIC
covar
arke
covar
y variab
ny m
y variab
aseline 
t any
aseline 
ne Peri
port 
ne Peri
2 to <1
uppo
2 to <1
zation 
o sup
zation 
Handli
ed t
Handli
Mis
 us
Mis
luation
not b
luation
the pu
cann
the pu
This document
nd for 
nt c
nd for 
day, 
men
day, 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
4.2.2 
Incomplete dates for first epilepsy diagnosis 
To calculate the time since first epilepsy diagnosis, a complete date will be imputed for partially 
missing first diagnosis date. First diagnosis dates will be displayed as reported in the subject data 
listings (ie, no imputed values will be displayed in data listing). 
 Missing the day, but month and year present: 
Assign the 1st day of the month or the subject’s birthday (imputing 1st for the day if only month 
and year are collected), whichever is later. 
 Missing the day and month, but year present: 
Assign January 1st of the year or the subject’s birthday, whichever is later. 
 Missing the day, month and year: 
No imputation will be done. 
4.2.3 
Incomplete dates for adverse events and concomitant medications 
The following rules are applied to impute partial start and stop dates for medications. The date as 
recorded on the CRF should be presented in subject data listings (no imputed dates should be 
included in subject data listings). 
Imputation of Partial Start Dates 
 If only the month and year are specified and the month and year of first dose is not the same 
as the month and year of the start date, then use the first day of the month. 
 If only the month and year are specified and the month and year of first dose is the same as 
the month and year of the start, then use the date of first dose. 
 If only the year is specified, and the year of first dose is not the same as the year of the start 
date, then use January 1st of the year of the start date. 
 If only the year is specified, and the year of first dose is the same as the year of the start date, 
then use the date of first dose. 
 If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose, then use the date of first dose. 
Imputation of Partial Stop Dates 
 If only the month and year are specified, then use the last day of the month. 
 If only the year is specified, then the end day and month will be set to the maximum of the 
date of study termination or the date equivalent to 30 days after the last intake of LCM. 
However, if the study termination year and year for the date which is 30 days after last intake 
of LCM are greater than the concomitant medication year, then the day and month are to be 
set to December 31st. 
 If the stop date is completely unknown, do not impute the stop date. 
In the event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication was concomitant or not, the medication will be considered as concomitant. 
REDACTED COPY 
the m
D CO
the m
en use
TED
en use
ied and
DACT
ied and
en use 
REDA
en use 
he
R
he
pport any marketing authorization application and any extensions or variations thereof.
mitant
d an
mitant
s for me
n an
s for me
(no imp
tion
(no imp
month a
ation
month a
e the fir
rizat
e the fir
nd the m
utho
nd the m
e the da
g au
e the da
e year o
keting
e year o
year of 
arke
year of 
and the
ny m
and the
dose.
any
dose.
mp
pp
mpletel
ppor
letel
sed to su
use the
supp
use the
tial Sto
d to 
tial Sto
d
This document cannot be u
e mont
use
e mont
ly the y
ot be
ly the y
te of st
nnot
te of st
Howev
can
Howev
of L
nt c
of L
n


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The following rules are applied to impute partial onset and resolution dates for AEs. AEs with 
partial onset date are classified as either non-treatment- or treatment-emergent based on the 
imputed onset date.  
Imputation of Partial Onset Dates 
 If only the month and year are specified and the month and year of first dose is not the same 
as the month and year of onset, then use the first day of the month. 
 If only the month and year are specified and the month and year of first dose is the same as 
the month and year of onset, then use the date of first dose. 
 If only the year is specified, and the year of first dose is not the same as the year of onset, 
then use January 1st of the year of onset. 
 If only the year is specified, and the year of first dose is the same as the year of onset, then 
use the date of first dose. 
 If the AE onset date is completely unknown, then use the date of first dose. 
Imputation of Partial Resolution Dates  
 If only the month and year are specified, then use the last day of the month. 
 If only the year is specified, then the end day and month will be set to the maximum of the 
date of study termination or the date equivalent to 30 days after the last intake of LCM. 
However, if the study termination year and year for the date which is 30 days after last intake 
of LCM are greater than the event year, then the day and month are to be set to December 
31st. 
 If the AE resolved and the resolution date is completely unknown, then do not impute the 
resolution date. 
4.2.4 
Incomplete date for the last administration of study medication 
No imputation should be performed for missing study medication start dates. This field on the 
CRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules will 
be applied for the purpose of calculating overall exposure: 
 If the day is missing (but month and year available), impute the last dose date as the 
minimum of the last day of the month or the date of last contact reported on the Study 
Termination CRF; if day and month are both missing (only year available), impute the last 
dose date as the minimum of the last day of the year or the date of last contact on the Study 
Termination CRF. 
 If a subject died and has a partial or missing last administration date, the date is set to the 
date of death. If there is a partial date of last dose and the month/year are prior to the month 
and year of the date of death, follow partial date imputation rules. 
 If the last dose date is completely missing and no information could be obtained from data 
cleaning exercises, the last dose date should be imputed as the date of last contact according 
to the Study Termination CRF. A review of the data for subjects with completely missing last 
REDACTED COPY
mon
PY 
mon
t to 30
COP
t to 30
year f
ED C
year f
then th
CTED
then th
ion da
RED
ion da
ort any marketing authorization application and any extensions or variations thereof.
as
va
as
f onset
ons 
f onset
ar of on
exte
ar of on
st dose
nd a
st dose
ay of th
icatio
ay of th
th will b
appl
th will b
0 days 
on ap
0 days 
for the 
atio
for the 
he day 
oriza
he day 
ate i
g a
ate is c
au
s c
for the
mark
for the
rmed fo
ny m
rmed fo
r missin
rt any
r missin
be used to supp
ate of la
ppo
ate of la
rpose o
sup
rpose o
missing
ed to
missing
o
u
of the l
used
f the l
ation C
be u
ation C
This document cannot
date a
ot b
date a
ermina
nno
ermina
If a 
nt ca
If a 
d
n
d


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
dose dates should be performed to ensure that the imputation does not result in an unrealistic 
value for duration of exposure.  
Imputed date of last dose dates should only be used for calculation of the duration of exposure. 
The date as recorded on the CRF should be presented in subject data listings (no imputed dates 
should be included in subject data listings). 
4.2.5 
Missing adverse event intensity 
If the intensity of an AE is missing then it will be counted as severe for analysis purposes. 
4.2.6 
Missing adverse event relationship to study medication 
If the AE relationship to study medication is missing then it will be counted as related for 
analysis purposes. 
4.3 
Interim analyses and data monitoring 
To enhance safety monitoring, 3 interim analyses are planned when 25%, 50%, and 75% of 
subjects experience an event (31, 62, and 93 events, respectively) or 24 weeks after 50, 100, 
and 150 subjects have been randomized, respectively, whichever comes first. An event is defined 
as the occurrence of the second PGTCS during the Treatment Period. 
These interim reviews for safety will be performed using an Independent Data Monitoring 
Committee (IDMC), with a single futility assessment planned at the second interim analysis. The 
IDMC will oversee the safety of the study by reviewing safety data periodically. Details are 
provided in an IDMC charter. Both safety and futility will be assessed in a manner that ensures 
that blinding is not compromised for individuals involved with operational aspects of the study, 
nor individuals involved with the planning and conduct of the final statistical analyses. Analysis 
of the primary efficacy endpoint (time to second PGTCS) will only be examined at the planned 
futility assessment; an unblinded, descriptive review of safety and seizure data will be provided 
for all IDMC meetings. 
No consideration will be made for stopping due to early demonstration of efficacy; however, the 
significance level will be set using a Haybittle-Peto boundary at alpha=0.0001 so as to require 
only a nominal alpha adjustment for the final analysis. Full details of the interim analysis are 
described in the Interim Analysis Statistical Analysis Plan. 
4.4 
Multicenter studies 
Due to the small number of subjects per site, all sites will be pooled together for analysis. There 
will be no planned analyses for multi-center effects. 
4.5 
Multiple comparisons/multiplicity 
A gatekeeping strategy (Marcus et al, 1996) will be used to test the key secondary efficacy 
variable provided that the primary efficacy endpoint is statistically significant (See Section 8.2.1 
for additional details). No additional adjustments for multiplicity are required as all additional 
inferences will be hypothesis-generating only. 
4.6 
Use of an efficacy subset of subjects 
The PPS will be used to evaluate subjects who completed at least 6 weeks of treatment and have 
no important protocol deviations related to the primary efficacy variable. This analysis set will 
REDACTED COPY
ng 
Y
ng 
t plan
OPY 
t plan
iewing
CO
iewing
futilit
ED C
futilit
duals i
CTE
duals i
ng and
DAC
ng and
e to se
REDA
e to se
scrip
RE
scrip
y marketing authorization application and any extensions or variations thereof.
d for 
ions
d for 
50%, a
any
50%, a
4 weeks
nd a
4 weeks
mes fir
n an
mes fir
riod.
ation
riod.
Indepe
plica
Indepe
nned at 
app
nned at 
g safety
ion a
g safety
ty will 
zatio
ty will 
involve
horiz
involve
d condu
utho
d condu
econd P
g au
econd P
ptive re
ting
ptive re
or stopp
y ma
or stopp
not be used to support an
sing a 
any 
sing a 
tment f
ort a
tment f
Analys
ppo
Analys
icent
o su
icent
l numb
sed t
l numb
anned a
use
anned a
M
This document ca
atekeep
ann
atekeep
ariable 
nt ca
ariable 
for ad
ment
for ad
inf
m
inf


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
provide additional information on the analysis of the primary efficacy variable and will describe 
findings in a subset of subjects who more closely followed the intentions of the study protocol. 
Other than the planned analyses based on the PPS, no other efficacy subsets are defined for 
statistical analyses. 
4.7 
Active-control studies intended to show equivalence 
This section is not applicable for this study. 
4.8 
Examination of subgroups 
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the 
FAS.  Disposition will be presented by age subgroup for the SS and FAS.  Exposure will be 
presented by age and region subgroups for the SS.  Overall TEAE incidence will be presented by 
age subgroup for the SS.  Selected disposition and safety analyses will be presented by 
Development for the purpose of addressing requirements set in Article 46 of the European 
Pediatric Regulation (see Section 12.5 for further details). 
The subgroups to be examined include: 
 Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65) 
 Development (Pediatric [≥4 to < 18 years old], Adult [≥18 years old]) 
 Racial group (white, non-white) 
 Gender (male, female) 
 Region  
 North America: United States, Puerto Rico 
 Latin America: Brazil, Mexico 
 Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy, 
Poland, Portugal, Slovakia, Spain 
 Eastern Europe: Bulgaria, Romania, Russia, Turkey 
 Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan 
 Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline 
Period) 
 Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the 
subject is taking when enrolled into the study (1, 2, 3). 
Separate age sub-groupings are used for the purpose of summarizing the following scales:  
 PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years) 
 Achenbach CBCL (4 to 5 years, 6 to 18 years) 
 BRIEF-P/BRIEF (4 to <5 years, ≥5 years). 
REDACTED COPY 
ult [
Y
ult [
, Puert
RED
, Puert
used to support any marketing authorization application and any extensions or variations thereof.
d for th
s or
d for th
will be
ions
will be
be pres
ensi
be pres
ented b
exte
ented b
f the Eu
ny e
f the Eu
of age
ation
of age
18 year
pplic
18 year
rto Rico
g au
rto Rico
Belgium
mar
Belgium
kia, Sp
ny m
kia, Sp
lgaria, 
ort a
lgaria, 
ther: Au
upp
ther: Au
CS freq
d to s
CS freq
This document cannot be
mitant A
be u
mitant A
ect is ta
ot b
ect is ta
arate ag
cann
arate ag

Ped
nt c
Ped

m



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
4.9 
Stratum Pooling 
The stratification factors for this study are Baseline PGTCS frequency (≤2 per 28 days vs >2 per 
28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age, 
≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from 
IRT.  
To determine if strata pooling should occur for time to event (2nd PGTCS) analysis: 
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age 
at informed consent categories will be summed.  For categories with < 3 total events, the 
combining should occur as follows: 
 If 2 of the age at informed consent categories combined have < 3 total events, then all age 
categories are combined for the analysis.  
 If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events 
or less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥18 years of age is the category with the smallest number of events that are 2 events or 
less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥12 and <18 years of age is the category with the smallest number of events that are 2 
events or less, it should be combined with the strata with the 2nd smallest number of events. 
Repeat the algorithm for combining strata for the subjects who did not have events if there are 
categories with < 3 total non-events. 
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to 
determine stratum pooling for both events and non-events.  
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling 
of the strata should be reassessed since the event distribution for the specific sensitivity may be 
different than the distribution in the primary efficacy endpoint analysis.  
Time to 1st PGTCS analyses: 
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that 
“events” will now be in reference to subjects having only 1 PGTCS. 
Seizure freedom analyses: 
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that 
“events” will now be in reference to subjects having 0 PGTCS. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The number of subjects screened and the number and percentage of screen failures will be 
summarized overall. Screen failures are those subjects who are in the ScS and either met an 
exclusion criterion or did not meet an inclusion criterion. The reason for screen failure will be 
presented. The number and percentage of baseline failures due to PGTCS frequency during the 
Combined Baseline Period will also be summarized. The study eligibility criteria and those 
REDACTED COPY
ata wi
OPY 
ata wi
D
subje
D CO
subje
equenc
ACT
equenc
nts an
EDA
nts an
ensi
R
ensi
marketing authorization application and any extensions or variations thereof.
age
aria
age
hen all 
nsio
hen all 
ents tha
ny e
ents tha
egory.
d any
egory.
vents th
n and
vents th
catego
tion 
catego
est num
lica
est num
th the 2
app
th the 2
ects
tion
ects wh
n 
wh
cy >2 p
thor
cy >2 p
nd non
aut
nd non
itivity 
eting
itivity 
used to support any m
e
rk
e the e
rket
the e
he pri
mar
he prim
ar
m
ratum p
port 
ratum p
n refere
upp
n refere
nalyses
d to s
nalyses
rithm f
used
rithm f
This document cannot be 
ll now
e us
ll now
The n
ment
The n
su
m
su


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
subjects who did not meet it will be listed. All disposition data for the ScS will be presented in 
subject data listings. 
The number of subjects in the ScS, Randomized Set (RS), SS, FAS, and PPS will be presented 
by investigator; the date of first subject in and date of last subject out will also be included in this 
summary. The subject populations will be listed. 
The overall number and percentage of subjects who completed and discontinued from the study 
will be presented for the SS, FAS, and PPS including number and percentages for each reason 
for discontinuation. The completion of the study is defined as meeting any of the predetermined 
exit criteria (including when the 125th event has occurred) or experiencing <2 PGTCS within the 
24-week treatment period. Discontinuation is defined as the completion of the ET Visit in all 
other cases.  This summary will be repeated for specific subgroups as detailed in Section 4.8 for 
the SS and FAS.  The study termination information will be presented in the subject data listings. 
A by-subject listing will be presented to show all visit dates and the associated relative day. 
5.2 
Protocol deviations 
The number and percentage of subjects without any important protocol deviations and with at 
least 1 important protocol deviation in each of the categories defined in the prior to database lock 
and unblinding will be summarized overall for the RS. 
All important protocol deviations for subjects in the RS will be listed by site, subject number, 
and protocol deviation category. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Unless otherwise specified, demographics and baseline characteristics will be summarized by 
treatment group and overall. 
6.1 
Demographics 
6.1.1 
Derivation of demographics variables 
6.1.1.1 
BMI 
The body mass index (BMI) will be derived at Baseline only, from the Baseline height and 
weight values. BMI will be calculated using the following formula: 
   


2
2
(cm)
height 
(kg)
weight 
*
10000
)
(kg/m
 
BMI

   
EDACTED COPY 
RS w
OPY
RS w
D OT
TED
D OT
R
S
A
S
phics 
RED
phics 
authorization application and any extensions or variations thereof.
ined 
var
ined 
ithin th
or v
ithin th
it
o
it in all
ns 
in all
ection
sio
ection 4
bject da
xten
bject da
ted 
ny
ted rela
y e
rela
ocol de
on a
ocol de
fined in
ation
fined in
will be l
app
will be l
TH
riz
TH
ed to support any marketing
ER
za
ER
and ba
ng a
and ba
demo
any m
demo
(BMI) w
supp
(BMI) w
I will b
to su
I will b
This document cannot be u
(kg/m
 I
use
(kg/m
 I


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
6.1.2 
Analysis of demographics variables 
Baseline demographics will be summarized for the SS and include gender, race, ethnicity, age, 
age category, age strata from IRT, height (cm), weight (kg), BMI (kg/m2). Note age from the 
CRF will be summarized. 
Demographics will be listed for all subjects screened. 
6.2 
Other Baseline characteristics 
6.2.1 
Derivation of other Baseline characteristics 
6.2.1.1 
Time since first diagnosis 
The time since first diagnosis of epilepsy is calculated as follows: 
the date of informed consent – the date of first epilepsy diagnosis/365.25.  
Imputation for partial dates of first epilepsy diagnosis will be imputed as described in 
Section 4.2.2. 
6.2.1.2 
Age at diagnosis 
Age at diagnosis of epilepsy will be calculated using the first epilepsy diagnosis date and the date 
of birth. Imputation for partial dates of first epilepsy diagnosis will be imputed as described in 
Section 4.2.2. 
6.2.2 
Analysis of other Baseline characteristics 
Combined Baseline PGTCS frequency, 12-week Historical Baseline PGTCS frequency, and 4-
week Prospective Baseline PGTCS frequency derived as frequencies per 28 days will be 
summarized as continuous data. Combined Baseline PGTCS frequency will also be summarized 
as categorical data (≤2 per 28 days and >2 per 28 days) from the CRF and IRT at randomization. 
The following Baseline characteristics will also be presented: 
 Time since first diagnosis at date of consent 
 Age at diagnosis of epilepsy 
 Number of lifetime AEDs and Benzodiazepines (0, 1-3, 4-6, ≥7)  
 Concomitant benzodiazepine use at study entry (yes, no) 
 ILAE (1989) Seizure classification history 
 Classification of epileptic syndrome 
 Etiology of epilepsy 
All Baseline characteristics will be presented in data listings. All reproductive potential and birth 
control information will be presented in data listings. 
6.3 
Subgroups 
All subgroups detailed in Section 4.8 will be summarized in a table for the SS and FAS. 
Subgroup identification will also be listed. 
REDACTED COPY 
g
Y
g
harac
D CO
harac
week H
CTED
week H
ency d
ACT
ency d
ined B
EDA
ined B
nd >2
RE
nd >2
used to support any marketing authorization application and any extensions or variations thereof.
escribed
ny e
escribed
ilepsy d
atio
ilepsy d
is will b
plica
is will b
cterist
tion 
cterist
Historic
oriza
Historic
derived
thor
derived
Baselin
aut
Baselin
2 per 2
ting a
2 per 2
cs will 
arket
cs will 
date of
y ma
date of
psy
rt a
psy
AEDs a
ppo
AEDs a
nzodiaz
to su
nzodiaz
9) Seizu
sed 
9) Seizu
This document cannot be
ication 
be u
ication 
ology o
not 
ology o
l Basel
t can
l Basel
contro
ent c
contro
6.
m
6.


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
6.4 
Medical history and concomitant diseases 
Previous and ongoing medical history conditions will be summarized by system organ class 
(SOC) and preferred term (PT) for the SS. A similar summary will be provided for concomitant 
diseases for the SS. Concomitant diseases are medical history events which are ongoing at the 
Screening Visit.  
The data, including the SOC, PT and verbatim reported term, will also be presented in data 
listings. A glossary of medical history SOC and PTs will also be completed. 
6.5 
Procedure history 
All procedure history will be presented in data listings. 
6.6 
Prior and concomitant medications 
Medications with a start date before the first dose of study medication will be considered prior 
medications. Medications taken on or after the date of the first dose of study medication will be 
considered concomitant medications. Medications with a missing start date whose stop date is 
either unknown or after the date of the first dose of study medication will be considered 
concomitant. Medications with a missing start date whose stop date is prior to the date of the first 
dose of study medication will be considered as prior medications.  
Details regarding imputation of incomplete dates are described in Section 4.2.3. 
Medications will be summarized using the Anatomical Therapeutic Chemical (ATC) codes from 
the WHO-DD. All tabulations will be sorted by frequency of the higher-level ATC code and by 
frequency of the lower level ATC code within the higher-level ATC code. 
Medications (excluding AEDs and benzodiazepines) will be summarized separately for prior and 
concomitant medications by ATC level 1 (anatomical main group) and ATC level 2 (therapeutic 
subgroup) for the SS. 
Lifetime AEDs and benzodiazepines will be summarized separately by ATC level 4 (chemical 
subgroup) and PT for the SS. AEDs and benzodiazepines at study entry will also be summarized 
separately by ATC level 4 and PT for the SS.  
Concomitant AEDs will be defined by a manual medical review of all unique ATC codes and 
indications reported in the database to identify medications taken to treat epilepsy. Concomitant 
AEDs and benzodiazepines taken for any epilepsy indication during the Treatment Period will be 
summarized separately by ATC level 4 and PT for the SS. 
A glossary of ATC codes and associated investigator’s terms for all AEDs or benzodiazepines 
and all other medications (excluding AEDs and benzodiazepines) will be listed separately in data 
listings. The WHO-DD coding and other information for AEDs or benzodiazepines and all other 
medications (excluding AEDS and benzodiazepines) will be listed separately in subject data 
listings. AEDs flagged as rescue medications will also be listed in subject data listings. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Compliance data will be included in subject data listings. 
REDACTED COPY
descr
OPY 
descr
omical
D CO
omical
by freq
TED 
by freq
hin th
ACTE
hin th
zodiaz
EDA
zodiaz
vel 1 
RE
vel 1 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
 consid
y ext
 consid
dy med
any 
dy med
date wh
nd a
date wh
n will b
n and
n will b
te is pr
tion 
te is pr
ns. 
ica
ns. 
ibed in
appl
ibed in
l Thera
tion 
l Thera
quency
izati
quency
he highe
horiz
he highe
zepine
auth
zepine
(anato
ing a
(anato
nes will
mar
nes will
AEDs an
ny m
AEDs an
nd PT f
rt any
nd PT f
be def
ppo
be def
n the d
sup
n the d
iazepin
d to s
iazepin
parately
sed 
parately
of ATC
be u
of ATC
ther m
ot be
ther m
gs. The
nno
gs. The
edicatio
t can
edicatio
listing
ent 
listing
7
m
7


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
8 
EFFICACY ANALYSES 
Most efficacy analyses will be performed using the FAS population; in other cases, the 
population will be stated. 
For primary efficacy endpoint analyses, only data up to and including the day of the event, the 
Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125th event, whichever 
is earlier, will be included. For the secondary efficacy endpoint analyses, only data up to and 
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day 
166 or the date of the 125th event, whichever is earlier, will be included. For all other exploratory 
efficacy variables, all appropriate seizure data during the Treatment Period, will be included. All 
seizure diary data will be listed including data not included in efficacy analyses. 
Testing for the primary efficacy endpoint will be done at the 5% level (2-sided). Provided that 
the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to 
test the key secondary efficacy variable, seizure freedom. No additional adjustments for 
multiplicity are required as all additional inferences will be hypothesis-generating only. 
8.1 
Statistical analysis of the primary efficacy variable 
8.1.1 
Derivations of primary efficacy variable 
For the primary efficacy variable, an event and how time to event is calculated is described in 
Section 3.2.3, keeping in mind Section 3.2.2. Censoring of subjects for this analysis will be as 
described in Section 3.2.4 . If a day is marked in the CRF as “not done”, it will be assumed that 
no seizures occurred on that day.  
8.1.2 
Primary analysis of the primary efficacy variable 
The primary efficacy variable, time to event during the 166-day Treatment Period, will be 
evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for 
treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 
days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, 
≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from 
IRT and pooled as described in Section 4.9.   
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
) 
 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The 
REDACTED COPY 
me t
Y
me t
oring o
OPY
oring o
the C
D CO
the C
e prim
DACT
e prim
o even
RED
o even
aza
R
aza
keting authorization application and any extensions or variations thereof.
ay 
ari
ay 
ratory 
r var
ratory 
uded. A
s or 
uded. A
Provide
tens
Provide
y will b
exte
y will b
ustmen
ny e
ustmen
generati
d any
generati
y varia
n an
y varia
event
pplic
event i
of subj
n app
of subj
CRF as 
tion 
CRF as 
mary e
thor
mary e
nt durin
g au
nt durin
ards reg
eting
ards reg
This document cannot be used to support any mark
’ Basel
arket
’ Basel
eriod) a
mar
eriod) a
yea
ny
years o
y m
rs o
d in Sec
rt an
d in Sec
assessm
ppo
assessm
β is the
not b
β is the
el.
an
el. The
ann
The


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
assumptions of proportional hazards will also be assessed graphically (e.g. log (log S) plot vs 
time, empirical score process) for any departure; non-proportionality is not expected when using 
a stratified Cox model. Depending on the departure from proportional hazards, a sensitivity 
analysis (e.g. piecewise proportional hazards, time-varying coefficient, restricted mean survival) 
may be performed.  
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. 
The 95% CI for the HR will also be reported.  
Additionally, a Kaplan-Meier (KM) plot for time to event as well as the KM estimate for the 
median time to event and 95% CI will be provided. If the median time is not estimable, then the 
25th percentile and 95% CI will be provided. The number of events will be reported by treatment 
group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects 
who were censored in the analysis. 
8.1.3 
Secondary analyses of the primary efficacy variable 
The summary of time to the event during the 166-day Treatment Period will be presented by all 
subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be 
provided.  
8.1.4 
Supportive and sensitivity analyses of the primary efficacy variable 
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted 
in order to assess the effect of dropouts, important protocol deviations, and operational bias on 
the primary endpoint:   
 Repeat the primary efficacy analysis using the PPS. 
 Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events after the 
date of the 125th event) through each subject’s first 166 days of treatment, on the FAS. 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed 
as treatment failures (ie, events at the time of discontinuation). 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures. 
 Repeat the primary efficacy analysis using the FAS, comparing the event rates prior to vs 
after each interim analysis to examine possible operational bias due to unblinding. 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue after their 1st PGTCS will be analyzed as treatment failures. 
8.2 
Statistical analysis of the secondary efficacy variables 
Provided that the primary efficacy endpoint is statistically significant, a gatekeeping strategy will 
be used to test the key secondary efficacy variable. Analyses of all other secondary efficacy 
variables will be descriptive in manner only. Any p-values or confidence limits provided other 
than those for the primary efficacy analysis of the primary efficacy variable (as described in 
Section 8.1.2) and the analysis of the key secondary efficacy variable will be exploratory only.  
REDACTED COPY 
prima
OPY
prima
t prot
CO
t prot
using th
ACT
using th
sis usi
RED
sis usi
ach
R
ach
keting authorization application and any extensions or variations thereof.
e
hen the
or v
hen the
y treatm
ons 
y treatm
% of su
nsio
% of su
e
n
e
will be
nd a
will be
subgrou
and
subgrou
the pri
plicat
the pri
ary effi
app
ary effi
tocol de
tion a
tocol de
the PPS
thor
the PPS
ing all 
g au
ing all 
o support any ma
h su
etin
h subjec
ing
bjec
lysis us
arke
lysis us
ficacy, 
y ma
ficacy, 
vents a
any 
vents a
ficacy a
port 
ficacy a
lack of
upp
lack of
t cannot be used t
mary ef
d to s
mary ef
nterim a
sed 
nterim a
the prim
be u
the prim
ontinue
ot b
ontinue
This documen
Provid
ent c
Provid
be u
me
be u


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
8.2.1 
Derivations of secondary efficacy variables 
8.2.1.1 
Variable: Seizure freedom for PGTCS for the 166-day Treatment 
Period 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not 
done” on the CRF will be counted as seizure-free days from PGTCS. 
A subject will have seizure freedom from PGTCS for the 166-day Treatment Period if the 
subject completed the Treatment Period and reported zero PGTCS or “not done” for all days 
during the 166-day Treatment Period. Ongoing subjects who are seizure-free from PGTCS on the 
date of the 125th event do not have seizure-freedom from PGTCS unless they are seizure-free 
from PGTCS for 166 days. 
8.2.1.2 
Variable: Time to first PGTCS during the 166-day Treatment Period 
For PGTCS, how the time to first PGTCS is calculated is described in Section 3.2.3.  Censoring 
of subjects for this analysis will be as described in Section 3.2.4 . 
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that 
seizure diary day. 
8.2.2 
Analysis of secondary efficacy variables 
Analyses of secondary efficacy variables will be performed for the FAS. 
8.2.2.1 
Analysis: Seizure freedom for PGTCS for the 166-day Treatment 
Period 
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the 166-day 
Treatment Period, will be evaluated using an extended Mantel-Haenszel testing procedure which 
takes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS 
frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at 
informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The 
analysis will use the stratification factors from IRT and pooled as described in Section 4.9.  
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure-freedom) is as 
follows: 
H0: S(t=166)LCM = S(t=166)PBO 
Versus 
H1: S(t=166)LCM ≠ S(t=166)PBO 
Where S(t=166) is the cumulative rate of subjects remaining seizure-free from PGTCS for 166 
days. 
Estimation of treatment difference: 
KM methods will be used to estimate the proportion of subjects remaining seizure-free from 
PGTCS at Day 166. The estimate for the difference in Day 166 seizure-freedom from PGTCS 
will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in 
the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 
years of age vs ≥18 years of age). The estimate for the stratified difference in proportion of 
REDACTED COPY
aria
PY 
aria
perform
COP
perform
m for P
TED 
m for P
y varia
EDA
y varia
using
RE
using
nt cannot be used to support any marketing authorization application and any extensions or variations thereof.
ys
or
ys
CS
s o
CS on 
or
on 
izure
ions
izure-
n
-fr
s
fr
atmen
exte
atmen
ction
any
ction 3
y
3
at no se
ion a
at no se
bles
ppl
bles
med fo
ion a
med fo
PGTC
izat
PGTC
able, se
aut
able, se
g an ex
ting 
g an ex
ere initi
ketin
ere initi
r 28 da
mark
r 28 da
ars of a
y m
ars of a
ation fa
t any
ation fa
sessme
port
sessme
e S
nn
S(
nno
(
S(
S
nn
S(
S t
no
t=1
o
=1
This documen
ys.
t c
ys.
Estim
ment
Estim
K
m
K


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
subjects who are seizure-free from PGTCS on LCM vs PBO and a corresponding 95% two-sided 
confidence interval (CILCM-PBO) will be produced using mantel Haenszel methods (LaVange et al, 
2005). The statistical methodology is expressed as follows: 
 d=∑
wh(Sh1-Sh2)
6
h=1
 
Where Shi=KM estimate of 166-day seizure freedom from PGTCS for treatment i (1=LCM and 
2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 
2= ≤2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days 
Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency 
and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years 
of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and 
wh={(nh1*nh2)/(nh1+nh2)}/∑
{(nh1*nh2)
6
h=1
/(nh1+nh2)}} 
where nhi is the number of subjects in I treatment group and stratum h.  The variance of d is 
calculated as Var(d)=∑
wh
2
6
h=1
{Var(Sh1)+Var(Sh2)} where Var(Sh1) and Var(Sh2) are the 
Greenwood estimates of variance for Sh1 and Sh2. 
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in 
each treatment group and the associated variance are derived as follows using Mantel Haneszel 
methods: 
The KM estimate for the LCM 166-day seizure-freedom from PGTCS rate is calculated as 
𝑆1=∑
𝑤ℎ
6
ℎ=1
𝑆ℎ1 
The KM estimate for the PBO 166-day seizure-freedom from PGTCS rate is calculated as 
𝑆2=∑
𝑤ℎ
6
ℎ=1
𝑆ℎ2 
The variance is S1 is calculated as Var (𝑆1) =∑
𝑤ℎ
6
6
ℎ=1
𝑉𝑎𝑟(𝑆ℎ1) 
The variance of S2 is calculated as Var (𝑆2) =∑
𝑤ℎ
6
6
ℎ=1
𝑉𝑎𝑟(𝑆ℎ2) 
In order to assess superiority, 2-sided testing with α=0.05 will be used. The superiority test 
statistic, Q=d2/Var(d) will be assessed by a chi-square distribution with 1 degree of freedom. 
This statistic is referred to as the “row mean score statistic” when using Proc Freq. 
The number and percentage of subjects who experience a PGTCS or censoring and the KM 
seizure-free rate from PGTCS (and 2-sided 95% CI) by Day 166 will be presented by treatment 
group for each stratum and overall. The stratified seizure-freedom rate from PGTCS (and 2-sided 
95% CI) at Day 166 for each treatment group and the difference between treatment groups will 
be presented. A Kaplan-Meier plot will be presented by treatment group for each stratum and 
overall. 
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level, 
then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the 
primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint 
will be exploratory only. 
8.2.2.2 
Analysis: Time to first PGTCS during the 166-day Treatment Period 
Time to the first PGTCS during the 24-week Treatment Period will be evaluated using a Cox 
proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for 
the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined 
REDACTED COPY
dom
PY
dom fr
Y 
fr
re
TE
re-
E
-free
TED 
free
r (
RE
(𝑆
ED
𝑆1
ED
1)
DA
)
R
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
ys
r
ys
uency 
var
uency 
18 year
s or 
18 year
ariance 
exte
ariance 
Var(S
ny e
Var(Sh2
y
h2
Sh
S
y
Sh
S )
e
)
TCS
n an
TCS fo
n
fo
ollows 
tion
ollows 
rom PG
app
rom PG
dom
izat
dom f
=∑
g au
∑6
aut
6
ℎ
a
ℎ
(
ke
(𝑆
eti
𝑆2
eti
2)
ting
) =
n
=
ed testi
mark
ed testi
sessed 
ny m
sessed 
the “ro
t any
the “ro
age
ppo
age of s
por
of s
PGTC
supp
PGTC
tum an
to s
tum an
166 fo
ed t
166 fo
A Kap
use
A Kap
e gatek
nnot
e gatek
n the k
can
n the k
This documen
primary
ent c
primary
will 
men
will 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age 
vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as 
described in Section 4.9.  
The hypothesis for the assessment of the time to first PGTCS is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
) 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05. The assumptions of proportional 
hazards will also be checked using the same approach as for the primary efficacy endpoint.  
The stratified HR will be calculated using the placebo arm as the reference group. The 95% CI 
for the HR will also be reported.  
Additionally, a KM plot for time to 1st PGTCS as well as the KM estimate for the median time to 
1st PGTCS and 95% CI will be provided. If the median time is not estimable, then the 25th 
percentile and 95% CI will be provided. The number of 1st PGTCS will be reported by treatment 
group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects 
who were censored. 
8.3 
Analysis of seizure related other efficacy variables 
All seizure data recorded during the treatment period will be summarized and listed for the 
seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will 
be performed for the FAS. For absence seizure analyses, this analysis population will be further 
restricted to the subset of subjects who reported a history of absence seizures or reported absence 
seizures during baseline or the 24-week treatment period.  For myoclonic seizure analyses, this 
analysis population will be further restricted to the subset of subjects who reported a history of 
myoclonic seizures or reported myoclonic seizures during baseline or the 24-week treatment 
period. 
8.3.1 
Derivations of seizure related other efficacy variables 
8.3.1.1 
Variable: PGTCS frequency per 28 days  
In order to account for potential differences in the durations of the study periods for individuals, 
PGTCS data will be normalized to 28 days. 
The 28-day PGTCS frequency (SF) will be calculated for the Combined Baseline and Treatment 
Periods as: 
SF =  
(# PGTCS in the relative period/# days in relative period with evaluable PGTCS data)*28 
REDACTED COPY 
well a
CO
well a
e medi
ED C
e medi
e num
CTE
e num
eeks
DAC
eeks
C
R
marketing authorization application and any extensions or variations thereof.
n the
s or
n the
ne haza
d an
ne haza
ssumpt
and
ssumpt
rimary 
tion a
rimary 
the refe
licat
the refe
as the K
on a
as the K
ian tim
zatio
ian tim
mber of 
horiz
mber of 
and 
utho
and Tr
o
Tr
e relat
keting
e relat
e treatm
mark
e treatm
cannot be used to support any
ariables
ny m
ariables
or abse
t any
or abse
subject
port 
subject
e or the
upp
e or the
will be
to su
will be
es or re
ed to
es or re
This document 
D
 
D
1
n
1
n order 
t ca
n order 
PGTC
ent
PGTC
T
m
T


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The percent change (PCH) in PGTCS frequency per 28 days from the Combined Baseline (CB) 
to the appropriate analysis period (T) is defined as: 
PCH = [(SFT – SFCB) / SFCB] x 100 
where SFT corresponds to the 28-day PGTCS frequency during the relative period and SFCB 
corresponds to the 28-day Combined Baseline PGTCS frequency. PCH is calculated for 6-week 
Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period. 
 
8.3.1.2 
Variable: Days with seizures per 28 days 
The number of days with absence seizures per 28 days will be calculated separately for the 
Prospective Baseline and the Treatment Period as:  
D = ([# days with absence seizures in the relative period] / [# days in relative period with 
evaluable seizure data]) * 28. 
Similarly, the number of days with myoclonic seizures per 28 days will be calculated. 
The percent change (PCH) in days with absence seizures per 28 days from the Prospective 
Baseline (B) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DB) / DB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DB corresponds to the number of days with absence seizures per 28 days 
during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such 
subjects will be excluded from the percent change summary. PCH will be calculated for the 6-
week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period. 
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from 
the Prospective Baseline Period will be calculated. 
8.3.1.3 
Variable: Seizure-free status 
A subject will have seizure-free status for PGTCS=yes for the Treatment Period if the subject 
completed the Treatment Period (with a minimum 166 days) and reported zero PGTCS or “not 
done” for all days during the Treatment Period. If the subject is exited from the study due to the 
125th event occurring reporting zero PGTCS or “not done” for all days and duration of the 
Treatment Period is < 166 days, then the subject has not achieved seizure-free status for PGTCS.  
A subject will have seizure free status=yes for all generalized seizure types for the applicable 
Treatment Period if the subject completed the Treatment Period and reported zero generalized 
seizures for all days during the Treatment Period when the number of generalized seizures was 
available, and had <10% of days during the Treatment Period with seizure data reported as “not 
done”. 
Seizure-free statuses will be calculated for 6-week Titration Period, first 12 weeks of the 
Treatment Period and the 24-week Treatment Period. 
8.3.1.4 
Variable: Responder status – reduction in PGTCS frequency   
Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.3.1.1 . A 50% responder is defined as a subject experiencing ≥50% 
REDACTED COPY 
h absen
COP
h absen
ber of 
ED C
ber of 
B is z
CTED
B is z
nt chan
DACT
nt chan
of the 
REDA
of the 
um
R
um
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
for the
ions
for the
period 
exte
period 
l be cal
nd a
l be cal
ys from
on a
ys from
c
nce sei
on a
nce sei
f days w
atio
f days w
zero, th
oriza
zero, th
nge sum
utho
nge sum
Treatm
aut
Treatm
mber of
eting
mber of
be calc
rke
be calc
re
y
re-
m
-fre
ma
fre
free sta
t an
free sta
Period
port
Period
ng the 
supp
ng the 
ng
to
ng repo
to su
repo
d is < 1
ed to
d is < 1
ll have
e us
ll have
t Perio
t be 
t Perio
es for a
not 
es for a
ilable, 
cann
ilable, 
one”.
nt c
one”.
Seiz
me
Seiz
T


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
reduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest 
(6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment 
Period). A 75% responder is defined as a subject experiencing ≥75% reduction in PGTCS 
frequency per 28 days from Combined Baseline to the period of interest (6-week Titration 
Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). 
8.3.1.5 
Variable: PGTCS frequency - worsening 
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per 
28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 
weeks of the Treatment Period or the 24-week Treatment Period).  
8.3.1.6 
Variable: Responder status – reduction in days with absence 
seizures   
Response to treatment for absence seizures per 28 days will be based on the percent change in 
days with absence seizures, calculated as described in Section 8.3.1.2. A 50% responder is 
defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of 
the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective 
Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment 
Period or the 24-week Treatment Period). 
8.3.1.7 
Variable: Responder status – reduction in days with myoclonic 
seizures 
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in 
days with myoclonic seizures, calculated as described in Section 8.3.1.2. A 50% responder is 
defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days 
from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of 
the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective 
Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment 
Period or the 24-week Treatment Period). 
8.3.1.8 
Variable: Days with absence and myoclonic seizures – worsening 
Safety of the LCM treatment will be based on the percent change in days with absence seizure 
per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence 
seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, 
>50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures 
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 
75%, and >75% for the Treatment Period. 
8.3.1.9 
Variable: Absence and myoclonic seizure frequencies per 28 days  
In order to account for potential differences in the durations of the study periods for individuals, 
absence and myoclonic seizure data will be normalized to 28 days. 
The 28-day absence SF will be calculated for the Prospective Baseline and Treatment Periods as: 
SF =  
REDACTED COPY 
iod
Y
iod
–
D
– red
D C
red
zures p
DAC
zures p
ated as
RED
ated as
0% r
R
0% r
used to support any marketing authorization application and any extensions or variations thereof.
r r 
ce
io
ce
ercent 
ext
ercent 
0% resp
any e
0% resp
seizure
d an
seizure
ion Per
and
ion Per
espond
tion 
espond
r 28 da
icatio
r 28 da
irst 12 
pplic
irst 12 
ductio
ation
ductio
per 28 
utho
per 28 
s descri
g au
s descri
reducti
eting
reducti
period 
rket
period 
ek Tre
mar
ek Tre
n days w
ny m
n days w
erest (6
rt any
erest (6
eatmen
port
eatmen
ble: D
sup
ble: D
M treat
d to
M treat
nd days
used
nd days
This document cannot be
r 28 da
be u
r 28 da
5%, an
ot be
5%, an
8 days 
nno
8 days 
%, and
t can
%, and
8.3.1
ment
8.3.1
In
m
In


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
(# absence seizures in the relative period/# days in relative period with evaluable absence seizure 
data)*28 
The PCH in Absence seizure frequency per 28 days from the Prospective Baseline (PB) to the 
appropriate analysis period (T) is defined as: 
PCH = [(SFT – SFPB) / SFPB] x 100 
where SFT corresponds to the 28-day absence seizure frequency during the relative period and 
SFPB corresponds to the 28-day Prospective Baseline absence frequency; if subjects had no 
absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for 
6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment 
Period. 
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm 
described above. 
8.3.1.10 
Variable: Responder status – reduction in absence and myoclonic 
seizure frequencies   
Response to treatment will be based on the percent change in absence and myoclonic seizure 
frequencies, calculated as described in Section 8.3.1.9. A 50% responder is defined as a subject 
experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the 
Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the 
Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from 
Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the 
Treatment Period or the 24-week Treatment Period). 
8.3.1.11 
Variable: Absence and myoclonic seizure frequency - worsening 
Safety of the LCM treatment will be based on the percent change in absence seizure frequency 
per 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure 
frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, 
>50 to 75%, and >75% for the Treatment Period. The increase in myoclonic seizure frequency 
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 
75%, and >75% for the Treatment Period. 
8.3.2 
Analysis of seizure related other efficacy variables 
8.3.2.1 
Analysis: Percent change in PGTCS frequency per 28 days from 
Combined Baseline  
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 
weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.   
All PGTCS frequency per 28 days data will be listed. 
8.3.2.2 
Analysis: Reduction in days with seizures per 28 days 
The following data will be summarized with descriptive statistics only: 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline 
REDACTED COPY 
c) s
Y
c) s
k Titr
OPY
k Titr
od). A
CO
od). A
myoclo
ED C
myoclo
st (6
CTE
st (6-
T
-w
E
w
ment Pe
DAC
ment Pe
and 
RED
and 
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
ed for 
or va
ed for 
ment 
s o
ment 
algorith
tens
algorith
ce and
d any
ce and
nce and
ion a
nce and
respond
catio
respond
zure
plic
zure fre
ic
fre
ation P
app
ation P
A 75% r
tion a
A 75% r
onic) se
zatio
onic) se
week T
horiz
week T
eriod).
utho
eriod).
 myoc
ng a
 myoc
based o
rket
based o
freque
mark
freque
spectiv
ny m
spectiv
he Trea
t any
he Trea
tive Ba
port 
tive Ba
e Treatm
upp
e Treatm
alysis 
to s
alysis 
Analy
used
Analy
Co
e us
Co
tive sta
not b
tive sta
This documen
s of
anno
s of (e
no
(e
All PGT
ent c
All PGT
8.3
me
8.3


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the first 12 weeks of the 
Treatment Period relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the 
Treatment Period relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
All seizure days data for absence and myoclonic seizures will be listed. 
8.3.2.3 
Analysis: Seizure-free status 
The following seizure-free status (yes/no) summaries will be provided: 
 Seizure-free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period 
(Titration Period) 
 Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the first 6 weeks of the 
Treatment Period (Titration Period) 
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
8.3.2.4 
Analysis: Responder status – reduction in PGTCS frequency 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 
6 weeks (Titration Period) compared to the Combined Baseline 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 
12 weeks of the Treatment Period compared to the Combined Baseline 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Treatment Period compared to the Combined Baseline 
REDACTED COPY 
ries wi
COP
ries wi
or the f
TED 
or the f
GTCS f
EDA
GTCS f
GT
R
GT
e used to support any marketing authorization application and any extensions or variations thereof.
to
ari
to
eks of th
ons 
eks of th
st 12 w
exte
st 12 w
the Tr
nd a
the Tr
 listed
atio
 listed
ill be p
on ap
ill be p
first 6 
izati
first 6 
for the
aut
for the
TCS for
eting
TCS for
all 
mar
all gen
ark
gen
Period)
y ma
Period)
no) for
rt an
no) for
us (yes, 
sup
us (yes, 
Analy
used
Analy
This document cannot b
wing da
t be 
wing da
Perce
nno
Perce
6
an
6

n



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 
6 weeks (Titration Period) compared to the Combined Baseline 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 
12 weeks of the Treatment Period compared to the Combined Baseline 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the 
Treatment Period compared to the Combined Baseline 
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS 
frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment 
Period by treatment group will be provided. 
8.3.2.5 
Analysis: Responder status – reduction in days with absence 
seizures   
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6 
weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the first 
12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the 
Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 
weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the first 
12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the 
Treatment Period compared to the Prospective Baseline 
 A histogram of ≥50% and ≥75% responder status for reduction in days with absence seizures 
during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period 
by treatment group will be provided. 
8.3.2.6 
Analysis: Responder status – reduction in days with myoclonic 
seizures 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline  
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
first 12 weeks of the Treatment Period compared to the Prospective Baseline  
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
Treatment Period compared to the Prospective Baseline  
REDACTED COPY 
Y
ction in
OPY
ction in
ve Bas
D CO
ve Bas
% redu
CTED
% redu
ion Pe
ACT
ion Pe
st a 75
RED
st a 75
co
R
co
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
atment 
or va
atment 
ence
nsio
ence
ure day
nd a
ure day
e Prosp
and
e Prosp
nce seiz
ation
nce seiz
ective B
plica
ective B
n absen
n app
n absen
seline
tion
seline
uction 
oriza
uction 
eriod)
thor
eriod)
5% red
g au
5% red
ompare
eting
ompare
east a 7
mark
east a 7
to the
y ma
to the P
a
P
d
t
d ≥75%
rt an
≥75%
ks
p
ks (Titr
port
(Titr
p will b
supp
p will b
alysis
d to s
alysis
seizur
sed 
seizur
ing dat
be u
ing dat
rcentag
not 
rcentag
first 6 w
ann
first 6 w

e

Per
nt 
Per


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
Treatment Period compared to the Prospective Baseline 
 A histogram of ≥50% and ≥75% responder status for reduction in days with myoclonic 
seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week 
Treatment Period by treatment group will be provided. 
8.3.2.7 
Analysis: Percent change in absence and myoclonic seizure 
frequency per 28 days from Prospective Baseline  
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure 
frequencies for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire 
Treatment Period.   
All absence and myoclonic seizure frequency per 28 days data will be listed. 
8.3.2.8 
Analysis: Responder status – reduction in absence and myoclonic 
seizure frequency 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency 
during the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
REDACTED COPY 
criptiv
CO
criptiv
50% r
TED
50% r
 comp
ACT
 comp
least a
RED
least a
ation
R
ation
upport any marketing authorization application and any extensions or variations thereof.
ure
nsio
ure
myoc
ny e
myocl
ks of, a
d any
ks of, a
ll be lis
tion 
ll be lis
 in ab
lica
 in ab
ve statis
tion 
ve statis
reducti
riza
reducti
pared t
thor
pared t
a 50% 
g au
a 50% 
n Perio
eting
n Perio
at least
arke
at least
Treatm
y ma
Treatm
ts with 
t any
ts with 
weeks
port
weeks
ot be used to s
subjec
sup
subjec
ent Per
d to s
ent Per
ntage of
used
ntage of
ing the 
be u
ing the 
This document canno
Percen
not 
Percen
the 
ann
the 

nt 



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency 
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency 
during the Treatment Period compared to the Prospective Baseline 
8.4 
Analysis of health outcome other efficacy variables 
8.4.1 
Derivations of health outcome other efficacy variables 
8.4.1.1 
QOLIE-31-P variables 
The Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Version 2 
will be used to evaluate the health-related quality of life (HRQoL) of study subjects ≥18 years of 
age. 
The QOLIE‑31‑P total score, subscale scores, and health status item score are calculated 
according to the scoring algorithm defined in Section 12.1 which accounts for the possibility of 
missing values. Scores range from 0 to 100 and higher scores indicating better functioning. 
QOLIE- 31-P data that are completely missing will not be replaced. 
Subscale scores 
As a first step to calculating the subscale scores, the individual responses for the 30 subscale 
items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the rescaled 
values for each item are defined in Section 12.1. Each subscale score is then calculated by 
summing the rescaled responses for that subscale and dividing by the number of items with a 
non-missing response. A subscale score will be calculated only if at least 50% of the items 
within the subscale are present. 
Total score 
Total score is calculated as a weighted sum of the subscale scores based on the weighting in 
Section 12.1. Total score will be missing if at least 1 subscale score is missing. Total score will 
range from 0 to 100 with a higher score reflecting better functioning. 
Health status item 
The response for the health status item is a multiple of 10 ranging from 0 to 100 with a higher 
score corresponding to a better health status. The health status item response is analyzed without 
rescaling. 
Distress items 
Each subscale includes 1 distress item. The response for each distress item is an integer ranging 
from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale (ie, 0, 25, 
50, 75, and 100) with a higher score corresponding to greater distress. 
Prioritization item 
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. The 
prioritization ranking is analyzed without rescaling. 
DACTED COPY 
Y
, the i
D C
, the i
gher s
CTED
gher s
n 12.
ACT
n 12.
RED
1
T
1
at subs
EDA
at subs
ore w
RE
ore w
orization application and any extensions or variations thereof.
1
t
1-
te
-P) V
xtens
P) V
ubjects 
ext
ubjects 
score ar
and 
score ar
ccounts
on a
ccounts
dicatin
atio
dicatin
placed.
plica
placed.
individ
ation
individ
scores r
oriza
scores r
sed to support any marketing auth
1. Each
thor
1. Each
scale a
aut
scale a
will be 
ting a
will be 
weighte
any 
weighte
will be m
ort a
will be m
h a high
ppo
h a high
m
o
m
r the he
sed t
r the he
This document cannot be u
ponding
use
ponding
ess ite
nnot
ess ite
ach sub
nt ca
ach sub
from 
ment
from 
50
m
50


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
8.4.1.2 
PedsQL variables 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations (<18 years), including those with acute or chronic health conditions.  
PedsQL generic core scale scores will be calculated for each of the following 4 PedsQL scales: 
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 (0 to 4 representing responses of: never, almost never, sometimes, often, or 
almost always). These scores of 0 to 4 will be transformed by the function: 100 – (response x 25) 
in order to generate scores of 0, 25, 50, 75, and 100, where a higher value represents a better 
HRQoL.  
Each scale score is then calculated as the mean of the non-missing categorized items if 50% or 
more of the items are non-missing.     
The above algorithm will also be used to calculate an overall total scale score (all scales) for 
each subject. To create the Total Scale Score, the mean is computed over the number of items 
answered on all the Scales 
8.4.1.3 
EQ-5D-3L quality of life variables 
The 3-Level EuroQol-5 Dimensional Quality of Life Assessment (EQ-5D-3L) is a self-
administered questionnaire designed to measure health status in subjects ≥12 years of age.  
The EQ-5D-3L defines health in terms of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each dimension is divided into 3 levels: 
 No problem=1 
 Some or moderate problems=2 
 Extreme problems=3 
The EQ-5D-3L also captures a self-rating of health status on a 20cm vertical visual analog scale, 
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at 
the bottom. 
At each time point, an EQ-5D-3L utility value will be mapped to each subject’s health state. 
Health state is derived from the subject’s numerical ratings of the 5 EQ-5D-3L Dimensions.  The 
order of the ratings is Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
Anxiety/Depression.  Health state is derived by concatenating the numerical ratings of the 5 
dimensions. For example, a health state may be derived as 11111, indicating best possible health. 
A utility value will then be mapped to the derived health states, using the UK EQ-5D-3L value 
set. This set is available to Global Statistical Programming in excel format. 
The mapped utility values will make up the utility variable. 
8.4.1.4 
Hospital stays 
An event logged on the Hospitalization/Emergency Room (ER) Visit form of the eCRF where 
“Emergency room” is marked as initial entry point will be defined as an ER visit. An ER visit 
with a subject transfer to an inpatient general ward will also be counted as a hospitalization. 
REDACTED COPY 
sse
Y
sse
lth sta
OPY
lth sta
ension
D CO
ension
ch dim
TED
ch dim
y marketing authorization application and any extensions or variations thereof.
r r 
x 25)
var
x 25)
etter 
or
etter 
ms if 5
ensi
ms if 5
ore (all
any 
ore (all
r the n
d a
r the n
ment (E
plic
ment (E
atus in 
app
atus in 
ns (mob
ation
ns (mob
mension
rizat
mension
lflf-
m
-f-f-f ratin
y ma
ratin
ed to support an
ble hea
any 
ble hea
EQ
up
EQ-
pp
-5D
ppo
5D
ed from
o sup
ed from
gs is M
d to
gs is M
t cannot be us
ession. 
used
ession. 
. For ex
be us
. For ex
y value
not b
y value
This se
ann
This se
This documen
The ma
ent c
The ma
8.4
me
8.4


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
However, all other instances of ER visits (where subject transfer is not to an inpatient general 
ward) will not be counted as hospitalizations.   
For hospital stays with a discharge date, the duration of each hospital stay will be calculated as 
the discharge date minus the admission date (Hospitalization/ER Visit Date on the eCRF) plus 1 
day. For hospitalizations with either a partial admission or discharge date, the duration of 
hospital stay will be set to missing.  The non-missing durations of hospital stays will be summed 
within each of the study periods (Baseline, Titration, and Maintenance, respectively). Should 
distinct records for hospital stays overlap, then the days during the overlap will only be counted 
once. Subjects with no hospital stays within a study period will have duration of 0 days for that 
period.  For subjects with hospital stays but no calculable hospital duration, the duration of 
hospitalization in the respective study period will be missing. 
8.4.2 
Analysis of health outcome other efficacy variables 
8.4.2.1 
QOLIE-31-P variables 
QOLIE-31-P data, for a specific visit may have a status of Abandoned if the subject doesn’t 
complete the questionnaire. If the subject has duplicate QOLIE-31-P data for the same visit, 
where one record is deemed as Abandoned and one record is deemed as Completed, the 
Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE-
31-P data will be listed. 
The observed values and change from Baseline will be summarized descriptively for the total 
score, the subscale scores, health score and the distress items for each visit and Last Visit. The 
mean observed values for the prioritization items will laso be summarized for each visit and Last 
Visit. They will all be summarized for both Visit 10 and Visit 10/ET.  The scores for individual 
subscales will only be analyzed when a total score can be calculated (ie, all subscales have a non-
missing score). Individual questions will not be summarized. Individual questions, subscale 
scores, and total scores will be presented in subject data listings. The means of the QOLIE-31-P 
total score, subscale scores and health status item score will be plotted by visit. 
8.4.2.2 
PedsQL variables 
The observed values and change from Baseline for the total scale score and each of the 4 scale 
scores will be summarized for each visit and Last Visit by treatment group. They will be 
summarized for both Visit 10 and Visit 10/ET.  Subgroup summaries by age will be performed 
using the age groupings for which different questionnaires were entered: 4 years, ≥5 to ≤7 years, 
≥8 to ≤12 years, and ≥13 to ≤18 years. 
All PedsQL data will be listed. The means of the PedsQL subscale scores and total score will be 
plotted by visit. 
8.4.2.3 
EQ-5D-3L quality of life variables 
The observed values for each dimension and the mapped utility values will be summarized for 
each visit and Last Visit.  They will be summarized for both Visit 10 and Visit 10/ET.   
Observed values and the change from Baseline for the VAS score for general health state will 
also be summarized. 
REDACTED COPY 
ll be s
COP
ll be s
distres
D C
distres
tems w
CTED
tems w
h Vis
ACT
h Vis
a total 
EDA
a total 
will n
RE
will n
rketing authorization application and any extensions or variations thereof.
ted 
var
ted 
r that 
or va
r that 
n of 
ns o
n of 
f the su
nd an
f the su
data fo
and
data fo
med as 
tion 
med as 
oned re
icatio
oned re
summa
on ap
summa
ss item
ation
ss item
will las
oriza
will las
it 10 a
thor
it 10 a
l score 
aut
l score 
not be 
ting a
not be 
ed in su
ketin
ed in su
d to support any ma
lth statu
mark
lth statu
bles
ny m
bles
hange f
ort a
hange f
ed for 
ppo
ed for 
Visit 1
sup
Visit 1
pings f
d to s
pings f
t cannot be use
, and ≥
sed 
, and ≥
L data w
be u
L data w
by visit
ot b
by visit
This documen
2.3
an
2.3
The ob
nt c
The ob
each
me
each


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
All EQ-5D-3L data will be presented in subject data listings. The mean of the EQ-5D-3L VAS 
will be plotted by visit.  For the EQ-5D-3L, the percentage of subjects reporting a level within 
each dimension will be plotted in a histogram. 
8.4.2.4 
Concomitant medical procedures 
Subjects who had any concomitant medical procedures during the course of the study based on 
the Concomitant Medical Procedures eCRF will be listed. Additionally, subjects who had any 
procedures or surgeries prior to study entry based on the Procedure History eCRF will also be 
listed. 
8.4.2.5 
Healthcare provider consultations 
All healthcare provider consultations data will be listed. 
8.4.2.6 
Hospital stays 
All hospitalization/ER data will be listed. 
8.4.2.7 
Number of working or school days lost due to epilepsy 
All working or school days lost data will be listed. 
8.4.2.8 
Number of days with help from a paid caregiver due to epilepsy 
All data regarding help from a paid caregiver will be listed. 
8.4.2.9 
Socio-professional data 
The number and percentage of subjects by each response level for highest level of education, 
housing status, current professional status, regular assistance in usual activities, and driving 
status will be summarized for each visit and Last Visit for the FAS. Percentages will be relative 
to the number of subjects with a response to each item. No statistical comparisons will be carried 
out for socio-professional data. 
All socio-professional data will be listed. 
9 
PHARMACOKINETICS  
LCM plasma concentration will be summarized using the SS. Descriptive statistics of LCM 
plasma concentrations will be presented by visit and actual dose. The actual dose is defined as 
the most recent dose administrated prior to PK sampling.  
The following parameters will be calculated for each of the sampling points: n, nLOQ (number 
of measurements above or equal to the lower limit of quantification [LOQ]), arithmetic mean, 
standard deviation (SD) and coefficient of variation (CV), median, minimum, and maximum 
value.  
Values below LOQ will be replaced by 0 in calculations of mean, SD, CV(%) and median.  
Mean, SD and CV(%) will only be calculated if at least 2/3 of the data are above LOQ at the 
respective time point. In tables showing mean values, where values below LOQ are included in 
the calculation of mean values, these mean values will be marked.   
A listing of LCM plasma concentration data by subject and visit will include actual doses, date 
and time of the most recent administration, date and time of sampling, time interval between 
REDACTED COPY
listed
OPY 
listed
ach res
TED
ach res
, regul
ACT
, regul
t and L
EDA
t and L
onse 
RE
onse 
be used to support any marketing authorization application and any extensions or variations thereof.
epileps
nd a
epileps
aregive
icati
aregive
d.
a
d.
sponse
riza
sponse
ular assi
thor
ular assi
Last V
auth
Last V
to each
ing a
to each
 listed.
mar
 listed.
OKIN
any 
OKIN
on will 
port
on will 
will be
supp
will be
e admin
to su
e admin
parame
sed 
parame
ments ab
e use
ments ab
This document cannot b
deviatio
t be 
deviatio
alues be
t can
alues be
Mean, 
ent 
Mean, 
resp
me
resp
t


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
plasma sample and the most recent administration (in hours), visit, relative day, and the kit 
number. Samples that were excluded from the descriptive statistics will be marked in the listing. 
10 
SAFETY ANALYSES 
10.1 
Extent of exposure 
10.1.1 
Derivation of exposure variables 
Study medication treatment duration will be calculated as ([last study medication dose during the 
Treatment Period – first study medication dose] + 1 day). Subject-years of exposure is the total 
treatment duration in days divided by 365.25. 
The mean exposure per day for an analysis period is calculated as the total exposure in 
milligrams during the analysis period (based on the randomized treatment group or protocol 
defined treatment regimen incorporating any scheduled dose changes) divided by the duration of 
exposure (days). Days during an analysis period with unknown dosing are to be excluded from 
both the numerator and the denominator for the calculation of mean exposure per day. 
10.1.2 
Analysis of exposure variables 
Total duration of exposure (days) for each treatment group during the Titration Period, 
Maintenance Period, and Treatment Period will be summarized by region for the SS using 
descriptive statistics. The number of days of exposure in the Treatment Period will be calculated 
as the last dose date minus the first dose date +1. Study medication taken during the Taper and 
Transition Periods will not be included in these calculations. 
Treatment duration will be summarized with the number and percentage of subjects with 
treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. 
Furthermore, the subject years exposed will be presented for the entire Treatment Period. 
If actual dosing information is presented, the LCM dose categories for oral solution are as 
follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg 
day.  The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to 
<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day. 
The mean dose per day will be presented for the 3 different weight categories: <30kg 
(mg/kg/day), ≥30kg to <50kg (mg/kg/day) and ≥50kg (mg/day).  
This analysis will be repeated for each subgroup as detailed in Section 4.8.  
Detailed LCM exposure, LCM dosing, and drug accountability will be presented in subject data 
listings. 
10.2 
Adverse events 
Adverse events will be coded using MedDRA, and tabulated by SOC and PT for each treatment 
group for the SS and will include the number and percentage of subjects experiencing each event 
at least once. All summaries will be sorted alphabetically by SOC and by frequency of events 
within each SOC, starting with the most frequent event for the LCM arm.  
Adverse events will be considered treatment-emergent if the event had onset on or after the date 
of the first study medication dose and within 30 days following the last study medication dose or 
REDACTED COPY
e in th
PY 
e in th
Study m
COP
Study m
calcu
D C
calcu
th the 
CTE
th the 
s: 1 to 
DAC
s: 1 to 
s, 127 
RED
s, 127 
ed w
R
ed w
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
the
ria
the
otal
va
otal
in 
sio
in 
or proto
ensi
or proto
by the 
exte
by the 
o be ex
ny e
o be ex
osure p
d any
osure p
ng the T
ation
ng the T
ed by re
plica
ed by re
he Trea
appl
he Trea
medica
on ap
medica
lations
atio
lations
numbe
horiz
numbe
 21 day
autho
 21 day
to 147
g au
to 147
will be
eting
will be
ented, t
marke
ented, t
>0 to <
y ma
>0 to <
es for ta
any
es for ta
0mg/da
ort a
0mg/da
y will b
upp
y will b
g to <50
to su
g to <50
ill be re
sed 
ill be re
CM exp
be u
CM exp
This documen
2
Advers
ent c
Advers
grou
me
grou
a


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
events whose intensity worsened on or after the date of first study medication dose and within 
30 days following the date of last study medication administration. 
If the last dose of study medication administration is unknown, any event occurring after the first 
study medication dose will be considered treatment-emergent. If the start date of an AE is 
completely missing and the stop date is either unknown or after the date of the first dose of study 
medication, the AE will be considered as treatment-emergent. Incomplete dates for AEs will be 
handled as described in Section 4.2.3. 
Treatment emergent adverse events (TEAEs) during the Treatment Period, Maintenance Period 
and Taper/Safety Follow-Up Period, respectively, are TEAEs with an onset date during the 
respective period. 
The following summaries will be presented by randomized treatment group: 
 Overview of TEAEs  
 Overview of TEAEs by subgroup as detailed in Section 4.8  
 Incidence of TEAEs  
 Incidence of TEAEs by subgroup as detailed in Section 4.8 
 Incidence of TEAEs in the Titration Period 
 Incidence of TEAEs in the Maintenance Period 
 Incidence of TEAEs in the Taper Period 
 Incidence of TEAEs in the Transition Period 
 Incidence of TEAEs by intensity  
 Incidence of common TEAEs for US labeling (above or equal to reporting threshold of 2% 
(prior to rounding) of subjects in the total LCM group)  
 Incidence of common drug-associated TEAEs (TEAEs occurring in ≥5% of subjects in the 
LCM group and occurring twice as often as in the placebo group) 
 Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1% 
(prior to rounding) of subjects in the total LCM group) and occurring >1% than in the 
placebo group 
 Incidence of serious TEAEs  
 Incidence of serious TEAEs – Subject numbers 
 Incidence of TEAEs leading to discontinuation  
 Incidence in TEAEs leading to discontinuation in the Titration Period 
 Incidence in TEAEs leading to discontinuation in the Maintenance Period 
 Incidence in TEAEs leading to discontinuation – Subject numbers 
 Incidence of other significant TEAEs (See Section 12.2.1  for details) 
REDACTED COPY 
d
C
d
Period
ACT
Period
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
riod 
va
riod 
he
o
he
d
th
d
US labe
ketin
US labe
n the to
marke
n the to
associa
ny m
associa
ng twic
rt any
ng twic
n TEA
ppo
n TEA
g) of su
sup
g) of su
of serio
used
of serio
nce of 
t be 
nce of 
ncidenc
anno
ncidenc
Inci
nt ca
Inci

me



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 12.2.2 for 
details) 
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review.  
The following PTs (including those identified from continuing medical review) will be 
summarized: petit mal epilepsy, myoclonus, and myoclonic epilepsy. 
 Incidence of TEAEs related to epilepsy by 3-month exposure period of TEAE onset 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2. AEs of unknown dosing are those with no known dose or known dosing and 
partial AE start or stop dates. 
 Incidence of TEAEs by actual dose at onset  
Subject data listings will be presented for the following: 
 Subjects experiencing adverse events on the ES 
 Subjects experiencing Serious TEAEs on the SS 
 Subjects experiencing TEAEs leading to discontinuation on the SS 
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC 
and PTs. 
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in 
Section 12.5. 
10.3 
Clinical laboratory evaluations 
Measurement and change from Baseline in continuous laboratory parameters, including 
hematology, clinical chemistry, endocrinology, and urinalysis will be summarized using 
descriptive statistics for the scheduled visits. When analyzing categorical data, the number and 
percentage of subjects in each category will be presented. In addition, summary statistics for the 
actual value and change from Baseline will be presented for Last Visit, minimum, and maximum 
post-Baseline values obtained during the Treatment Period. Repeated or unscheduled laboratory 
assessments during the study will not be presented in by-visit summaries, but will be considered 
when determining the last visit, minimum, and maximum post-Baseline values during the 
Treatment Period. 
Shifts based on the normal range (ie, low, normal, high, and missing) for each hematology and 
clinical chemistry lab parameter will be presented by maximum value during the Treatment 
Period relative to Baseline by treatment group. Similar shift tables for Baseline versus minimum 
value during the Treatment Period will also be presented. Unscheduled visits will be considered 
when determining the maximum and minimum value during the defined treatment period.  
Treatment-emergent markedly abnormal (TEMA) values indicate significant deviations from the 
expected range of age-appropriate values. TEMA laboratory abnormalities results are those that 
are observed post-Baseline during the Treatment Period but are not present at Baseline. TEMA 
values for serum chemistry and hematology laboratory parameters are provided in UCB 
conventional (traditional) and standard units. The definition of MA values for hematology and 
chemistry values can be found in Section 12.3. The number and percentage of subjects with at 
REDACTED COPY 
and cl
CO
and cl
valua
ACT
valua
ine in 
RED
ine in 
crin
R
crin
pport any marketing authorization application and any extensions or variations thereof.
ed in
varia
ed in
nd 
or
nd 
he SS
tion
he SS
investi
plica
investi
linicalt
tion 
linicalt
ations
thor
ations
contin
g au
contin
nology,
eting
nology,
d visits
rket
d visits
egory w
mar
egory w
Baseline
ny m
Baseline
d durin
rt any
d durin
udy wil
port
udy wil
nnot be used to sup
last vis
supp
last vis
the nor
sed 
the nor
mistry la
e use
mistry la
ative to
t be 
ative to
urin
not
uring t
ot 
g t
This document ca
en deter
cann
en deter
Treatm
ent 
Treatm
exp
me
exp


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
least 1 TEMA value will be summarized by scheduled visit, Last Visit, minimum and maximum 
post-Baseline values obtained during the Treatment Period for each laboratory parameter 
(hematology and clinical chemistry) with markedly abnormal criteria specified. TEMA values 
are those that are observed during the defined treatment period at scheduled or unscheduled visits 
and were not observed at any visit during the Baseline period.  
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria will also be presented. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) 
can be found in Section 12.4. The number and percentage of subjects with treatment emergent 
laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will 
be summarized by treatment group, laboratory parameter, and visit for the Treatment Period. 
Treatment emergent abnormalities of grade 2 or higher are those that were observed during the 
Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the 
Baseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher 
will be presented in a subject number listing. 
Subject data listings of all laboratory data will also be presented. Within the listings TEMA 
values will be identified. Separate tables will also be provided to show the subject numbers of 
those who meet any of the TEMA and NCI CTC grade 2 or higher criteria. 
Any additional lab data will be listed, including positive pregnancy test results listed by subject. 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
Observed values and changes from Baseline in vital sign parameters will be summarized using 
descriptive statistics for the scheduled visits. In addition, summary statistics for the observed 
value and change from Baseline will be presented for Last Visit, minimum, and maximum post-
Baseline values obtained during the Treatment Period. Repeated or unscheduled assessments 
during the study will not be presented in by-visit summaries, but will be considered when 
determining the minimum, and maximum post-Baseline values during the Treatment Period. 
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high 
value, at each post-Baseline visit, for which systolic blood pressure, diastolic blood pressure, 
pulse rate, and body weight were scheduled to be assessed, and Last Visit, will be presented. 
Percentages will be relative to the number of subjects with a value at each time point. All TEMA 
results summarized will be presented in a subject number listing. The abnormal vital sign criteria 
are defined in Section 12.3.3. 
A subject data listing of all vital signs data will be created, indicating any abnormal values. 
10.4.2 
Electrocardiograms 
ECGs will be performed locally and no standardization techniques will be employed. The data 
will be analyzed as reported. 
10.4.2.1 
Derivation of corrected QT values 
The Bazett corrected QT (QTcB) will be calculated as 
REDACTED COPY 
Y
itive p
OPY
itive p
ngs, 
ED C
ngs, 
aseli
RE
aseli
nnot be used to support any marketing authorization application and any extensions or variations thereof.
C)
v
)
ergent 
or v
ergent 
mistry) 
ons 
mistry) 
nt Peri
nsio
nt Peri
rved du
xten
rved du
normal
y ext
normal
CTC gr
any 
CTC gr
Within th
on a
Within th
o show 
ation
o show 
igher c
plica
igher c
pregnan
n app
pregnan
 and o
ation
 and o
ine in v
ing a
ine in v
visits. 
ketin
visits. 
ll be pr
mark
ll be pr
the Tre
y ma
the Tre
resente
any
resente
and m
ort a
and m
ntage o
supp
ntage o
Baselin
to su
Baselin
ody we
ed to
ody we
will be r
used
will be r
marize
be u
marize
ed in
ot b
ed in S
This document ca
ubject d
cann
ubject d
10.4.2
ent c
10.4.2
EC
m
EC


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
QT/√𝑅𝑅, where RR = 60/heart rate. 
The Fridericia corrected QT (QTcF) will be calculated as 
QT/√𝑅𝑅
3
, where RR = 60/heart rate. 
10.4.2.2 
Analysis of ECG parameters 
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR 
Interval and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
statistics of the actual values and change from Baseline will be summarized using descriptive 
statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-Baseline 
values obtained during the Treatment Period, and in each of the TEMA ECG criteria age 
categories. Last visit is the value from the last post baseline visit during the Treatment Period. 
Repeated or unscheduled ECG assessments during the study will not be presented in by-visit 
summaries, but will be considered when determining the last visit, minimum, and maximum 
post-Baseline values during the Treatment Period. If repeat measurements are taken at a 
particular visit, then the average value is used in summaries and the original values are listed. 
The number and percentage of subjects who met each of the TEMA criteria specified in 
Section 12.3.4 will be presented within the specified age groups. For each parameter, the number 
and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific 
to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and 
corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated 
or unscheduled ECG assessments during the study will not be presented in by-visit summaries, 
but will be considered when determining the last visit values during the Treatment Period. 
Subject numbers for those with TEMA ECG values will be listed by abnormality criteria. TEMA 
results for a subject are those that are observed during the defined treatment period at scheduled 
or unscheduled visits and were not observed at any visit during the Baseline period. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
10.4.3 
Physical examination 
A listing of abnormal physical examination findings will be provided. 
10.4.4 
Safety Seizure Information 
10.4.4.1 
New Seizure Type 
The number and percentage of subjects with seizure types present or absent in the Treatment 
Period vs whether the seizure type was present or absent in Combined Baseline will be tabulated. 
The number and percentage of subjects with seizure types present or absent in the Treatment 
Period vs whether the seizure type was present or absent in Seizure History (including Combined 
Baseline) will be tabulated. 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period with absence or myoclonic seizure type, respectively, 
indicated by the Seizure History Classification but not experienced in the Combined Baseline as 
recorded in the diary will be summarized.  
REDACTED COPY
ec
Y
ec
nterval
OPY 
nterval
t Visit
COP
t Visit
udy w
ED C
udy w
e last v
CTE
e last v
ECG va
DACT
ECG va
observ
REDA
observ
bserv
RE
bserv
ot be used to support any marketing authorization application and any extensions or variations thereof.
ve
r v
ve
ine 
or
ine 
age
on
age
ment Pe
nsio
ment Pe
ed in b
xten
ed in b
, and m
y ex
, and m
s are tak
any
s are tak
ginal v
nd a
ginal v
A criter
on a
A criter
. For e
catio
. For e
who me
plica
who me
l, QRS
app
l, QRS
t durin
ion a
t durin
will not 
zatio
will not 
visit va
oriza
visit va
values w
utho
values w
ved dur
g au
ved dur
rved at 
ting 
rved at 
tive an
arke
tive an
amina
t any
amina
ysical e
pport
ysical e
ty Seiz
o sup
ty Seiz
ew Se
ed to
ew Se
and pe
e use
and pe
whethe
t be 
whethe
This document cann
umber a
not 
umber a
od vs w
cann
od vs w
Baseline
nt ca
Baseline
The
me
The


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period but not experienced in the Combined Baseline or indicated 
in Seizure History Classification will also be summarized. 
The number and percentage of subjects with new absence or myoclonic seizure types in the 
Treatment Period, with absence or myoclonic, respectively, indicated by the Seizure History 
Classification but not experienced in the Combined Baseline Period or subjects with ≥50% 
worsening in days with absence or myoclonic seizures, respectively, will be summarized.  
10.4.4.2 
Increase in days with absence seizures   
Response to treatment regarding absence seizures will be based on the percent change in the 
number of days with absence seizures per 28 days, calculated as described in Section 8.3.1.2. 
The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, 
>50% to 75%, and >75% in the number of days with absence seizures per 28 days during the 
Treatment Period compared to the Prospective Baseline Period will be presented.  
10.4.4.3 
Increase in days with myoclonic seizures   
Response to treatment regarding myoclonic seizures will be based on the percent change in the 
number of days with myoclonic seizures per 28 days, calculated as described in Section 8.3.1.2. 
The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, 
>50% to 75%, and >75% in the number of days with myoclonic seizures per 28 days during the 
Treatment Period compared to the Prospective Baseline Period will be presented.  
10.4.4.4 
Increase in absence seizure frequency   
Response to treatment regarding absence seizures will also be based on the percent change in the 
absence seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The number 
and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, 
and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the 
Prospective Baseline Period will be presented.  
10.4.4.5 
Increase in myoclonic seizure frequency   
Response to treatment regarding myoclonic seizures will also be based on the percent change in 
the myoclonic seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The 
number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% 
to 75%, and >75% in myoclonic seizure frequency per 28 days during the Treatment Period 
compared to the Prospective Baseline Period will be presented.  
10.4.5 
Tanner stage assessment 
The investigator will evaluate the subject’s sexual development using the 3-item Tanner scale 
(ie, for females: breasts, pubic hair, and overall stage; and for males: genitals, pubic hair, and 
overall stage). The investigator should use clinical judgment in deciding which subjects are 
selected for evaluation of Tanner stage (ie, those subjects who are pubescent at Visit 2 or who 
will enter puberty during the course of the study). 
A listing of Tanner stage assessments will be provided. 
REDACTED COPY
myoc
PY 
myoc
seline 
COP
seline 
re fre
ED C
re fre
eizure
ACT
eizure
calcu
EDA
calcu
ing an
RED
ing an
R
cannot be used to support any marketing authorization application and any extensions or variations thereof.
n the
s or
n the
8.3.1.
ions
8.3.1.
25% to 
ensi
25% to 
ays dur
exte
ays dur
ented.
ny ex
ented.
on the p
n an
on the p
as desc
ation
as desc
ase of u
licat
ase of u
lonic s
appl
lonic s
Period
on ap
Period
equenc
zatio
equenc
es will
hor
es will
ulat
au
ulated a
auth
ed a
n incre
ng a
n incre
y
k
y per 2
keting
per 2
presen
arke
presen
yoclon
ny m
yoclon
rding m
ort a
rding m
equenc
ppor
equenc
ge of su
supp
ge of su
in
to
in myo
to s
myo
 Prospe
sed t
 Prospe
Tan
e us
Tan
estigat
not b
estigat
for fem
anno
for fem
This document 
verall s
t ca
verall s
select
ent
select
wi
m
wi


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
10.4.6 
Neurological examination 
Summaries of shift from Baseline to Last Visit will be provided by major neurological category 
and treatment group based on categories normal, abnormal, not clinically significant, and 
abnormal, clinically significant. The major neurological categories collected on the CRF are 
General, Cranial Nerves, Reflexes, Motor System (including General, Muscle Strength and 
Muscle Tone), Coordination/Cerebellar Function and Sensation (including Upper and Lower 
Extremities). A listing of abnormal neurological examination findings will also be provided.  
10.4.7 
Assessment of suicidality 
Suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). This 
scale will be used for screening as well as to assess suicide ideation and behavior that may occur 
during the study. All subjects who are ≥6 years of age will complete the “Baseline/Screening” 
version of the C-SSRS at the first visit and will complete the “Since Last Visit” version at 
subsequent visits. If a subject becomes 6 years of age during the study, the “Already Enrolled” 
version of the C-SSRS should be used at the first visit at which the subject is 6 years of age and 
the “Since Last Visit” version should be used at subsequent visits. The C-SSRS is not validated 
for subjects <6 years of age and will not be used for this population.  
Subject data listings of the data for the C-SSRS will be provided. No summaries of the C-SSRS 
data are planned. 
10.4.8 
Achenbach Child Behavior Checklist 
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the 
Achenbach CBCL is used. The CBCL/1½-5 is intended for use in children 4 years to 5 years and 
11 months of age. For subjects ≥6 years to <17 years, the CBCL/6-18 will be used. For each 
subject, the same version (CBCL/1½-5 or CBCL/6-18) that is used at Visit 2 (Baseline) should 
be used at all following visits, even if the subject passes the applicable age range during the 
study, and should be completed by the same parent/legal representative.  
10.4.8.1 
Derivation of Achenbach variables 
The CBCL/1½-5 will be grouped according to syndrome scales in Table 2 and the CBCL/6-18 
will be grouped according to empirically based syndrome scales in Table 3. The Achenbach 
CBCL has a 6 month recall. If a subject leaves the study early, and has been in the study for less 
than 6 months, this subject’s data will not be included in the analysis and will be listed only. 
Table 2: 
CBCL/1½-5  
Syndrome scale 
Questions 
Aggressive behavior 
8, 15, 16, 18, 20, 27, 29, 35, 40, 42, 44, 53, 58, 66, 
69, 81, 85, 88, 96 
Anxious/depressed 
10, 33, 37, 43, 47, 68, 87, 90 
Attention problems 
5, 6, 56, 59, 95 
Emotionally reactive 
21, 46, 51, 79, 82, 83, 92, 97, 99 
REDACTED COPY 
eckli
COP
eckli
 inten
ED C
 inten
on th
CTE
on th
½
DA
½-
A
-5 is
DAC
5 is
ars to <
RED
ars to <
5 o
R
5 o
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
S). This
s or
S). This
at may o
ions
at may o
e/Scree
ensio
e/Scree
” versio
exte
” versio
“Alread
ny ex
“Alread
ct is 6 y
d any
ct is 6 y
e C
and
e C-
nd
-SSR
nd 
SSR
n.
o
n.
ed. No 
icatio
ed. No 
st
n
st
nded to 
zatio
nded to 
he subje
horiz
he subje
s intend
utho
s intend
<17 ye
g au
<17 ye
or CBC
ting
or CBC
f the su
rket
f the su
y the sa
mar
y the sa
Ache
any 
Ache
groupe
port
groupe
ding to
supp
ding to
nth reca
to s
nth reca
this sub
sed t
this sub
CB
e u
CB
rome sc
nno
rome sc
ot
ggressi
t ca
ggressi
an
m
A
m
A
me
um


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Table 2: 
CBCL/1½-5  
Syndrome scale 
Questions 
Sleep problems 
22, 38, 48, 64, 74, 84, 94 
Somatic complaints 
1, 7, 12, 19, 24, 39, 45, 52, 78, 86, 93 
Withdrawn 
2, 4, 23, 62, 67, 70, 71, 98 
Other problems 
3, 9, 11, 13, 14, 17, 25, 26, 28, 30, 31, 32, 34, 36, 
41, 49, 50, 54, 55, 57, 60, 61, 63, 65, 72, 73, 75, 76, 
77, 80, 89, 91, 100 
CBCL= Child Behavior Checklist 
 
Table 3:  
CBCL/6-18 
Syndrome scale 
Questions 
Aggressive behavior 
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 
94, 95, 97, 104 
Anxious/depressed 
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112 
Attention problems 
1, 4, 8, 10, 13, 17, 41, 61, 78, 80 
Rule-breaking behavior 
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 
101, 105, 106 
Social problems 
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79 
Somatic complaints 
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g 
Thought problems 
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 
100 
Withdrawn/depressed 
5, 42, 65, 69, 75, 102, 103, 111 
CBCL= Child Behavior Checklist  
The Syndrome scale scores are calculated as the sum of the associated individual items scores. 
Each individual item score has the response options of:  
0=not true (as far as known) 
1=somewhat or sometimes true 
2=very true or often true. 
Missing data will not be replaced. Standardized T-scores are determined for each subject’s raw 
syndrome and overall scores based on the subject’s age and gender. Tables mapping each raw 
score to the appropriate T-score are provided in the CBCL Professional Manual and will be 
reproduced programmatically.  
10.4.8.2 
Analysis of Achenbach variables 
Calculated T-score values and change from Baseline for each CBCL/1½-5 syndrome (aggressive 
behavior, anxious/depressed, attention problems, emotionally reactive, other problems, sleep 
REDACTED COPY
4, 8, 1
OPY 
4, 8, 1
Y
2, 26
D CO
2, 26
10
D 
10
OP
ED
TE
DA
R
upport any marketing authorization application and any extensions or variations thereof.
ati
36,
va
36,
, 75, 76
or v
, 75, 76
iat
at
ns
a
ny
23, 37
and
23, 37
d 
, 32, 33
licat
, 32, 33
tio
0, 13, 1
app
0, 13, 1
pli
6, 28, 39
tion
6, 28, 39
01, 105
izati
01, 105
n a
11, 1
hor
11, 1
riz
uth
uth
uth
uth
ut
ing
ma
any
ores are
ppo
ores are
This document cannot be used to s
score h
sup
score h
s far as
ed to
s far as
what or 
use
what or 
ry true
ot be
ry true
sing da
ann
sing da
yndrom
nt ca
yndrom
score
ment
score
rep
m
rep


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
problems, somatic complaints, and withdrawn) will be summarized for each visit, and Last Visit, 
by treatment group. 
Calculated T-score values and change from Baseline for each CBCL/6-18 syndrome (aggressive 
behavior, anxious/depressed, attention problems, rule-breaking behavior, social problems, 
somatic complaints, thought problems, and withdrawn/depressed) will be summarized for each 
visit, and Last Visit, by treatment group. 
Subject data listings of the data for the Achenbach CBCL will be provided. The means of the 
calculated T-score will be plotted by visit. 
10.4.9 
BRIEF-P and BRIEF assessment 
The BRIEF-P and BRIEF are validated tools that will be used for the evaluation of subjects ≥4 to 
<5 years of age, and ≥5 years of age, respectively. The BRIEF-P and BRIEF will be used only in 
countries where a translated scale is available. For each subject, the same version (BRIEF-P or 
BRIEF) that is used at Visit 2 (Baseline) should be used at all following visits, even if the subject 
passes the applicable age range during the study. The BRIEF-P and BRIEF have a 6 month 
recall. If a subject leaves the study early, and has been in the study for less than 6 months, this 
subject’s data will not be included in the analysis and will be listed only. 
10.4.9.1 
BRIEF-P scores 
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), 
Sometimes (scored as 2 points), and Often (scored as 3 points).  
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges 
from 63 to 189, with higher scores reflecting poorer functioning. 
The 3 subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 4 . 
Table 4: 
BRIEF-P questionnaire scoring 
 
Scale/Index 
Questions 
Inhibit 
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 
60, 62 
Shift 
5,10, 15, 20, 25, 30, 35, 40, 45, 50 
Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
Inhibitory self-control 
All from {Inhibit and Emotional Control} 
Flexibility 
All from {Shift and Emotional Control} 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 
59, 61, 63 
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
Emergent metacognition 
All from {Working Memory and Plan/Organize} 
REDACTED COPY 
h can b
OPY
h can b
d as 3
CO
d as 3
Execu
TED
Execu
ng po
ACT
ng po
l comp
REDA
l comp
marketing authorization application and any extensions or variations thereof.
subject
nsion
subject
l be use
tens
l be use
sion (B
ext
sion (B
sits, ev
any 
sits, ev
EF hav
d a
EF hav
or less t
and
or less t
d only.
tion 
d only.
be answ
app
be answ
3 points
tion 
3 points
utive C
rizat
utive C
oorer fu
thor
oorer fu
mponent
g au
mponent
onnair
mark
onnair
t be used to support any m
rt
pp
d 
l Contr
be 
l Contr
u
annot 
bitory s
nno
bitory s
nt can ot
Flexibil
t ca
Flexibil
an
ment
Wo
men
Wo
This docum nt
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Table 4: 
BRIEF-P questionnaire scoring 
 
Scale/Index 
Questions 
GEC Score 
1-63 
GEC=Global Executive Composite 
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, 
flexibility, emergent metacognition, and component scores based on the subject’s age and 
gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P 
Professional Manual and will be reproduced programmatically. 
Two validity scales will also be derived: Negativity to assess the extent to which the respondent 
answers selected BRIEF-P items in an unusually negative manner and Inconsistency to assess the 
extent to which the respondent answers similar BRIEF-P items in an inconsistent manner. The 
Negativity scale is the number of items in 30, 44, 46, 47, 53, 55, 56, 57, 59 and 63 with a score 
of 3, and so has a range of 0 to10. A score of 2 or less is considered acceptable, 3 as elevated 
and 4 or more highly elevated. 
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale 
is the sum of the absolute values of the difference in scores for the items in each item pair, and so 
ranges from 0 to 20. The item pairs are questions 1 and 11, 3 and 33, 5 and 45, 10 and 20, 
11 and 26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is 
acceptable and 8 or more inconsistent.  
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and 
GEC for the BRIEF-P questionnaire will be summarized at each visit, and Last Visit, by 
treatment group.  
All BRIEF-P assessment data will be listed. The means of the BRIEF-P assessment data will be 
plotted by visit. 
10.4.9.2 
BRIEF scores 
The BRIEF form comprises of 86 questions which can be answered as Never (scored as 1 point), 
Sometimes (scored as 2 points), and Often (scored as 3 points).  
The first 72 items are included in the GEC score which ranges from 72 to 216, with higher scores 
reflecting poorer functioning. 
The 2 subscale scores and 8 individual component scores that make up these subscale scores are 
outlined in Table 5 . 
Table 5: 
BRIEF questionnaire scoring 
Scale/Index 
Questions 
Inhibit 
38, 41, 43, 44, 49, 54, 55, 56, 59, 65 
Shift 
5, 6, 8, 12, 13, 23, 30, 39 
Emotional Control 
1, 7, 20, 25, 26, 45, 50, 62, 64, 70 
REDACTED COPY
relat
PY 
relat
n score
OPY
n score
 1 and
D CO
 1 and
3 and 
TED 
3 and 
from B
EDA
from B
will b
RE
will b
ment cannot be used to support any marketing authorization application and any extensions or variations thereof.
ioio
d d 
BRIEF
ons 
BRIEF
ch the r
exte
ch the r
nsistenc
ny ex
nsistenc
nsisten
any
nsisten
7, 59 a
and 
7, 59 a
d accep
on a
d accep
d quest
pplic
d quest
es for t
n app
es for t
d 11, 3
tion 
d 11, 3
52, an
izati
52, an
Baselin
aut
Baselin
be sum
ting a
be sum
be list
mar
be list
res
ort a
res
prises o
upp
prises o
as 2 po
to su
as 2 po
ms are i
sed t
ms are i
orer fun
e use
orer fun
bscale 
ot be
bscale 
ed in
nno
ed in T
Table
nt c
Table
This docume
Sc
m
Sc
me
um


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Table 5: 
BRIEF questionnaire scoring 
Scale/Index 
Questions 
BRI 
All from {Inhibit, Shift, and Emotional Control} 
Initiate 
3, 10, 16, 47, 48, 61, 66, 71 
Working Memory 
2, 9, 17, 19, 24, 27, 32, 33, 37, 57 
Plan/Organize 
11, 15, 18, 22, 35, 36, 40, 46, 51, 53, 58 
Organization of Materials 
4, 29, 67, 68, 69, 72 
Monitor 
14, 21, 31, 34, 42, 52, 60, 63 
MI 
All from {Initiate, Working Memory, 
Plan/Organize, Organization of Materials, and 
Monitor} 
GEC Score 
1-72 
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite 
The BRI score is the total of 28 items and ranges from 28-84. The MI score is the total of 
44 items and ranges from 44 to 132. 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and gender. Tables that map each raw score to the appropriate 
T-score are provided in the BRIEF Professional Manual and will be reproduced 
programmatically. 
Two validity scales will also be derived: Negativity to assess the extent to which the respondent 
answers selected BRIEF items in an unusually negative manner, and Inconsistency to assess the 
extent to which the respondent answers similar BRIEF items in an inconsistent manner. The 
Negativity scale is the number of items in 8, 13, 23, 30, 62, 71, 80, 83, and 85 with a score of 3, 
and so has a range of 0 to 9. A score of 4 or less is considered acceptable, 5 and 6 elevated, and 
7 or more highly elevated. 
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale 
is the sum of the absolute values of the difference in scores for the items in each item pair, and so 
ranges from 0 to 20. The item pairs are questions 7 and 25, 11 and 22, 27 and 17, 33 and 32, 38 
and 59, 41 and 65, 42 and 63, 44 and 54, 43 and 60, and 55 and 44. A score of 6 or less is 
acceptable, 7 and 8 questionable, and 9 or more inconsistent. 
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and 
GEC for the BRIEF questionnaire will be summarized at each visit, and Last Visit, by treatment 
group.  
All BRIEF assessment data will be listed. The means of the BRIEF assessment data will be 
plotted by visit. 
10.4.10 
Vagus nerve stimulation 
Vagus nerve stimulation (VNS) status is recorded only for subjects with an implanted VNS 
device.  
REDACTED COPY 
ubject’
COPY
ubject’
ables th
D CO
ables th
nal Ma
TED
nal Ma
ed: Ne
REDA
ed: Ne
unus
RE
unus
marketing authorization application and any extensions or variations thereof.
ati
iat
at
a
v
s
emory, 
xten
emory, 
n of Ma
ext
n of Ma
si
an
an
utive Co
n an
utive Co
he MI 
atio
he MI 
’s raw G
n ap
’s raw G
that ma
ation
that ma
anual a
rizat
anual a
egativit
g aut
egativit
sually n
ting 
sually n
rs simil
rketi
rs simil
tems in
mark
tems in
ort any m
c
n
c
nt cannot be used to supp
ore of
ny m
ore of
ale, ther
ppor
ale, ther
ute val
supp
ute val
0. The i
to s
0. The i
65, 42 a
ed t
65, 42 a
and 8 
use
and 8 
d T
t b
d T-
b
-sc
be
sc
for the 
nnot
for the 
up.
ca
up.
This documen
All BR
ent
All BR
plo
me
plo


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
A listing of VNS status data will be provided only for those subjects with an implanted VNS 
device. No summaries of VNS data are planned. 
10.4.11 
Ketogenic diet 
A listing of ketogenic diet findings will be provided. 
 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
11 
REFERENCES 
Allison, PD. Survival Analysis Using SAS®: A Practical Guide. 2nd ed. Cary: SAS Institute; 
2010 
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive 
lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-
controlled study. Epilepsy & Behavior. 2010; 19: 352-8. 
Collett D. Modelling survival data in medical research. 3rd ed. London: CRC Press; 2015 
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 
1972;34(2):187-220.  
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of 
lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. 
Epilepsia. 2007;48(S6):77-78.  
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the 
analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301. 
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered 
analysis of variance. Biometrika. 1976;63:655-60. 
SAS®/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 2015 
 
REDACTED COPY 
nc; 20
OPY
nc; 201
Y
1
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
analysis
ensi
analysis
onic se
xte
onic se
etric m
nd a
etric m
01.
a
01.
th spec
ation
th spec
15
a
15


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12 
APPENDICES 
12.1 
Appendix 1: QOLIE-31-P total and subscale score calculations 
The following outlines the calculation of the subscale scores for the QOLIE‑31‑P. The rescaled 
responses are provided for each item. The subscale scores are calculated by summing the 
rescaled responses for that subscale and dividing by the number of items with a non-missing 
response. Note that the divisors shown assume that all items for each subscale have a response; 
the divisor will differ if there are missing responses. A subscale score will be calculated only if at 
least 50% of the items within the subscale are present. 
 
 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
if at 
ariat
if at 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Response Final Score 
                                                                         Response                                                              Final Score 
Scale/Item Numbers     1             2             3             4             5            6           Subtotal       0-100 point scale  
Seizure Worry 
      30.                               0            20           40           60           80        100           _____ 
      31.                               0          33.3       66.7        100           ––          ––            _____ 
      32.                               0            50          100                        ––          ––            _____ 
      33.                               0          33.3       66.7        100           ––          ––            _____ 
      34.                             100         75           50           25            0           ––            _____ 
  
                                                                                                              TOTAL :     _____        ÷ 5 = _____ 
Overall Quality of Life 
      1.                                Multiply each response by 10                                          _____ 
      36.                             100         75           50           25            0          ––             _____ 
  
                                                                                                              TOTAL :     _____        ÷ 2 = _____ 
Emotional Well-Being 
      7.                                 0            20           40           60           80        100           _____ 
      8.                                 0            20           40           60           80        100           _____ 
      9.                               100         80           60           40           20           0             _____ 
      10.                               0            20           40           60           80        100           _____ 
      11.                             100         80           60           40           20           0             _____ 
  
                                                                                                              TOTAL :     _____        ÷ 5 = _____ 
REDACTED COPY 
OP
se by 1
DAC
se by 1
50
RE
50
sed to support any marketing authorization application and any extensions or variations thereof.
__
d
__
___
on
___
TOTA
app
TOTA
0
u
0
uth
ing
25
g 
25
ny
o
0
su
0
s
This document cannot be use
se
t b
10.
an
10.
a
e


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Energy/Fatigue 
      2.                               100         80           60           40           20           0             _____ 
      3.                               100         80           60           40           20           0             _____ 
      4.                                 0            20           40           60           80        100           _____ 
      5.                                 0            20           40           60           80        100           _____ 
  
                                                                                                              TOTAL :     _____        ÷ 4 =  _____  
Cognitive Functioning 
      19.                               0            20           40           60           80        100           _____ 
      20.                               0          33.3       66.7        100            ––         ––            _____ 
      21.                               0            20           40           60           80        100           _____ 
      22.                               0            20           40           60           80        100           _____ 
      23.                               0            20           40           60           80        100           _____ 
      24.                             100         75           50           25            0            ––           _____ 
  
                                                                                                              TOTAL :     _____        ÷ 6 =  _____ 
Medication Effects 
      28.                               0          33.3       66.7        100           ––           ––          _____ 
      26.                             100         75           50           25            0          ––            _____ 
      27.                             100         75           50           25            0          ––            _____ 
  
                                                                                               TOTAL : _____          ÷ 3 =        _____ 
 
 
 
REDACTED COPY 
80
PY
80
PY
D C
CT
60
CTE
60
50
RE
50
RE
y marketing authorization application and any extensions or variations thereof.
4 =
te
4 = __
en
__
_____
an
_____
ati
100
ppl
100
p
80
tio
80
tio
ho
8
ed to support any 
g
25
g a
25
y
0
su
0
s
This document cannot be used
ed
be
en


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Daily Activities/Social Functioning 
      13.                               0            20           40           60           80        100           _____ 
      14.                               0            25           50           75          100        ––            _____ 
      15.                               0            25           50           75          100        ––            _____ 
      16.                             100          75           50           25            0          ––            _____ 
      17.                             100          75           50           25            0          ––            _____ 
  
                                                                                                              TOTAL :     _____        ÷ 5 = _____ 
Total score is calculated as a weighted sum of the subscale scores based on the weighting shown 
below. Total score will be missing if at least 1 subscale score is missing. Total score will range 
from 0 to 100 with a higher score reflecting better functioning. 
  
QOLIE-31-P Scale 
  
Final Scale 
Score 
  
  
Weight 
  
  
Subtotal 
  
  
  
  
  
  
  
Seizure worry 
(a) 
____ 
 
0.08 
= 
____ 
Overall quality of life 
(b) 
____ 
 
0.14 
= 
____ 
Emotional well-being 
(c) 
____ 
 
0.15 
= 
____ 
Energy/fatigue 
(d) 
____ 
 
0.12 
= 
____ 
Cognitive functioning 
(e) 
____ 
 
0.27 
= 
____ 
Medication effects 
(f) 
____ 
 
0.03 
= 
____ 
Daily activities/Social functioning 
(g) 
____ 
 
0.21 
= 
____ 
  
  
  
  
  
  
  
TOTAL SCORE : Sum subtotals (a) through (g) 
  
  
____ 
 
 
 
REDACTED COPY 
ale
Y
ale
ore
OP
ore
CO
)
A
)
(c)
EDA
(c)
(d
RED
(d
t any marketing authorization application and any extensions or variations thereof.
ny
÷ 5 
y e
÷ 5 
ed on th
and 
ed on th
ssing. T
on a
ssing. T
ica
ca
n
___
iz
___
___
tho
___
d)
n
d)
(e)
ketin
(e)
(f)
k
(f)
ing
y m
ing
This document cannot be used to suppo
subtot
ort a
subtot


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.2 
Appendix 2: Adverse Events 
12.2.1 
Other Significant AEs 
Table 6:  
Other Significant AEs 
MedDRA Preferred Term 
CARDIAC AND ECG RELATED TERMS 
Atrioventricular block third degree               
Atrioventricular block second degree 
Bradyarrhythmia* 
Bradycardia* 
Cardiac pacemaker insertion 
Atrial fibrillation 
Atrial flutter 
Sinus bradycardia* 
Ventricular tachycardia 
Ventricular fibrillation 
Heart Rate decreased* 
Sick sinus syndrome 
Atrial conduction time prolongation 
Atrioventricular dissociation 
Conduction disorder 
Cardiac fibrillation 
Cardiac flutter 
Sinus arrest 
Torsade de pointes 
Ventricular asystole 
REDACTED COPY 
Y
C
ycardi
DAC
ycardi
CT
bril
R
bril
ED
support any marketing authorization application and any extensions or variations thereof.
v
s
ns
y e
nd
tio
p
io
ia
au
ia
or
llation
ting
llation
a
decrea
mar
decrea
ke
sinus s
t any
sinus s
y
Atrial 
uppo
Atrial 
ort
ed to su
A
This document cannot be used
su
ed
be
an
nt
n


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
MedDRA Preferred Term 
Ventricular flutter 
Ventricular tachyarrhythmia 
Implantable defibrillator insertion 
SUICIDALITY RELATED TERMS 
Completed suicide 
Depression suicidal 
Suicidal behavior 
Suicidal ideation 
Suicide attempt 
Intentional self-injury 
Self injurious behavior 
Self-injurious ideation 
Intentional overdose 
Multiple drug overdose intentional 
Poisoning deliberate 
ADDITIONAL TERMS 
Loss of consciousness 
Syncope 
Appetite disorder 
Decreased appetite 
Diet refusal 
Hypophagia 
Food allergy 
REDACTED COPY 
CO
ation
ACT
ation
TE
verdo
RE
verdo
DA
eting authorization application and any extensions or variations thereof.
v
or
sio
ex
d a
n
lic
n
iz
se
ng
se
au
marketi
ug over
arke
ug over
e used to support any m
eti
ning del
any 
ning del
m
RMS
por
RMS
t a
Lo
s
Lo
up
d
This document cannot be 
e
no
nt
nt
nt
nt 
nt


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
MedDRA Preferred Term 
Abnormal behavior 
  *All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia (marked 
reduction in heart rate) with heart rate <45 bpm will be listed as ‘Other Significant AEs’. 
 
12.2.2 
List of AEs for Potentially Drug Induced Liver Injury (PDILI) 
Table 7:  
AEs for PDILI 
MedDRA Preferred Term for PDILI 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
Drug-induced liver injury 
Hepatitis cholestatic 
Hyperbilirubinaemia 
Icterus index increased 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Mixed liver injury 
Ocular icterus 
Acute hepatic failure 
Asterixis 
Cholestatic liver injury 
Coma hepatic 
Cryptogenic cirrhosis 
REDACTED COPY
er inj
PY 
er inj
choles
D CO
choles
OP
erbilir
ACTE
erbilir
ED
cterus
RED
cterus
AC
R
arketing authorization application and any extensions or variations thereof.
ion
xte
an
a
ury
p
ury
ca
static
tion
static
ap
rubinae
horiz
rubinae
za
s index
g au
s index
th
ing
This document cannot be used to support any ma
an
pp
to
us
ot
ca
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Drug-induced liver injury 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic failure 
Hepatic infiltration eosinophilic 
Hepatic necrosis 
Hepatic steatosis 
Hepatitis fulminant 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatotoxicity 
Liver disorder 
Liver injury 
Mixed liver injury 
Non-alcoholic steatohepatitis 
Subacute hepatic failure 
Allergic hepatitis 
Chronic hepatitis 
Hepatitis 
Hepatitis acute 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
REDACTED COPY
injur
OPY 
injur
otoxic
D C
otoxic
O
Liver d
ACT
Liver d
ED
DA
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
iat
iaiaia
or
sio
ex
a
me
ati
me
n
y
a
y
lic
city
atio
city
n a
disorde
thor
disorde
iza
Liver 
ng a
Liver 
ut
Mix
rke
Mix
tin
Non
ny m
Non
ma
a
pp
d to
u
no
t c
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Hepatitis fulminant 
Hepatitis toxic 
Non-alcoholic steatohepatitis 
Blood bilirubin abnormal 
Blood bilirubin increased 
Hyperbilirubinaemia 
 
 
 
 
 
REDACTED COPY 
or variations thereof.
iat
iaia
sions or
ia
or
This document cannot be used to support any marketing authorization application and any extensio
sio


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.3 
Appendix 3: Markedly abnormal values 
12.3.1 
Hematology 
Table 8:  
Hematology - Markedly Abnormal Values 
Parameter 
Age 
Range 
UNIT 
(conventional) 
Abnormality 
Criteria 
(conventional unit) 
Unit 
(standard) 
Abnormality 
Criteria (standard 
unit) 
Hematocrit 
2y - <17y 
% 
 
≤29 
>47 
% 
≤29 
>47 
≥17y 
≤85% of LLN 
≥115% of ULN 
≤85% of LLN 
≥115% of ULN 
Hemoglobin 
2y - <17y 
g/dL 
 
≤9.5 
>16.0 
g/L 
≤95 
>160 
≥17y 
≤85% of LLN 
≥115% of ULN 
≤85% of LLN 
≥115% of ULN 
WBC/ 
Leukocytes 
All 
109/L 
≤3.0 
≥16.0 
G/L 
≤3.0 
≥16.0 
Lymphocytes 
Absolute 
2y - <6y 
109/L 
<0.7 
>6.9 
G/L 
<0.7 
>6.9 
≥6y 
<0.6 
>5.0 
<0.6 
>5.0 
Basophils 
>1m 
% 
≥5.0 
% 
≥5.0 
Basophils 
Absolute 
>1m 
109/L 
≥0.4 
G/L 
≥0.4 
Eosinophils 
>1m 
% 
≥10 
% 
≥10 
Eosinophils 
Absolute 
>1m 
109/L 
≥1.0 
G/L 
≥1.0 
Monocytes 
>1m 
% 
≥20.0 
% 
≥20.0 
Monocytes 
Absolute 
>1m 
109/L 
≥2.0 
G/L 
≥2.0 
Neutrophils 
Absolute 
>1m 
109/L 
<1.5 
 
G/L 
<1.5 
Platelets 
>1m 
109/L 
≤100 
≥600 
G/L 
≤100 
≥600 
RBC/ 
Erythrocytes 
≥2y 
1012/L 
<3.5 
T/L 
<3.5 
Abbreviations: ANC = absolute neutrophil count; LLN = lower limit of normal; m  = month; ULN = 
upper limit of normal; y = year.  
A month is defined as 30 days; a year is defined as 365.25 days. 
 
 
 
REDACTED COPY 
.0
D C
.0
OP
≥5.0
TED
≥5.0
ED
CT
AC
REDAC
R
thorization application and any extensions or variations thereof.
tio
ar
%
i
% of LL
ions
of LL
115%
nsi
115% o
ns
≤95
xte
≤95
>16
ex
>16
en
y e
y
G/L
n
G/L
a
cat
G
a
G
ca
ca
ca
ca
ap
at
g autho
≥0.4
uth
≥0.4
o support any marketing a tho
g
ng
rk
%
a
%
ny
po
1
o
1
po
po
po
ot be used to 
po
>1m
d to
>1m
o
se
us
nt cannot 
s
throcyte
cann
throcyte
ot
t
This documen
Abbre
ent 
Abbre
upp
me
upp


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.3.2 
Chemistry 
Table 9:  
Chemistry: Markedly Abnormal Values 
PARAMETE
R 
AGE 
RANG
E 
UNIT 
(conventional
) 
ABNORMALIT
Y CRITERIA 
(conventional) 
UNIT 
(standard
) 
ABNORMALIT
Y CRITERIA 
(standard) 
AST (SGOT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
ALT (SGPT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
Alkaline 
Phosphatase 
4y - <10y U/L 
≥834 
U/L 
≥834 
10y - 
<17y 
≥1761 
≥1761 
≥17y 
≥3.0 x ULN 
≥3.0 x ULN 
GGT 
1y - <13y U/L 
≥66 
U/L 
≥66 
13y - 
<17y 
≥126 
≥126 
≥17y 
≥3.0 x ULN 
≥3.0 x ULN 
Total Bilirubin 
>1m 
mg/dL 
≥2.0 
umol/L 
≥34.208 
Total Protein 
1y - <17y g/dL 
<4.3 
>12.0 
g/L 
<43 
>120 
≥17y 
<4.3 
>13.0 
<43 
>130 
Albumin 
≥1y - 
<17y 
g/dL 
<2.4 
>8.4 
g/L 
<24 
>84 
≥17y 
<2.6 
<26 
BUN 
1y - <17y mg/dL 
≥36 
mmol/L 
≥12.852 
≥17y 
≥40 
≥14.28 
Urea 
≥1y 
mg/dL 
>60 
mmol/L 
>10.02 
Creatinine 
1y - <10y mg/dL 
>1.2 
umol/L 
>106.8 
10y - 
<16y 
>1.8 
>159.12 
≥16y 
≥2.0 
≥176.8 
Creatinine 
Clearance* 
All 
mL/min 
<50 
mL/s 
<0.835 
REDACTED COPY 
0
C
0 x U
COP
x U
OP
≥2.0
TED
≥2.0
ED
CT
DA
marketing authorization application and any extensions or variations thereof.
N
v
N
tio
N
o
N
ULN
ns o
ULN
0.0
sio
0.0 x U
ion
x U
va
≥
te
≥834
tens
834
si
e
≥
e
≥
ex
y e
U/L
on a
U/L
a
at
at
at
ca
LN
on
LN
ap
at
<4.3
aut
<4.3
>
a
>
uth
g
port any ma
dL
y
dL
sed to suppo
ma
o
po
<17y
sup
<17y
up
≥
ed t
≥17
t
17
to
se
ment cannot be use
≥
se
se
se
ne
t
ne
be
This docum


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
PARAMETE
R 
AGE 
RANG
E 
UNIT 
(conventional
) 
ABNORMALIT
Y CRITERIA 
(conventional) 
UNIT 
(standard
) 
ABNORMALIT
Y CRITERIA 
(standard) 
Bicarbonate 
>1m - 
<17y 
mEq/L 
<15 
>38 
mmol/L 
<15 
>38 
≥17y 
<18 
>38 
<18 
>38 
Calcium 
1y - <17y mg/dL 
<7.4 
>11.7 
mmol/L 
<1.85 
>2.925 
≥17y 
≤7.6 
≥11.0 
≤1.9 
≥2.75 
Chloride 
>1m 
mEq/L 
≤90 
≥112 
mmol/L 
≤90 
≥112 
Phosphorous 
1y - <17y mg/dL 
<1.8 
>7.4 
mmol/L 
<0.5814 
>2.3902 
≥17y 
≤2.0 
≥6.0 
≤0.646 
≥1.938 
Potassium 
≥1y 
mEq/L 
≤3.0 
≥6.0 
mmol/L 
≤3.0 
≥6.0 
Sodium 
>1m 
mEq/L 
<127 
>151 
mmol/L 
<127 
>151 
Glucose 
>1m - 
<17y 
mg/dL 
<50 
≥180 
mmol/L 
<2.775 
≥9.99 
≥17y 
<50 
≥200 
<2.775 
≥11.1 
Total 
Cholesterol 
≥1y 
mg/dL 
>250 
mmol/L 
>6.475 
LDL 
(calculated) 
1y - <17y mg/dL 
>140 
mmol/L 
>3.626 
≥17y 
>200 
>5.18 
HDL 
>2y 
mg/dL 
<20 
mmol/L 
<0.518 
Triglycerides 
≥1y 
mg/dL 
>300 
mmol/L 
>3.39 
Uric Acid 
1y - <13y mg/dL 
>6.5 
umol/L 
>386.62 
13y - 
<17y 
>8.6 
>511.528 
≥17y 
>9.5 
>565.06 
Thyroxine (T4) 
≥1y 
ug/dL 
≤3.8 
≥13.5 
nmol/L 
≤48.9098 
≥173.7585 
Globulin 
≥1y 
g/dL 
<1.2 
>5.3 
g/L 
<12 
>53 
REDACTED COPY 
51
C
51
PY
<50
ED
<50
≥
CTE
≥1
E
1
D
CT
C
R
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
tio
tio
tio
tio
75
io
75
or
90
en
90
≥112
xte
≥112
sio
e
<0
e
<0
ex
y e
mm
atio
mm
ion
cat
pp
80
ho
80
ati
<50
uth
<50
≥
a
≥2
tho
g
ng
dL
m
dL
ar
mg
ort
mg
rt
po
1y
o s
1y
upp
1y 
d t
1y -
t
- <
o
<
to
e
13
e
13
ed
se
Thyroxi
t ca
Thyroxi
an
me
G
m
G
me
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
dL = deciliter; GGT: gamma-glutamyltransferase; L = liter; LLN = lower limit of normal; m = month; mg = 
milligram; mmol = millimoles; μg = microgram; U = unit; ULN = upper limit of normal; y = year.  
*Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine   Cockroft equation (subjects >12); 
Male: Cr Cl ml/min =  [(140-age) x body weight (kg)] / (72 x serum creatinine); 
Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85. 
 
12.3.3 
Vital signs 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below: 
Table 10:  
Vital Signs - Abnormality Criteria 
Parameter 
Age Range 
Abnormality Criteria 
Pulse Rate 
(beats/minute) 
 
 
3y - <12y 
<60 
>130 
12y - <17y 
<50 
>120 
≥17y 
<50 and a decrease from Baseline of ≥15 
>120 and an increase from Baseline of ≥15 
<60a 
>100a 
Systolic Blood Pressure 
(mmHg) 
3y - <12y 
<80 
>140 
12y - <17y 
<90 
>160 
≥17y 
≤ 90 and a decrease from Baseline of ≥20 
≥ 180 and an increase from Baseline of ≥20 
<90a 
>140a 
>160a 
Diastolic Blood 
Pressure (mmHg) 
3y - <12y 
<50 
>80 
12y - <17y 
<50 
>105 
≥17y 
<50 and a decrease from Baseline of ≥15 
>105 and an increase from Baseline of ≥ 15 
<50a 
>90a 
>100a 
Body Weight 
1m - <17y 
<3% or 97% of the normal body weight growth curve 
ranges based on gender and the age of subject on date of 
weight assessmenta 
≥17y 
≥ 10% change from Baseline (an increase or a decrease)b 
≥7% change from Baseline (an increase or a decrease)a 
Abbreviations: y = year.  
REDACTED COPY
decre
PY 
decre
d an in
OPY
d an in
00
ED
00a
D
a
<80
CTE
<80
>14
AC
>14
ED
DA
DA
DA
DA
DA
DA
uthorization application and any extensions or variations thereof.
e given
ons o
e given
Criteri
any
Criteri
e
a
n
se from
pplic
se from
ncrease 
app
ncrease 
lic
40
th
40
iza
ting aut
<90
au
<90
>16
ng 
>16
ort any marketing
ut
tin
≤
tin
tin
tin
tin
t cannot be used to suppor
3y 
ppo
3y -
po
- <
o
<
or
su
su
su
su
ment c
Body 
ent c
Body 
This docum
t c
m


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
A month is defined as 30 days; a year is defined as 365.25 days.  
a Type C Meeting Written Response Dated 4 Mar 2019 (Response to the Type C Meeting Request submitted on Dec 
12, 2018 to IND 057939 Sequence No. 1268 cross-reference IND 068407 and IND 073809) 
bsource: http://www.cdc.gov/growthcharts/ 
 
 
 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.3.4 
ECGs 
Abnormality criteria to be applied in the assessment of ECG parameter values are given below: 
Table 11:  
ECGs - Abnormality Criteria 
Parameter 
Age 
Abnormality Criteria 
QT interval (ms) 
1m-<12y 
>500 
>12y 
<450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 
increase from Baseline 
QTc(F) (ms) 
 
 
3y-<12y 
 
 
>440, or >15% increase from Baseline 
>12y- <17y 
>440, or >15% increase from Baseline 
≥17y 
<450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 
increase from Baseline 
>450, >480a 
QTc(B) (ms) 
 
 
3y-<12y 
 
 
>450, or >15% increase from Baseline 
>12y- <17y 
>450, or >15% increase from Baseline 
≥17y 
<450, 450-<480, 480-<500, >500 or <30, 30-<60, ≥60 
increase from Baseline 
>450, >480a 
PR interval (ms) 
 
 
3y-<12y 
 
 
>180, or >25% increase from Baseline 
>12y - <17y 
>200, or >25% increase from Baseline 
≥17y 
Treatment-emergent value >200, >220, >250 
QRS interval (ms) 
3y-<12y 
 
 
>100, or >25% increase from Baseline 
>12y - <17y 
>110, or >25% increase from Baseline 
≥17y 
Treatment-emergent value >100, >120, >140 
Heart rate (bpm) 
3y-<12y 
<60, >130 
>12y 
<50, >120 
a Type C Meeting Written Response dated 4 Mar 2019 (Response to the Type C Meeting Request submitted on Dec 
12, 2018 to IND 057939 Sequence No. 1268 cross-reference IND 068407 and IND 073809) 
Abbreviations: bpm = beats per minute; m = month; ms = milliseconds; QTc = corrected QT interval; y = years.  
A month is defined as 30 days; a year is defined as 365.25 days.  
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit during the Treatment Period 
(including unscheduled visits) and not meeting the same criteria during Baseline. 
 
 
REDACTED COPY
rom B
PY 
rom B
>480
COP
>480a
P
a
>18
ACT
>18
CO
AC
>
AC
>
AC
AC
AC
AC
ED
R
marketing authorization application and any extensions or variations thereof.
iat
ar
on
30, 30
tens
30, 30-<
s
<
ns
from B
on a
from B
ny
ase from
atio
ase from
on
80
plic
80-
lic
-<50
ica
<50
plic
aseline
ppl
aseline
at
0, or
hori
0, or >
r
>2
on
>200, o
auth
>200, o
tho
Trea
g a
Trea
au
n
be used to support any marketing
ng
in
<17y
ny m
<17y
m
y
t
y
ny
3y
up
3y
t a
su
d
Written
sed
Written
D 05793
e us
D 05793
This document cannot
ions: bp
ot b
ions: bp
nth is d
ann
nth is d
Note: Tr
nt c
Note: Tr
(incl
me
(incl


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.4 
Appendix 4: NCI CTC 
Table 12:  
NCI CTC 
Medical Term 
Lab 
parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Blood/bone marrow 
Anemia 
Hemoglobin 
<LLN - 10.0 g/dL 
(C) 
<LLN - 6.2 mmol/L 
 <LLN -100 g/L (S) 
 <10.0 - 8.0 g/dL 
(C) 
<6.2 - 4.9mmol/L 
<100 - 80g/L (S) 
 <8.0 g/dL (C) 
<4.9 mmol/L 
<80 g/L (S) 
* 
Neutrophil count 
decreased 
Neutrophil 
count 
<LLN - 1500/mm3 
 <LLN - 1.5 x10e9 
/L (C) 
<LLN – 1.5G/L (S) 
 
<1500 - 1000/mm3 
<1.5 - 1.0 x10e9/L 
(C) 
<1.5 - 1.0G/L (S) 
 
<1000 - 500/mm3 
 <1.0 - 0.5 
x10e9/L (C) 
<1.0 - 0.5G/L (S) 
 
<500/mm3 
<0.5 x 10e9/L 
(C) 
<0.5G/L (S) 
White blood cell 
decreased 
 
White blood 
cell (WBC) 
<LLN - 3000/mm3 
<LLN - 3.0x10e9/L 
(C) 
<LLN - 3.0G/L (S) 
 
<3000 - 2000/mm3 
<3.0 - 2.0x10e9/L 
(C) 
<3.0 - 2.0G/L (S) 
 
<2000 -
1000/mm3 
<2.0 - 1.0x10e9/L 
(C) 
<2.0 - 1.0G/L (S) 
 
<1000/mm3 
<1.0 x 10e9/L 
(C) 
<1.0G/L (S) 
Platelet count 
decreased 
Platelet count 
<LLN - 75,000/mm3 
<LLN -75.0 x 
10e9/L(C) 
<LLN -75.0G/L (S) 
 
<75,000 - 
50,000/mm3 
<75.0 -50.0 x 
10e9/L(C) 
<75.0 -50.0G/L (S) 
 
<50,000 -
25,000/mm3 
<50.0 -25.0 x 
10e9/L(C) 
<50.0 -25.0G/L 
(S) 
 
<25,000/mm3 
<25.0 x 
10e9/L(C) 
<25.0G/L (S) 
Lymphocyte count 
decreased 
Lymphocyte 
count 
<LLN-800/mm3 
<LLN-0.8x10e9/L 
(C) 
<LLN-0.8G/L (S) 
<800 -500/mm3 
<0.8 – 0.5x10e9/L 
(C) 
<0.8 – 0.5G /L (S) 
<500 - 200/mm3 
<0.5 – 
0.2x10e9/L (C) 
<0.5 – 0.2G/L (S) 
<200mm3 
<0.2x10e9/L 
(C) 
<0.2G/L (S) 
Metabolic/chemistry 
GGT increased 
Gamma 
glutaryl 
transferase 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Hypercalcemia 
Calcium, 
corrected 
serum 
>ULN - 11.5 mg/dL 
(C) 
>ULN - 2.9mmol/L 
(S) 
>11.5 - 12.5 mg/dL 
(C) 
>2.9 - 3.1mmol/L 
(S) 
>12.5 - 13.5 
mg/dL (C) 
>3.1 - 3.4mmol/L 
(S) 
>13.5 mg/dL 
(C) 
>3.4 mmol/L 
(S) 
Hypocalcemia 
Calcium, 
corrected 
serum 
<LLN - 8.0 mg/dL 
(C) 
<LLN - 2.0mmol/L 
(S) 
<8.0 - 7.0 mg/dL 
(C) 
<2.0 - 1.75 mmol/L 
(S) 
<7.0 - 6.0 mg/dL 
(C) 
<1.75 - 
1.5mmol/L (S) 
<6.0 mg/dL 
(C) 
 <1.5 mmol/L 
(S) 
Hyperglycemia 
Glucose, 
fasting 
>ULN -160 mg/dL 
(C) 
>ULN - 8.9 mmol/L 
(S) 
>160 -250 mg/dL 
(C) 
>8.9 - 13.9 mmol/L 
(S) 
>250 - 500 
mg/dL (C) 
>13.9 - 
27.8mmol/L (S) 
>500 mg/dL 
(C) 
>27.8 mmol/L 
(S) 
Hypoglycemia 
Glucose 
<LLN - 55 mg/dL 
(C) 
<LLN - 3.0mmol/L 
(S) 
<55 - 40 mg/dL (C) 
 <3.0 - 2.2mmol/L 
(S) 
<40 - 30 mg/dL 
(C) 
 <2.2 - 
1.7mmol/L (S) 
<30 mg/dL (C) 
 <1.7 mmol/L 
(S) 
Hyperkalemia 
Potassium 
>ULN - 5.5 mmol/L 
(S) 
>5.5 - 6.0 mmol/L 
(S) 
>6.0 - 7.0 
mmol/L (S) 
>7.0 mmol/L 
(S) 
Hypokalemia 
Potassium 
<LLN - 3.0 mmol/L 
(S)  
* 
<3.0 - 2.5 
mmol/L (S) 
<2.5 mmol/L 
(S) 
Hypernatremia 
Sodium 
>ULN - 150 mmol/L 
(S) 
>150 - 155 mmol/L 
(S) 
>155 - 160 
mmol/L (S) 
>160 mmol/L 
(S) 
REDACTED COPY
e9/L(C
PY 
e9/L(C
<75.0 
OP
<75.0 
D
3
T
3
0e9/L 
ACT
0e9/L 
0.8G/L
REDA
0.8G/L
ED
RE
M
E
M
RE
g authorization application and any extensions or variations thereof.
at
mm3
or
mm3
5 x 10e9
s o
5 x 10e9
(C)
io
(C)
<0.5G
nsio
<0.5G
v
en
3
.0x10e9
any
.0x10e9
2.0 
an
2.0 -
n
- 1.0
d
1.0
te
50.0G/L
n ap
50.0G/L
<50
on
<50
2
n 
tio
(S)
a
(S)
<800 
riza
<800 5
<0.8
or
<0.8
(C
(C
za
ho
not be used to support any marketing a
Metabol
ting 
Metabol
g a
-
k
- 2.5 x U
ket
2.5 x U
eti
>ULN
ny m
>ULN
(C)
any
(C)
m
a
ium,
up
ium,
rrected
o su
rrected
serum
d to
serum
pp
e
G
e
G
e
This document canno
e
se
poglycem
ann
poglycem
no
me
me
H
me
me
me


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Medical Term 
Lab 
parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
Sodium 
<LLN - 130 mmol/L 
(S)  
Not defined 
<130 - 120 
mmol/L (S) 
<120 mmol/L 
(S) 
Hyper-
triglyceridemia 
Triglycerides 
150 - 300 mg/dL (C) 
1.71 - 3.42 mmol/L 
(S) 
 
>300 - 500 mg/dL 
(C) 
 >3.42 - 5.7 mmol/L 
(S) 
 
>500 - 1000 
mg/dL (C) 
 >5.7 - 11.4 
mmol/L (S) 
 
>1000 mg/dL 
(C) 
 >11.4 mmol/L 
(S) 
Hyperuricemia 
Uric acid  
 
>ULN - 10 mg/dL 
(C) 
>ULN - 0.5948 
mmol/La  
>ULN – 594.8 
umol/L (S) 
Not defined 
* 
 
>10 mg/dL (C) 
>0.5948 
mmol/La  
>594.8 umol/L 
(S)  
Hypoalbuminemia 
Albumin 
<LLN - 3 g/dL (C) 
<LLN - 30 g/L (S) 
  
 
<3 - 2 g/dL (C) 
<30 - 20 g/L (S) 
<2 g/dL (C) 
<20 g/L (S) 
 
 
* 
Hypo-
phosphatemia 
Phosphorus 
<LLN - 2.5 mg/dL 
(C) 
 <LLN - 0.8mmol/L 
(S) 
 
<2.5 - 2.0 mg/dL 
(C) 
<0.8 - 0.6mmol/L 
(S) 
 
<2.0 - 1.0 mg/dL 
(C) 
<0.6 - 0.3mmol/L 
(S) 
 
<1.0 mg/dL 
(C) 
<0.3 mmol/L 
(S) 
Alanine 
aminotransferase 
increased 
Alanine amino-
transferase 
(ALT) 
>ULN - 3.0 x ULN  
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Alkaline 
phosphatase 
increased 
Alkaline 
phosphatase 
>ULN - 2.5 x ULN  
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
increased 
Aspartate 
amino-
transferase 
(AST) 
>ULN - 3.0 x ULN  
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Blood bilirubin 
increased 
Bilirubin 
>ULN - 1.5 x ULN 
 >1.5 - 3.0 x ULN 
>3.0 - 10.0 x 
ULN 
>10.0 x ULN 
Cholesterol high 
Cholesterol, 
total 
>ULN - 300 mg/dL 
(C) 
>ULN - 7.75mmol/L 
(S) 
 
>300 - 400 mg/dL 
(C) 
>7.75-10.34 
mmol/L (S) 
 
>400 - 500 
mg/dL (C) 
>10.34-12.92 
mmol/L (S) 
 
>500 mg/dL 
(C) 
>12.92 mmol/L 
(S) 
Creatinine 
increased 
Creatinine 
>ULN - 1.5x ULN 
 
>1.5 - 3.0x ULN 
 
 >3.0 - 6.0 x ULN  >6.0 x ULN 
Abbreviations: LLN = lower limit of normal; ULN = upper limit of normal. 
The cutoffs are according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) 
(C)=Conventional units, (S)=Standard units 
 
 
REDACTED COPY 
>2.5 
COP
>2.5 
OP
D
ULN
CTE
ULN
TE
RE
N
R
N -
R
- 1
R
1
RE
horization application and any extensions or variations thereof.
t
C)
ri
C)
.8 umol/
or 
.8 umol/
)
t
at
*
nsi
*
sio
en
1.0 mg/
d any
1.0 mg/
)
<0.6 
an
<0.6 -
n
- 0
(S)
on a
(S)
ny
tio
N
ic
N
at
5.0 x UL
n a
5.0 x UL
ap
>3.0 
oriz
>3.0 
iza
support any marketing autho
5 x ULN
ting
5 x ULN
g
LN
a
LN -
ark
- 300
rk
300
C)
m
C)
>ULN
ny m
>ULN
(S)
any
(S)
ke
a
ne
p
ne
or
up
sed to s
wer lim
o su
wer lim
ding to t
d to 
ding to t
, 2009 (
sed 
, 2009 (
This document cannot be u
nal units
use
nal units


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
12.5 
Appendix 5: Registry Required Tables 
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or 
Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the 
CSR required Tables. 
Disposition and Discontinuation Reasons by Development 
Discontinuation due to AEs 
Demographics by Development 
Baseline Characteristics by Development 
ILAE Seizure Classification History by Development 
Classification of Epileptic Syndrome by Development 
AEDs and Benzodiazepines at Study Entry by Development 
Summary of Time to Second PGTCS by Development 
Proportion of Subjects with Seizure Freedom at Day 166 by Development 
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by 
Development 
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline 
by Development 
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline 
by Development 
Responder Status for PGCTS by Development 
Responder Status for Absence Seizure Frequency by Development 
Responder Status for Myoclonic Seizure Frequency by Development 
Seizure-free Status for PGTCS by Development 
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline 
by Development 
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective 
Baseline by Development 
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective 
Baseline by Development 
Responder Status and Seizure Worsening for Days with Absence Seizures by Development 
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective 
Baseline by Development 
Increase in Days with Myoclonic Seizures During the Treatment Period Compared to 
Prospective Baseline by Development 
REDACTED COPY 
d Perce
COP
d Perce
esults 
ACTE
esults 
velopm
RE
velopm
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
opment
on a
opment
m Com
icati
m Com
ent Cha
on ap
ent Cha
and Pe
horiz
and Pe
pment
ing a
pment
e Frequ
rket
e Frequ
Seizure
y ma
Seizure
CS by D
t any
CS by D
ures Ob
ppor
ures Ob
with Ab
d to 
with Ab
evelopm
used
evelopm
n Absen
be u
n Absen
e by D
not b
e by D
sponder
can
sponder
Days w
ent 
Days w
Bas
me
Bas


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Increase in Myoclonic Seizure Frequency During the Treatment Period Compared to Prospective 
Baseline by Development 
Responder Status and Seizure Worsening for Days with Myoclonic Seizures by Development 
Incidence of Absence Seizure Emergence or Worsening by Development 
Incidence of Myoclonic Seizure Emergence or Worsening by Development 
Seizure-free Status for All Generalized Seizure Types by Development 
Study Medication Duration by Development 
Cumulative Study Medication Duration by Development 
Study Medication Daily Dosing by Development 
Incidence of TEAEs by Development – Overview 
Incidence of TEAEs by Development 
Incidence of Serious TEAEs by Development 
Incidence of Non-serious TEAEs  
Incidence of TEAEs by Relationship and Development 
Incidence of TEAEs Leading to Discontinuation by Development 
Incidence of Serious TEAEs by Relationship  
Incidence of Non-serious TEAEs by Relationship  
Incidence of Fatal TEAEs by Relationship  
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects 
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship 
12-Lead ECG Summary by Development 
Treatment-Emergent Abnormal 12-Lead ECG Findings for Subjects by Development 
 
12.6 
Additional Subgroups to be programmed in ADSL 
The following subgroup variable will also be programmed: 
Subjects enrolled at Japanese study sites (Japanese, non-Japanese) 
Subjects enrolled at Asian study sites (Asian, non-Asian) – Asian sites are those in Taiwan, 
South Korea, China and Japan 
 
REDACTED COPY 
Devel
OPY
Devel
onship
CTE
onship
hip
EDA
hip
ove 
RE
ove 
support any marketing authorization application and any extensions or variations thereof.
lopmen
app
lopmen
p
h
p
Report
ting 
Report
bove Re
arke
bove Re
elopme
y m
elopme
mal 12
rt an
mal 12
nnot be used to
ditiona
to su
ditiona
subgrou
sed 
subgrou
rolled 
be u
rolled 
ts enrol
not b
ts enrol
This document ca
th Kore
ann
th Kore


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP)  
13.1 
Amendment 1 
13.1.1 
Rationale for the amendment 
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v1.0 which affected 
the definition of the titration and maintenance periods and the rules for pooling strata with low 
numbers of events in the SAP. The compliance derivation was also updated to allow for subjects 
that take more than 2 tablets as they titrate to a higher dose. 
13.1.2 
Modification and changes 
13.1.2.1 
Specific changes 
The information below was revised: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Has been changed to: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Section 3.2.1, the following text was changed from: 
 Treatment Period: 24-week period following the 4-week Prospective Baseline. The 
Treatment Period is composed of the Titration Period and the Maintenance Period. 
 Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration 
Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before 
Visit 6 (or the date of the Early Termination (ET) visit in the situation where a subject 
discontinues prior to the last visit in the Titration Period). 
 Maintenance Period: 18-week period following the 6-week Titration Period. The 
Maintenance Period starts on the day of Visit 6 and continues until 1 of the following 
occurs (whichever occurs first): 
◦ 
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures 
and completion of the ET Visit 
◦ 
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 
2 PGTC seizures. 
And revised as follows: 
 Treatment Period: 24-week period following the 4-week Prospective Baseline. The 
Treatment Period is composed of the Titration Period and the Maintenance Period. 
 Titration Period: 6-week period following the 4-week Prospective Baseline. The Titration 
Period starts on the date of the Randomization Visit (Visit 2) and ends on the day before 
REDACTED COPY 
from:
TED 
from:
llowin
DACT
llowin
he Tit
REDA
he Tit
d f
R
d f
d to support any marketing authorization application and any extensions or variations thereof.
jects 
vari
jects 
ng the 4
utho
ng the 4
tration 
aut
tration 
follow
eting
follow
e Rand
rke
e Rand
Early T
ma
Early T
e last v
any m
e last v
d: 18
ort a
d: 18-w
a
w
riod sta
uppo
riod sta
hever o
o sup
hever o
annot be used
pletion
ed to
pletion
d comp
use
d comp
Com
t be
Com
2 
ot 
2 
This document c
nd revis
t can
nd revis

me

T
n
T


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Visit 5 (or the date of the Early Termination (ET) visit in the situation where a subject 
discontinues prior to the last visit in the Titration Period). 
 Maintenance Period: 18-week period following the 6-week Titration Period. The 
Maintenance Period starts on the day of Visit 5 and  continues until 1 of the following 
occurs (whichever occurs first): 
◦ 
Completion of ≥6 weeks of the Treatment Period, occurrence of ≥2 PGTC seizures 
and completion of the ET Visit 
◦ 
Completion of 18 weeks (Visit 10) of the Maintenance Period without occurrence of 
2 PGTC seizures. 
Section 7, the following bullet point was changed from: 
 Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of 
tablets prescribed per day (2 tablets) x Number of days between x 100. 
And revised as follows: 
 Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of 
tablets prescribed per day x Number of days between x 100. 
Section 8.1.2, the following text was changed from: 
If no events (ie, no subjects who had a second PGTC seizure) occur in a stratum, then data will 
be pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
 If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days. 
 If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, then this group will be combined for analysis with the group of subjects 
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
And revised as follows: 
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, 
then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
REDACTED COPY 
TC seiz
COP
TC seiz
for an
D CO
for an
cts wh
CTE
cts wh
 then 
DAC
 then 
re ≥4 
REDA
re ≥4 
cts w
RE
cts w
pport any marketing authorization application and any extensions or variations thereof.
nce of 
or va
nce of 
ned) / (N
exte
ned) / (N
ablets r
n an
ablets r
izure) o
n ap
izure) o
nalysis 
ation
nalysis 
ho are ≥
horiz
ho are ≥
this gr
utho
this gr
to <12
g au
to <12
who ar
ting
who ar
has the 
rket
has the 
up of su
y ma
up of su
s, then 
any 
s, then 
o <18 y
ort a
o <18 y
nt cannot be used to sup
in the g
upp
in the g
days, th
to su
days, th
to <18 
ed to
to <18 
y, rules 
e use
y, rules 
es per 2
t be 
es per 2
evised 
nno
evised 
f 5 even
nt ca
f 5 even
This documen
then d
ment
then d



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
 If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
Section 8.2.2.1, the following text was changed from: 
If no events (ie, no subjects who had a second PGTC seizure) occur in a stratum, then data will 
be pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
 If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days. 
 If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, then this group will be combined for analysis with the group of subjects 
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
And revised as follows: 
If 5 events or less (ie, less than 6 subjects who had a second PGTC seizure) occur in a stratum, 
then data will be pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
 If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
 If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
REDACTED COPY 
m
Y
m
are ≥4
COPY
are ≥4
will be
D CO
will be
with ≤
TED 
with ≤
jects w
DACT
jects w
up wil
REDA
up wil
with
RE
with
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
C 
r
C 
, then d
xten
, then d
s of ag
d any
s of ag
bined fo
and 
bined fo
h ≤2 Ba
on a
h ≤2 Ba
ge with 
atio
ge with 
of even
plica
of even
4 to <1
n app
4 to <1
e comb
tion
e comb
≤2 Base
rizat
≤2 Base
who ar
utho
who ar
ll be co
g aut
ll be co
h ≤2 Ba
ting 
h ≤2 Ba
hose ag
arke
hose ag
s than 6
port
s than 6
ed by B
supp
ed by B
less occ
d to 
less occ
GTC se
sed 
GTC se
e group
e us
e group
8 days 
t be
8 days 
izures p
nnot
izures p
If 5 e
t ca
If 5 e
Ba
nt 
Ba


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
Section 8.2.2.3, the following text was changed from: 
If no events (ie, no subjects who had a PGTC seizure) occur in a stratum, then data will be 
pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If no events occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
 If no events occur in the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days. 
 If no events occur in the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, then this group will be combined for analysis with the group of subjects 
who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
And revised as follows: 
If 5 events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data 
will be pooled by Baseline PGTC seizure frequency for analysis as follows:  
 If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
 If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
 If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
 Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
13.2 
Amendment 2 
13.2.1 
Rationale for the amendment 
The SAP was amended to include flexibility as an index for BRIEF-P. 
REDACTED COPY
ithin
PY 
ithin
who ha
ACTE
who ha
re freq
DAC
re freq
oup o
RE
oup o
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
izures
or va
izures
TC 
ns
TC 
ith ≤2 B
xten
ith ≤2 B
s with t
y ext
s with t
ures pe
any 
ures pe
ge with
and 
ge with
ysis wi
on a
ysis wi
zures p
atio
zures p
subject
pplic
subject
ad a PG
horiz
ad a PG
quency 
autho
quency 
of subj
ting a
of subj
ys, then
ketin
ys, then
o are ≥4
mark
o are ≥4
ubjects
y m
ubjects
chever 
t any
chever 
cur in th
port
cur in th
izures p
supp
izures p
ts who 
to s
ts who 
nts or le
e us
nts or le
C seizu
t be
C seizu
bjects w
nnot
bjects w
Simil
t ca
Simil
se
nt 
se
1
m
1


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
13.2.2 
Modification and changes 
13.2.2.1 
Specific changes 
The information below was revised: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Has been changed to: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Amendment #2 
14 Mar 2017 
Section 10.4.9.1, the following text was changed from: 
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), 
Sometimes (scored as 2 points), and Often (scored as 3 points).  
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges 
from 63 to 189, with higher scores reflecting poorer functioning. 
The 2 subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 4 . 
Table 4: BRIEF-P questionnaire scoring 
Scale/Index 
Questions 
Inhibit 
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 
60, 62 
Shift 
5,10, 15, 20, 25, 30, 35, 40, 45, 50 
Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
BRI 
All from {Inhibit, Shift, and Emotional Control} 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 
59, 61, 63 
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
MI 
All from {Working Memory and Plan/Organize} 
GEC Score 
1-63 
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and gender. Tables that map each raw score to the appropriate 
T-score are provided in the BRIEF-P Professional Manual and will be reproduced 
programmatically. 
And revised as follows: 
REDACTED COPY 
ncti
Y
ncti
scores
COP
scores
ing
CTE
ing
AC
RE
d to support any marketing authorization application and any extensions or variations thereof.
Never 
and 
Never 
site (GE
catio
site (GE
ning.
pplic
ning.
s that m
n ap
s that m
th
g a
ark
y
t a
pp
nt cannot be used t
d t
us
Score
not 
Score
t b
nn
=Behav
can
=Behav
This documen
Standa
ent 
Standa
sco
me
sco


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The BRIEF-P form comprises of 63 questions which can be answered Never (scored as 1 point), 
Sometimes (scored as 2 points), and Often (scored as 3 points).  
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges 
from 63 to 189, with higher scores reflecting poorer functioning. 
The 3 subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 4 . 
Table 4: BRIEF-P questionnaire scoring 
Scale/Index 
Questions 
Inhibit 
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 
60, 62 
Shift 
5,10, 15, 20, 25, 30, 35, 40, 45, 50 
Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
Inhibitory self-control 
All from {Inhibit and Emotional Control} 
Flexibility 
All from {Shift and Emotional Control} 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 
59, 61, 63 
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
Emergent metacognition 
All from {Working Memory and Plan/Organize} 
GEC Score 
1-63 
GEC=Global Executive Composite 
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, 
flexibility, emergent metacognition, and component scores based on the subject’s age and 
gender. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P 
Professional Manual and will be reproduced programmatically. 
13.3 
Amendment 3 
13.3.1 
Rationale for the amendment 
The SAP was amended to reflect changes adopted in Protocol Amendment 5 v4.0. The primary 
purpose of Protocol Amendment 5 v4.0 was to stop the subjects’ study participation once 125 
events are observed to avoid exposing subjects to placebo unnecessarily.  This SAP amendment 
provides more detail in how PGTCS data will be analyzed for the primary and secondary 
efficacy endpoints. In general, all variables and all statistical analyses are more clarified. 
13.3.2 
Modification and changes 
13.3.2.1 
Specific changes 
The information below was revised from: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
TED COPY
 61, 
PY 
 61, 
4, 9, 
CO
4, 9, 
OP
D C
D
REDACTE
TE
DA
d fr
R
d fr
rization application and any extensions or variations thereof.
v
2, 54, 5
ions
2, 54, 5
s
5, 50
exte
5, 50
ten
6, 41, 4
any
6, 41, 4
y e
nd Emo
and
nd Emo
d a
and Em
tion 
and Em
a
 22, 27
lica
 22, 27
3
ati
14, 19
on a
14, 19
ap
All fro
izat
All fro
tio
ng authori
1
o
1-6
d to support any market
riz
utho
rom ea
eting
rom ea
and com
arke
and com
score t
ma
score t
be repro
any m
be repro
ent 3
ort a
ent 3
ale fo
upp
ale fo
ended to
d to 
ended to
This document cannot be use
tocol A
sed 
tocol A
bserved
e us
bserved
more d
t be
more d
cy endp
nnot 
cy endp
.3.2
t can
.3.2
13.3
men
13.3
T


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Amendment #2 
14 Mar 2017 
has been revised to: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Amendment #2 
14 Mar 2017 
Amendment #3 
4 Jan 2019 
The following abbreviations were revised from: 
IGE 
idiopathic generalized epilepsy 
ILAE 
International League Against Epilepsy 
IRT 
Interactive response technology 
LCM 
lacosamide 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Metacognition Index 
PCH 
percent change 
PedsQL 
Pediatric Quality of Life Inventory  
PGTC 
primary generalized tonic-clonic 
Has been revised to: 
IGE 
idiopathic generalized epilepsy 
IIA 
Absence seizures 
IIB 
Myoclonic seizures 
IIC 
Clonic seizures 
IID 
Tonic seizures 
IIE 
(primary generalized) tonic-clonic seizures 
IIF 
Atonic seizures 
III 
Unclassified seizures 
ILAE 
International League Against Epilepsy 
IRT 
Interactive response technology 
KM 
Kaplan-Meier 
LCM 
Lacosamide 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Metacognition Index 
REDACTED COPY 
ality o
D CO
ality o
genera
TED
genera
idiop
RE
idiop
t cannot be used to support any marketing authorization application and any extensions or variations thereof.
tory Ac
tion 
tory Ac
of Life I
tion 
of Life I
alized t
riza
alized t
pathic 
ting 
pathic 
Absenc
rket
Absenc
My
ma
My
This document ca
T
n
T
KM
t ca
KM
L
n
L


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
PCH 
percent change 
PedsQL 
Pediatric Quality of Life Inventory  
PGTC 
primary generalized tonic-clonic 
PGTCS 
Primary generalized tonic-clonic seizure 
Section 2.2.1.2 Secondary efficacy variables were changed from: 
The key secondary efficacy variable is: 
 Seizure freedom for during the 24-week Treatment Period, estimated using Kaplan-Meier 
analysis 
The other secondary efficacy variables are: 
 The percent change in PGTC seizure frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Combined Baseline (combined 12-week 
Historical and 4-week Prospective Baseline) 
 The percent change in PGTC seizure frequency per 28 days during the Treatment Period 
relative to the Combined Baseline  
 Time to the first PGTC seizure during the 24-week Treatment Period 
And revised as follows: 
The key secondary efficacy variable is: 
 Seizure freedom for PGTCS during the 24-week Treatment Period, estimated using Kaplan-
Meier analysis 
The other secondary efficacy variable is: 
  Time to first seizure during the 24-week Treatment Period 
Section 2.2.1.3 Other efficacy variables were changed from: 
Other efficacy variables are: 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline 
REDACTED COPY 
Y
week
D CO
week
ng th
RE
ng th
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
plan
nsio
plan-
si
-M
o
M
the firs
nd a
the firs
seline (
n an
seline (
ys
pli
ys duri
plica
duri
k Treat
tion 
k Treat
he 24
ing a
he 24-
g
-w
a
w
able is:
mar
able is:
ng the 2
any 
ng the 2
cacy va
port 
cacy va
les are:
supp
les are:
ys with
d to
ys with
e Ba
used
e Basel
ed
sel
nt chang
t be 
nt chang
atment
not 
atment
Percen
t can
Percen
re
nt 
rela
c
la

m



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline 
 Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period 
 Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
first 12 weeks of the Treatment Period compared to Combined Baseline 
 Percentage of subjects with at least a 50% reduction in PGTC seizure frequency during the 
Treatment Period compared to Combined Baseline 
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
 Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or 
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age 
 Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 
Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and 
change in utility as converted from the 5 dimensions (for subjects ≥12 years of age) 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
 Number of working or school days lost by subject due to epilepsy 
 Number of days with help from a caregiver due to epilepsy 
And revised as follows: 
Other efficacy variables are: 
 The percent change in PGTCS frequency per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Combined Baseline Period (combined 12-
week Historical and 4-week Prospective Baseline Periods) 
 The percent change in PGTCS frequency per 28 days during the first 12 weeks of the 
Treatment Period relative to the Combined Baseline Period 
REDACTED COPY 
ualit
COP
uality 
OP
y 
aily A
ED C
aily A
Menta
CTED
Menta
ts) and
DACT
ts) and
tric Qu
REDA
tric Qu
ing, 
RE
ing, 
marketing authorization application and any extensions or variations thereof.
eriod 
varia
eriod 
during
sion
during
quency
y ex
quency
he first 
and 
he first 
es for th
licati
es for th
of Life
on a
of Life
Activitie
zatio
Activitie
al Acti
oriza
al Acti
d total 
utho
d total 
uality o
g au
uality o
 Social
ting 
 Social
e
r
e
annot be used to support any m
of treat
ma
of treat
Assess
any 
Assess
verted f
ort a
verted f
e use: m
uppo
e use: m
rking or
to s
rking or
f days w
used
f days w
d as fo
be u
d as fo
efficac
nnot
efficac
This document ca
The p
t ca
The p
Tr
nt 
Tr


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 The percent change in PGTCS frequency per 28 days during the Treatment Period relative to 
the Combined Baseline Period 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline Period 
 Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Prospective Baseline Period 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline Period 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline Period 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline Period 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Prospective Baseline Period 
 Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Titration Period compared to Combined Baseline Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 12 
weeks of the Treatment Period compared to Combined Baseline Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Treatment Period compared to Combined Baseline Period 
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
 Change from Baseline in Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) subscale (Seizure Worry, Daily Activities/Social Functioning, 
Energy/Fatigue, Emotional Well-being, Mental Activity/Cognitive Functioning, Overall 
Quality of Life and Medication Effects) and total scores in subjects ≥18 years of age or 
change from Baseline in the Pediatric Quality of Life Inventory (PedsQL) subscale (Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age 
REDACTED COPY 
ction i
COPY
ction i
for th
CTED
for th
TCS fo
EDAC
TCS fo
st a 
RE
st a 
t any marketing authorization application and any extensions or variations thereof.
pared to
ons 
pared to
Period
exte
Period
the fir
nd a
the fir
aseline
n an
aseline
during
catio
during
in myo
n ap
in myo
e first 
oriza
e first 
for the 2
auth
for the 2
50% re
ting 
50% re
mbined B
rketi
mbined B
least a
ma
least a
riod co
any 
riod co
This document cannot be used to suppo
with a
port 
with a
ompare
uppo
ompare
atus (ye
to s
atus (ye
eriod 
ed t
eriod 
free sta
be us
free sta
d 
t
d 
Change
anno
Change
(QOL
nt ca
(QOL
En
nt
En


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Change from Baseline to end of treatment or early termination (ET) in the 3-Level EuroQol-5 
Dimension Quality of Life Assessment (EQ-5D-3L) visual analogue scale (VAS) score and 
change in utility as converted from the 5 dimensions (for subjects ≥12 years of age) 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
 Number of working or school days lost by subject due to epilepsy 
 Number of days with help from a caregiver due to epilepsy 
Section 2.2.2 was revised from: 
The safety variables are: 
 Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed 
by the investigator 
 Subject withdrawal due to AEs 
 Changes in hematology, chemistry, endocrinology, and urinalysis parameters 
 Changes in 12-lead electrocardiograms (ECGs) 
 Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings 
 Incidence of new seizure types during the Treatment Period 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
And revised as follows: 
The safety variable is: 
 Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed 
by the investigator 
Section 2.2.2.1 was revised from: 
Other safety variables are: 
 Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18) 
 Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool 
Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF]) 
And revised as follows: 
Other safety variables are: 
 Subject withdrawal due to AEs 
 Incidence of new seizure types during the Treatment Period 
REDACTED COPY
exam
PY 
exam
atment
COP
atment
25% to
TED 
25% to
ng the 
ACTE
ng the 
o 25%
RE
o 25%
d to support any marketing authorization application and any extensions or variations thereof.
r 
n
r or ob
sio
or ob
aramet
nd a
aramet
P] and p
icatio
P] and p
nation 
pplic
nation 
t Perio
on ap
t Perio
o 50%,
izati
o 50%,
Treatm
horiz
Treatm
%, >25
ting a
%, >25
ys durin
ketin
ys durin
Es) as r
upp
Es) as r
tor
to
tor
This document cannot be use
was rev
sed 
was rev
y variab
be u
y variab
haviora
not 
haviora
Cogni
t can
Cogni
Ve
nt c
Ve
An
m
An


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with absence seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in the days 
with myoclonic seizures per 28 days during the Treatment Period relative to the Prospective 
Baseline 
 Changes in hematology, chemistry, endocrinology, and urinalysis parameters 
 Changes in 12-lead electrocardiograms (ECGs) 
 Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) (including body 
weight and height) and physical and neurological examination findings 
 Behavioral assessment (Achenbach Child Behavior Checklist [CBCL]/1½-5 or CBCL/6-18) 
 Cognitive function assessment (Behavior Rating Inventory of Executive Function®-Preschool 
Version [BRIEF-P] or Behavior Rating Inventory of Executive Function® [BRIEF]) for 
pediatric subjects only 
Section 2.3.1, 2nd paragraph was revised from: 
Approximately 200 subjects (100 per treatment arm) will be randomized to achieve a total of 
125 events, where an event is defined as the occurrence of the second PGTC seizure. 
Has been revised to: 
Up to 250 subjects across 150 to 180 sites in the US, Europe, Asia, and Australia, with possible 
extension to other countries and regions, are planned to be randomized in this study to see 125 
events. An event is the occurrence of each subject’s second PGTCS. The maximum duration of 
study medication administration is 28 weeks. The study will last a maximum of 36 weeks per 
subject.  
Section 2.3.1, 5th paragraph, the following sentence was added: 
Seizures reported on the Historical Seizure Count CRF with incomplete dates will be assumed to 
have occurred with the 12-week Historical Baseline Period when checking eligibility for the 
study and inclusion in baseline PGTCS frequency per 28 days. 
Section 2.3.1, 2nd paragraph from end, newly states: 
If the 125th event occurs while the subject is still participating in the study, the subject can: 
 Complete the Visit 10 (Week 24) or ET Visit (if the next scheduled visit is not Visit 10) and 
choose to continue in EP0012 by completing a blinded transition followed by a Final Clinic 
Visit. 
 Discontinue from the study by completing the Visit 10 (Week 24) or ET Visit (if the next 
scheduled visit is not Visit 10) and an up to 4-week blinded taper followed by an End of 
Taper visit.  
Section 2.4, 2nd paragraph was revised from: 
This is an event-driven study. The study will be closed to enrollment once 125 events have been 
observed. If 125 events are observed prior to 200 randomized subjects, then enrollment will stop 
REDACTED COPY
will b
PY 
will b
ence o
OPY
ence o
n the U
CTE
n the U
, are
DAC
, are p
AC
p
each s
RED
each s
w
R
w
marketing authorization application and any extensions or variations thereof.
uding b
ons 
uding b
5 or C
exte
5 or C
ve Fu
any
ve Func
y 
nc
nction
nd a
nction®
a
®
e rando
pplic
e rando
of the s
n app
of the s
US, Eu
horiz
US, Eu
planned
autho
planned
subject
g au
subject
weeks. T
eting
weeks. T
t be used to support any 
follow
y ma
follow
torical 
rt any
torical 
week 
port
week 
baselin
upp
baselin
paragra
d to s
paragra
ent occ
used
ent occ
lete the
t be 
lete the
This document canno
oose to 
not 
oose to 
Visit.
ann
Visit.

Dis
nt c
Dis


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
and fewer than 200 subjects will be randomized. However, if 125 events are not observed 
after 200 subjects are randomized, then the study will continue to enroll up to a maximum of 
250 subjects randomized or 125 events, whichever occurs first. 
Has been revised to: 
This is an event-driven study. Enrollment in the study will continue up to 125 events occurring 
or a maximum of 250 subjects randomized, whichever comes first. 
Section 3.1 was revised from: 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS® Version 9.4 or higher.  
Descriptive statistics will be used to provide an overview of the primary, secondary, and other 
variable results. For categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based on the number of 
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will 
be displayed to 1 decimal place except 100% which will be displayed to 0 decimal places. For 
continuous parameters, descriptive statistics will include number of subjects, mean, standard 
deviation, median, minimum, and maximum.  
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. 
Data provided at these visits will be included in subject data listings. Subject data listings will be 
provided and will present source data and key derived variables for statistical analyses. 
Was revised to: 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier 
New font size 9. 
Descriptive statistics will be used to provide an overview of the primary, secondary, and other 
variable results. For categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based on the number of 
subjects appropriate for the purpose of the analysis. Unless otherwise noted, all percentages will 
be displayed to 1 decimal place. No percentage will be displayed for zero counts, and no decimal 
will be presented when the percentage is 100%. For continuous parameters, descriptive statistics 
will include number of subjects, mean, standard deviation, median, minimum, and maximum.  
Decimal places for descriptive statistics will always apply the following rules: 
 “n” will be an integer 
 Mean, SD and median will use 1 additional decimal place compared to the original data. 
 Minimum and maximum will have the same number of decimal places as the original value. 
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. 
Data provided at these visits will be included in subject data listings. A complete set of data 
listings containing all documented data and all calculated data (eg, change from Baseline) will be 
generated. 
Section 3.2.1, Analysis Time Points, the following sentence was inserted: 
REDACTED COPY 
ule
Y
ule
ject da
OPY
ject da
rived v
CO
rived v
les, fig
DAC
les, fig
on 9.4 
REDA
on 9.4 
ot be used to support any marketing authorization application and any extensions or variations thereof.
utput 
or v
utput 
ry, and 
ensio
ry, and 
ects in 
exten
ects in 
n the n
y ex
n the n
ed, a
d any
ed, all 
ny
ll 
to 0 de
and a
to 0 de
f subjec
n an
f subjec
linic v
plic
linic v
ata listi
app
ata listi
variabl
tion 
variabl
gures, s
utho
gures, s
 or hig
g au
 or hig
provid
arke
provid
aramet
y ma
aramet
e denom
any 
e denom
purpos
ort a
purpos
al place
ppor
al place
en the p
supp
en the p
er of su
d to s
er of su
s for de
used
s for de
ll be an
t be 
ll be an
canno
ea
nn
ea
This document ca
n, SD
nnot
n, SD
Mini
nt ca
Mini
By
me
By
n
D
m
D


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
First 12 weeks: this is defined as the Titration Period + the first 6 weeks of the Maintenance 
Period 
Section 3.2.2, Seizure cluster, this section was moved to occur earlier in Section 3 and the text 
was revised from: 
For PGTC seizures, if a seizure cluster is reported, it will be assigned to the most dominant ILAE 
seizure type and the frequency will be set to 2 times the number of clusters reported. 
Was revised to: 
If a seizure cluster is reported, it will be assigned to the International League Against Epilepsy 
(ILAE) seizure type reported and the frequency will be set to 2 times the number of clusters 
reported. 
Section 3.2.3, Event, was added: 
In the primary efficacy analysis, an event for analysis purposes is: 
 The 2nd PGTCS 
While keeping in mind the definition of seizure clusters in Section 3.2.2. 
For the primary and secondary efficacy analyses, these endpoints will be assessed using the at 
most the first 166 days, which is the 24-week Treatment Period minus a protocol-allowed 2 day 
window.  For all other efficacy parameters, all data reported during the Treatment Period will be 
used in the analysis. 
The primary efficacy endpoint, time to event, is defined as the “stop date” - the date of first dose 
of study drug + 1 day where the “stop date” is the first of the following to occur: 
 date of the event,  
 date of the premature discontinuation,  
 date of last dose of study medication in the Treatment Period, 
 date of the completion of the Treatment Period,  
 date of the 125th event,  
 Day 166 
The same algorithm applies for the other secondary endpoint, where time to event, is replaced by 
time to 1st PGTCS. 
Section 3.2.4, Censoring, was revised from: 
Subjects who complete the Treatment Period without having a second PGTC seizure during the 
Treatment Period will be censored. If the subject’s Treatment Period participation is less than 
24 weeks minus the visit window for Visit 10, they will be censored on the date of the last dose 
of study drug. If the subject’s Treatment Period participation is greater than 24 weeks minus the 
visit window for Visit 10, they will be censored as of 24 weeks minus the visit window for Visit 
10.  
Subjects who have important protocol deviations for inappropriate use of AEDs and 
benzodiazepines will be censored. The important protocol deviations and rules for censoring due 
REDACTED COPY
ent P
PY 
ent P
repor
COPY
repor
t, is de
CTED
t, is de
te” is t
DACT
te” is t
d to support any marketing authorization application and any extensions or variations thereof.
lepsy 
or v
lepsy 
usters 
ons o
usters 
3.2.2
on a
3.2.2
nts w
licat
nts wil
t
il
riod m
pplic
riod m
rted du
n ap
rted du
defined 
oriza
defined 
the firs
utho
the firs
ion,
rketi
ion,
ication
ma
ication
the Tre
t any
the Tre
nt, 
pp
nt, 
This document cannot be used
thm app
ed to
thm app
TCS.
use
TCS.
2.4, C
t be
2.4, C
ects wh
anno
ects wh
eatmen
t can
eatmen
24
en
24 we
nt 
we
of s
me
of s


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
to important protocol deviations will be determined and documented prior to the database lock 
and unblinding. 
Has been changed to: 
For the primary and secondary efficacy analyses, a Treatment Period of 166 days will be utilized. 
The censoring for the primary efficacy analysis will be as follows: 
 Subjects who complete the Treatment Period without having an event during the Treatment 
Period will be censored as of Day 167.  
 If the subject’s Treatment Period participation is less than or equal to 166 days (premature 
discontinuation), their PGTCS information will be censored on the date after the last dose of 
study drug.  
 If the subject’s Treatment Period participation is greater than 166 days, their PGTCS 
information will be censored as of Day 167.  
 For the subjects who are ongoing in the study when the 125th event occurs, their PGTCS 
information for the primary efficacy endpoint analysis will be censored as of the day after the 
125th event, even if the subjects experience an event after the date of the 125th event but 
before 166 days of treatment is completed. 
 Only 125 events will be included in the primary efficacy endpoint analyses. In case of ties on 
the same date in reporting the 125th event, the first event reported to IRT will be deemed the 
125th event.  Data after the 125th event will be censored. 
Censoring for time to 1st PGTCS will be calculated in a similar manner, except using the date of 
the 1st PGTCS instead of the date of the event. For subjects who are ongoing in the study when 
the 125th event occurs, the time to 1st PGTCS information will be censored in the same manner 
as the time to event information (ie., censor all PGTCS information beyond the date of the 125th 
event). 
Section 3.2.5, AEDs and Benzodiazepines, the 1st paragraph has been revised from: 
Antiepileptic drugs and benzodiazepines (medications used for rescue) will be collected on the 
concomitant and prior medication case report form (CRF) for AEDs. At study entry, a subject 
should be taking 1 to 2 non-benzodiazepines or 1 to 3 AEDs where only 1 of the AEDs is 
identified as a benzodiazepine. This dosing regimen must be stable for at least 28 days prior to 
Visit 1. The subject must maintain this AED dosing regimen throughout the Prospective Baseline 
and the Treatment Period. 
Has been changed to: 
AEDs and benzodiazepines (medications used for rescue) will be collected on the concomitant 
and prior medication case report form (CRF) for AEDs. At study entry, a subject should be 
taking a stable dose of 1 to 2 non-benzodiazepines marketed AEDs or 2 to 3 AEDs (with only 1 
of the AEDs is identified as a benzodiazepine). This dosing regimen must be stable for at least 28 
days prior to Visit 1. The subject must maintain this AED dosing regimen throughout the 
Prospective Baseline and the Treatment Period with or without additional concurrent stable 
VNS. Vagus nerve stimulation must have been in place for at least 6 months prior to Visit 1 with 
REDACTED COPY
effica
OPY 
effica
first e
COP
first e
be cen
D C
be cen
alculat
ACTE
alculat
event
DAC
event
PGTC
RED
PGTC
cen
R
cen
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
mature
or v
mature
ast dose
ons 
ast dose
ir PGT
exte
ir PGT
occurs,
nd a
occurs,
nsored 
n and
nsored 
date of 
tion 
date of 
cy endp
app
cy endp
event re
on a
event re
nsored
atio
nsored
ted in a
horiz
ted in a
t. For s
autho
t. For s
CS info
g au
CS info
nsor all
eting
nsor all
iazepin
y ma
iazepin
zodiaze
rt any
zodiaze
edicatio
port
edicatio
2 non
supp
2 non-
p
-b
p
b
odiaze
o su
odiaze
u
ect mu
ed to
ect mu
ment Pe
use
ment Pe
change
t be 
change
s and b
nno
s and b
d prior 
t can
d prior 
taking
ent 
taking
of t
me
of t
d


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
constant settings for at least 28 days prior to Visit 1 and must remain unchanged during the 
Treatment Period. 
Section 3.2.5.1, Prohibited concomitant treatments, has been added: 
The following medications/therapies are prohibited during the Treatment Period: 
 Clozapine 
 Any MAO inhibitors 
 Barbiturates (except as antiepileptic medications) 
 Unstable dosing of non-benzodiazepine anxiolytics or once-daily hypnotics 
 Herbal medicines for epilepsy 
The study physician will review the concomitant medications and flag prohibited medications. 
Section 3.2.8, Month, has been added: 
A month is defined as 28 days. 
Section 3.3, Definition of baseline values, the 2nd paragraph had been revised from: 
Baseline values for seizure data will be based on data collected during the Combined Baseline 
Period, excluding data collected on the day of Visit 2. 
Has been revised to: 
For PGTCS efficacy analyses, the data used for Baseline calculations come from the Combined 
Baseline Period. For absence and myoclonic seizure analyses, the data used for Baseline 
calculations come from the Prospective Baseline Period only.  
Section 3.9, Changes to protocol-defined analyses, has been revised from: 
There are no changes to analyses specified in the protocol. 
Has been revised to: 
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for 
PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. 
The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate using 
an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each 
stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric 
method that provides a more robust method to assess seizure freedom. 
Section 4.2.1, Missing seizure diary days, 2nd paragraph has been revised from: 
For the purpose of the derivation of the primary endpoint of time to second PGTC seizure and 
for PGTC seizure-free status, if there are seizure counts reported as “not done” on a specific day, 
then the seizure count will be assumed to be zero on that date.  
Has been changed to: 
For the purpose of the derivation of the primary efficacy endpoint, secondary efficacy endpoints 
and for PGTC seizure-free status, if there are PGTCS counts reported as “not done” on a specific 
day, then the PGTCS count will be assumed to be zero on that date.  
REDACTED COPY 
ol
Y
ol
2.
OP
2.
for Ba
CTED
for Ba
nic se
DACT
nic se
e Base
REDA
e Base
ned
R
ned
o support any marketing authorization application and any extensions or variations thereof.
ited me
ext
ited me
be
tio
been re
tion
en re
ed duri
plica
ed duri
aseline
oriza
aseline
eizure a
utho
eizure a
eline P
aut
eline P
d analy
eting
d analy
pecified
mark
pecified
cacy va
ort a
cacy va
week Tr
ppo
week Tr
ey seco
sup
ey seco
d to
l
cannot be use
-
t
-Haen
d to s
Haen
tended
ed 
tended
provide
e us
provide
4.2.1, M
ot be
4.2.1, M
the pur
cann
the pur
This document 
or PGT
t ca
or PGT
then t
men
then t
H


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Section 4.2.2, Incomplete dates for first epilepsy diagnosis, the following final imputation note 
was added: 
 Missing the day, month and year: 
No imputation will be done. 
Section 4.4, Multicenter studies, was revised from: 
Due to the small number of subjects per site, pooling the sites for statistical analysis will be 
necessary. All sites will be pooled together for analysis. 
has been changed to: 
Due to the small number of subjects per site, all sites will be pooled together for analysis. There 
will be no planned analyses for multi-center effects. 
Section 4.8, Examination of subgroups, was revised from: 
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the 
FAS.  Disposition will be presented by age subgroup for the SS and FAS.  Exposure will be 
presented by age and region subgroups for the SS.  Overall TEAE incidence will be presented by 
age subgroup for the SS.  Selected disposition and safety analyses will be presented by age at 
enrollment for the purpose of addressing requirements set in Article 46 of the European Pediatric 
Regulation (see Section 12.5 for further details). 
The subgroups to be examined include: 
 Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65) 
 Racial group (white, non-white) 
 Gender (male, female) 
 Region  
 North America: United States 
 Latin America: Brazil, Mexico 
 Western Europe: Belgium, France, Germany, Italy, Portugal, Spain 
 Eastern Europe: Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, 
Turkey 
 Asia/Pacific/Other: Australia, Israel, Japan, South Korea, Taiwan 
 Baseline PGTC seizure frequency (≤2 per 28 days and >2 per 28 days in the Combined 
Baseline Period) 
 Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the 
subject is taking when enrolled into the study (1, 2, 3). 
Separate age sub-groupings are used for the purpose of summarizing the following scales:  
 PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years) 
 Achenbach CBCL (4 to 5 years, 6 to 18 years) 
REDACTED COPY 
set
Y
set
ag
CT
age, ≥1
CTE
e, ≥1
not be used to support any marketing authorization application and any extensions or variations thereof.
alysis. T
sion
alysis. T
will be 
d an
will be 
FAS.  E
and
FAS.  E
inciden
ion a
inciden
ses will
catio
ses will
Article
plica
Article
12 to <
oriza
12 to <
tates
y m
tates
zil, Mex
rt an
zil, Mex
e: Belgi
uppo
e: Belgi
rope: B
to s
rope: B
a/Pacifi
be us
a/Pacifi
eline P
not b
eline P
This document can
Baselin
anno
Baselin
Con
nt c
Con
n


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 BRIEF-P/BRIEF (4 to <5 years, ≥5 years). 
Has been changed to: 
Descriptive statistics by all subgroups for the primary efficacy variable will be presented for the 
FAS.  Disposition will be presented by age subgroup for the SS and FAS.  Exposure will be 
presented by age and region subgroups for the SS.  Overall TEAE incidence will be presented by 
age subgroup for the SS.  Selected disposition and safety analyses will be presented by 
Development for the purpose of addressing requirements set in Article 46 of the European 
Pediatric Regulation (see Section 12.5 for further details). 
The subgroups to be examined include: 
 Age at enrollment (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65) 
 Development (Pediatric [≥4 to < 18 years old], Adult [≥18 years old]) 
 Racial group (white, non-white) 
 Gender (male, female) 
 Region  
 North America: United States, Puerto Rico 
 Latin America: Brazil, Mexico 
 Western/Central Europe: Belgium, Czech Republic, France, Germany, Hungary, Italy, 
Poland, Portugal, Slovakia, Spain 
 Eastern Europe: Bulgaria,  Romania, Russia,  Turkey 
 Asia/Pacific/Other: Australia, China, Israel, Japan, South Korea, Taiwan 
 Baseline PGTCS frequency (≤2 per 28 days and >2 per 28 days in the Combined Baseline 
Period) 
 Concomitant AEDs at study entry, ie the total number of AEDs and benzodiazepines the 
subject is taking when enrolled into the study (1, 2, 3). 
Separate age sub-groupings are used for the purpose of summarizing the following scales:  
 PedsQL (4 years, ≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years) 
 Achenbach CBCL (4 to 5 years, 6 to 18 years) 
 BRIEF-P/BRIEF (4 to <5 years, ≥5 years). 
Section 4.9, Stratum Pooling has been moved from a later section and the algorithm modified 
from saying: 
The analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 
subjects who had a second PGTC seizure) occur in a stratum, then data will be pooled by 
Baseline PGTC seizure frequency for analysis as follows:  
1. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
REDACTED COPY 
ch Rep
ED C
ch Rep
ania, R
DAC
ania, R
 Chin
RE
 Chin
be used to support any marketing authorization application and any extensions or variations thereof.
≥65)
nsio
≥65)
public, 
ation
public, 
Russia,
autho
Russia,
na, Isra
ing a
na, Isra
per 28 d
arket
per 28 d
dy entr
any
dy entr
enro
ort a
enrolle
t a
lle
pings a
upp
pings a
ars, ≥5 t
d to s
ars, ≥5 t
h CBCL
used
h CBCL
ot be
F-
b
-
nt can
P/BR
t be 
P/BR
on 4.9, 
nno
on 4.9, 
om sayi
t can
om sayi
This documen
The a
ment
The a
sub
m
sub


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
2. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
3. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
4. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
Has been revised to: 
The stratification factors for this study are Baseline PGTCS frequency (≤2 per 28 days vs >2 per 
28 days in the Combined Baseline Period) and age at informed consent (≥4 to <12 years of age, 
≥12 to <18 years of age vs ≥18 years of age). The analyses will use the stratification factors from 
IRT.  
To determine if strata pooling should occur for time to event (2nd PGTCS) analysis: 
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age 
at informed consent categories will be summed.   
 If 2 of the age at informed consent categories combined have < 3 total events, then all age 
categories are combined for the analysis.  
 If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events 
or less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥18 years of age is the category with the smallest number of events that are 2 events or 
less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥12 and <18 years of age is the category with the smallest number of events that are 2 
events or less, it should be combined with the strata with the 2nd smallest number of events. 
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to 
determine stratum pooling.  
Time to 1st PGTCS analyses: 
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that 
“events” will now be in reference to subjects having only 1 PGTCS. 
Seizure freedom analyses: 
The prior algorithm for stratum pooling will be used to determine stratum pooling, except that 
“events” will now be in reference to subjects having 0 PGTCS. 
Section 5.1, Subject disposition, the 3rd paragraph was modified from: 
The overall number and percentage of subjects who completed and discontinued from the study 
will be presented for the SS, FAS and PPS including number and percentages for each reason for 
REDACTED COPY 
eve
Y
eve
≤2 per 
COP
≤2 per 
D
gories 
CTE
gories 
ysis.
DAC
ysis.
ategor
RED
ategor
h
R
h
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
p of 
var
p of 
ys. 
o
ys. 
e PGTC
sions
e PGTC
2 per 2
d any
2 per 2
t (≥4 to
and a
t (≥4 to
the str
n an
the str
t (2
ppli
t (2nd
lica
nd P
c
P
28 day
n ap
28 day
combi
horiz
combi
ry with
ng a
ry with
the ≥1
keting
the ≥1
ory wit
mar
ory wit
with th
ny m
with th
f age is 
ort a
f age is 
uld be c
ppo
uld be c
h Basel
o su
h Basel
m pooli
d to
m pooli
GTCS 
use
GTCS 
r algori
ot be
r algori
ts” will
nnot
ts” will
eizure f
t ca
eizure f
The 
men
The 
“e
m
“e


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
discontinuation. The completion of the study is defined as meeting any of the predetermined exit 
criteria or experiencing <2 PGTC seizures within the 24-week treatment period. Discontinuation 
is defined as the completion of the ET Visit.  This summary will be repeated for specific 
subgroups as detailed in Section 4.8 for the SS and FAS.  The study termination information will 
be presented in the subject data listings. 
Has been changed to: 
The overall number and percentage of subjects who completed and discontinued from the study 
will be presented for the SS, FAS, and PPS including number and percentages for each reason 
for discontinuation. The completion of the study is defined as meeting any of the predetermined 
exit criteria (including when the 125th event has occurred) or experiencing <2 PGTCS within the 
24-week treatment period. Discontinuation is defined as the completion of the ET Visit in all 
other cases.  This summary will be repeated for specific subgroups as detailed in Section 4.8 for 
the SS and FAS.  The study termination information will be presented in the subject data listings. 
Section 6.2.2, Analysis of baseline characteristics, the 2nd paragraph has been changed from: 
The following Baseline characteristics will also be presented: 
 Time since first diagnosis at date of consent 
 Age at diagnosis of the disease 
 International League Against Epilepsy (ILAE) Seizure classification history 
 Classification of epileptic syndrome 
 Etiology of epilepsy 
Has been changed to: 
The following Baseline characteristics will also be presented: 
 Time since first diagnosis at date of consent 
 Age at diagnosis of epilepsy 
 Number of lifetime AEDs and Benzodiazepines (0, 1-3, 4-6, ≥7)  
 Concomitant benzodiazepine use at study entry (yes, no) 
 ILAE (1989) Seizure classification history 
 Classification of epileptic syndrome 
 Etiology of epilepsy 
Section 7, Measurements of Treatment Compliance, the following text was removed: 
For oral solution, compliance will be calculated using the following formula:  
Compliance (%) = Actual weight of used oral solution (g) / Expected weight of used oral 
solution (g) x 100. 
For tablets, compliance will be calculated using the following formula:  
REDACTED COPY 
Seizu
COP
Seizu
R
rt any marketing authorization application and any extensions or variations thereof.
y 
r
y 
on
v
on
rmined
or v
rmined
 within
ons 
 within
Visit in
nsio
Visit in
x
Sectio
ten
Sectio
xte
subject
y ext
subject
s been c
d any
s been c
ure clas
on ap
ure clas
will al
keting
will al
ate of c
mar
ate of c
This document cannot be used to suppo
sy
a
sy
EDs an
port 
EDs an
zodiaze
supp
zodiaze
Seizure
d to
Seizure
ation of
use
ation of
ogy of 
ot be
ogy of 
ion 7, M
ann
ion 7, M
For ora
ent c
For ora
Co
me
Co


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Compliance (%) = (Number of tablets dispensed – Number of tablets returned) / (Number of 
tablets prescribed per day x Number of days between x 100. 
Rates of compliance will be calculated and summarized by category: <75%, 75-125%, >125%. 
Section 8, Efficacy Analyses, were revised from: 
All efficacy analyses will be performed using the FAS population. 
For all efficacy analyses, only data up to and including the day of the second PGTC seizure, the 
Visit 10 date or the last maintenance dose date, whichever is earlier, will be included. All seizure 
diary data will be listed including data not included in the efficacy analyses. 
Testing for the primary endpoint will be done at the 5% level (2-sided). Provided that the 
primary endpoint is statistically significant, a gatekeeping strategy will be used to test the key 
secondary efficacy variable. No additional adjustments for multiplicity are required as all 
additional inferences will be hypothesis-generating only. 
Has been revised to: 
Most efficacy analyses will be performed using the FAS population; in other cases, the 
population will be stated. 
For primary efficacy endpoint analyses, only data up to and including the day of the event, the 
Visit 10 date, last Treatment Period dose date, Day 166 or the date of the 125th event, whichever 
is earlier, will be included. For the secondary efficacy endpoint analyses, only data up to and 
including the day of the first PGTCS, the Visit 10 date, the last Treatment Period dose date, Day 
166 or the date of the 125th event, whichever is earlier, will be included. For all other exploratory 
efficacy variables, all appropriate seizure data during the Treatment Period, will be included. All 
seizure diary data will be listed including data not included in efficacy analyses. 
Testing for the primary efficacy endpoint will be done at the 5% level (2-sided). Provided that 
the primary efficacy endpoint is statistically significant, a gatekeeping strategy will be used to 
test the key secondary efficacy variable, seizure freedom. No additional adjustments for 
multiplicity are required as all additional inferences will be hypothesis-generating only. 
Section 8.1.1, Derivations of primary efficacy variable, has been revised from: 
For PGTC seizures, the number of days until the second seizure will be derived using the date of 
the second PGTC seizure – date of first dose of study medication +1. For subjects who 
prematurely discontinue or complete the 24-week Treatment Period prior to having a second 
PGTC seizure, time to censor will be calculated as the date of censoring - date of first dose of 
study medication + 1. Only data up to Week 24 will be included. Censoring of subjects for this 
analysis will be as described in Section 3.2.2.If a day is marked in the CRF as “not done”, it will 
be assumed that no seizures occurred on that day. 
Has been changed to: 
For the primary efficacy variable, an event and how time to event is calculated is described in 
Section 3.2.3, keeping in mind Section 3.2.2. Censoring of subjects for this analysis will be as 
described in Section 3.2.4 . If a day is marked in the CRF as “not done”, it will be assumed that 
no seizures occurred on that day. 
Section 8.1.2, Primary analysis of the primary efficacy variable, has been modified from: 
REDACTED COPY
an
Y
an
66 or
OPY 
66 or
ca
C
cacy e
COP
cy e
10 da
ED C
10 da
r is ea
CTE
r is ea
e data 
DAC
e data 
ding da
REDA
ding da
i
R
i
e used to support any marketing authorization application and any extensions or variations thereof.
e 
r
e 
izure 
vari
izure 
t the
ions
t the
test the
ensio
test the
uired as
exten
uired as
; in oth
n an
; in oth
ncludin
plica
ncludin
r the da
app
r the da
endpoin
ion a
endpoin
ate, the
zatio
ate, the
arlier, w
horiza
arlier, w
during
utho
during
ata not 
g au
ata not 
int will
keting
int will
istically
arke
istically
ariable,
y ma
ariable,
additio
any 
additio
of prim
port 
of prim
he numb
supp
he numb
eizure
to s
eizure
continu
ed t
continu
e, time 
use
e, time 
This document cannot b
ication
be u
ication
s will b
not b
s will b
ssumed
ann
ssumed
Has be
ent c
Has be
For
me
For


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The primary efficacy variable, time to second PGTC seizure during the 24-week Treatment 
Period, will be evaluated using a Cox proportional hazards regression model (Cox, 1972), with 
an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 
days vs >2 per 28 days in the Combined Baseline Period) and age at informed consent (≥ 4 to 
<12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The analysis will use the 
stratification factors from IRT. If 5 events or less (ie, less than 6 subjects who had a second 
PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC seizure frequency 
for analysis as follows:  
5. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
6. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
7. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
8. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
 The stratified HR will be calculated using the placebo arm as the reference group. 
Additionally, a KM plot for time to second PGTC seizure as well as the KM estimate for the 
median time to second PGTC seizure will be provided. If the median time is not estimable, then 
the 25th percentile will be provided.  
Has been changed to: 
The primary efficacy variable, time to event during the 166-day Treatment Period, will be 
evaluated using a Cox proportional hazards regression model (Cox, 1972), with an effect for 
treatment, stratifying for the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 
days in the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, 
≥12 to <18 years of age vs ≥18 years of age). The analysis will use the stratification factors from 
IRT and pooled as described in Section 4.9.   
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
REDACTED COPY
be com
OPY 
be com
≤2 Ba
COP
≤2 Ba
group
TED
groups
D 
s
sing th
EDA
sing th
eco
R
eco
keting authorization application and any extensions or variations thereof.
h ≤2
or va
h ≤2
with
ns o
with
TC seiz
ion
TC seiz
ne PGT
tens
ne PGT
ars of a
any 
ars of a
ned for
nd a
ned for
ine PG
n an
ine PG
≥18
plic
≥18 ye
ca
ye
mbined
app
mbined
aseline
on a
aseline
s within
izati
s within
he plac
aut
he plac
ond PG
eting
ond PG
t be used to support any mark
e will b
arket
e will b
d.
m
d.
able, ti
port 
able, ti
propor
upp
propor
g for th
to su
g for th
bined B
ed to
bined B
ars of a
used
ars of a
ooled as
be u
ooled as
This document canno
pothes
not 
pothes
Versu
ment
Versu


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The 
assumptions of proportional hazards will also be checked.  
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. 
The SE and 95% CI for the HR will also be reported.  
Additionally, a Kaplan-Meier (KM) plot for time to event as well as the KM estimate for the 
median time to event and 95% CI will be provided. If the median time is not estimable, then the 
25th percentile and 95% CI will be provided. The number of events will be reported by treatment 
group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects 
who were censored in the analysis. 
Section 8.1.3, Secondary analyses of the primary efficacy variable, has been changed from: 
The summary of time to the second PGTC seizure during the 24-week Treatment Period will be 
presented by subgroup for the FAS.  A KM plot for time to second PGTC seizure by selected 
subgroups will also be provided.  
Has been changed to: 
The summary of time to the event during the 166-day Treatment Period will be presented by all 
subgroup for the FAS. A KM plot for time to second PGTCS by all subgroups will also be 
provided.  
Section 8.1.4, Supportive and sensitivity analyses of the primary efficacy variable, has been 
changed from: 
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted 
in order to assess the effect of dropouts, important protocol deviations, and operational bias on 
the primary endpoint:   
 Repeat the primary analysis using the PPS. 
 Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue 
due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed as treatment 
failures (ie, events at the time of discontinuation). 
 Repeat the primary analysis using the FAS, except all subjects who prematurely discontinue 
due to lack of efficacy or AEs only will be analyzed as treatment failures. 
 Repeat the primary analysis using the FAS, comparing the event rates prior to vs after each 
interim analysis to examine possible operational bias due to unblinding. 
Has been changed to: 
The following additional sensitivity analyses on the primary efficacy endpoint will be conducted 
in order to assess the effect of dropouts, important protocol deviations, and operational bias on 
the primary endpoint:   
 Repeat the primary efficacy analysis using the PPS. 
DACTED COPY 
6
D
6-
D
-day
D CO
day
o secon
TED
o secon
RE
ity ana
REDA
ity ana
authorization application and any extensions or variations thereof.
p.
ri
p.
r the 
s or
r the 
ble, then
sions
ble, then
ed by tr
ensi
ed by tr
the % 
exte
the % 
been c
nd a
been c
ek Tre
n an
ek Tre
nd PGT
ation
nd PGT
y Treatm
ation
Treatm
nd PGT
riza
nd PGT
d to support any marketing 
alyses 
g au
alyses 
analys
arke
analys
opouts,
y ma
opouts,
alysis u
port 
alysis u
y analy
supp
y analy
efficacy
d to s
efficacy
nnot be use
events 
sed t
events 
the prim
be us
the prim
o lack 
ot be
o lack 
This document ca
Repeat 
ann
Repeat 
inter
nt ca
inter
Has
me
Has


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through 
each subject’s first 166 days of treatment, on the FAS. 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue due to lack of efficacy, consent withdrawn, or lost to follow-up will be analyzed 
as treatment failures (ie, events at the time of discontinuation). 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue due to lack of efficacy or AEs only will be analyzed as treatment failures. 
 Repeat the primary efficacy analysis using the FAS, comparing the event rates prior to vs 
after each interim analysis to examine possible operational bias due to unblinding. 
Section 8.2.1.1, Seizure freedom for PGTCS for the 166-day Treatment Period, has been 
modified from: 
A seizure-free day will be defined as a day where no PGTC seizures were reported in the seizure 
diary and seizures were assessed. Days in the seizure diary which are marked as “not done” on 
the CRF will be counted as a seizure free day. 
A subject will have seizure freedom (seizure free status=yes) for the 24-week Treatment Period 
if the subject completed the Treatment Period and reported zero seizures or “not done” for all 
days during the Treatment Period. 
Has been changed to: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary and PGTCS were assessed. Days in the seizure diary which are marked as “not 
done” on the CRF will be counted as seizure-free days from PGTCS. 
A subject will have seizure freedom from PGTCS for the 166-day Treatment Period if the 
subject completed the Treatment Period and reported zero PGTCS or “not done” for all days 
during the 166-day Treatment Period. Ongoing subjects who are seizure-free from PGTCS on the 
date of the 125th event do not have seizure-freedom from PGTCS unless they are seizure-free 
from PGTCS for 166 days. 
Section 8.2.1.2, Time to 1st PGTCS during the 166-day Treatment Period, has been changed 
from: 
For PGTC seizures, the number of days until the first seizure will be derived using the date of the 
first PGTC seizure – date of first dose of study medication +1. For subjects who prematurely 
discontinue or complete the 24-week Treatment Period prior to having a PGTC seizure, time to 
censor will be calculated as the date of censoring - date of first dose of study medication + 1. 
Only data up to Week 24 will be included. Censoring of subjects for this analysis will be as 
described in Section 3.2.2. 
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that 
seizure diary day. 
Has been changed to: 
For PGTCS, how the time to first PGTCS is calculated is described in Section 3.2.3.  Censoring 
of subjects for this analysis will be as described in Section 3.2.4 . 
REDACTED COPY 
ed as a
ED C
ed as a
ays in
CTE
ays in
zure
DAC
zure-
A
-f
C
f
from 
RE
from 
d
o support any marketing authorization application and any extensions or variations thereof.
o vs
or v
o vs
s been 
nsio
s been 
eported
ny e
eported
rked as
d any
rked as
the
tio
the 24
on 
24
o seizu
icati
o seizu
a day w
izatio
a day w
n the se
horiz
n the se
free da
autho
free da
PGTC
ing a
PGTC
d and r
ketin
d and r
od. Ong
marke
od. Ong
ve seiz
y ma
ve seiz
PGTC
port
PGTC
nnot be used t
s, the n
d to s
s, the n
ure
ed
ure –
ed
– d
or comp
e use
or comp
ll be ca
t be 
ll be ca
ata up 
not 
ata up 
This document ca
ribed i
ann
ribed i
If a da
ent c
If a da
seiz
me
seiz


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
If a day is marked in the CRF as “not done”, it will be assumed that no seizures occurred on that 
seizure diary day. 
Section 8.2.2 has been updated to: 
Analyses of secondary efficacy variables will be performed for the FAS. 
Section 8.2.2.1: Seizure freedom for the 166-day Treatment Period, has been modified from: 
Analysis of the key secondary efficacy variable, seizure freedom for PGTC seizures for the 
24-week Treatment Period, will be evaluated using a Cox proportional hazards regression model 
(Cox, 1972), with an effect for treatment, stratifying for the subjects’ Baseline PGTC seizure 
frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at 
informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The 
analysis will use the stratification factors from IRT. If 5 events or less (ie, less than 6 subjects 
who had a second PGTC seizure) occur in a stratum, then data will be pooled by Baseline PGTC 
seizure frequency for analysis as follows:  
9. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
10. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
11. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
12. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
The percentage of seizure-free subjects at 24 weeks will be estimated from the KM estimates of 
time to first seizure using 2-sided 95% confidence intervals. A stratified estimate of the seizure 
freedom rate in each treatment arm will be derived using KM methods to estimate the seizure 
freedom rate for each stratum and then combining the rates using a Cochran-Mantel-Haenszel-
like approach. The stratified HR will be calculated using the placebo arm as the reference group. 
If the primary endpoint is statistically significant at the 5% level, then the key secondary efficacy 
endpoint will also be assessed at the 5% significance level. If the primary endpoint fails to reach 
statistical significance, then the key secondary efficacy endpoint will be exploratory only. 
Has been modified to: 
Analysis of the key secondary efficacy variable, seizure freedom for PGTCS for the 166-day 
Treatment Period, will be evaluated using an extended Mantel-Haenszel testing procedure which 
takes into account that the subjects were initially stratified for the subjects’ Baseline PGTCS 
frequency (≤2 per 28 days vs >2 per 28 days in the Combined Baseline Period) and age at 
REDACTED COPY
numb
PY 
numb
cts wh
CO
cts wh
this gr
ED C
this gr
ears o
CTE
ears o
oup o
RE
oup o
h
R
h
used to support any marketing authorization application and any extensions or variations thereof.
model
vari
model
zure 
or
zure 
e at 
ons
e at 
age). T
nsion
age). T
han 6 su
tens
han 6 su
by Bas
ext
by Bas
<18 yea
and a
<18 yea
mbined
n an
mbined
with ≤2 
ation
with ≤2 
age wi
plica
age wi
er of ev
appl
er of ev
ho are ≥
tion 
ho are ≥
group w
izatio
group w
of age w
horiz
of age w
of subje
ing a
of subje
his grou
ketin
his grou
ars of a
arke
ars of a
to thos
ny m
to thos
re
p
re-
p
-free 
ppor
free 
sing 2
supp
sing 2
ch treat
d to s
ch treat
r each s
sed t
r each s
annot be u
h. Th
e use
h. The s
se
e s
mary e
ot be
mary e
oint wil
nno
oint wil
This document c
tistical
t can
tistical
Has b
ment
Has b
A
m
A


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age vs ≥18 years of age). The 
analysis will use the stratification factors from IRT and pooled as described in Section 4.9.  
The hypothesis for the assessment of the key secondary efficacy (PGTC seizure-freedom) is as 
follows: 
H0: S(t=166)LCM = S(t=166)PBO 
Versus 
H1: S(t=166)LCM ≠ S(t=166)PBO 
Where S(t=166) is the cumulative rate of subjects remaining seizure-free from PGTCS for 166 
days. 
Estimation of treatment difference: 
KM methods will be used to estimate the proportion of subjects remaining seizure-free from 
PGTCS at Day 166. The estimate for the difference in Day 166 seizure-freedom from PGTCS 
will be adjusted for subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in 
the Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 
years of age vs ≥18 years of age). The estimate for the stratified difference in proportion of 
subjects who are seizure-free from PGTCS on LCM vs PBO and a corresponding 95% two-sided 
confidence interval (CILCM-PBO) will be produced using mantel Haenszel methods (LaVange et al, 
2005). The statistical methodology is expressed as follows: 
 d=∑
wh(Sh1-Sh2)
6
h=1
 
Where Shi=KM estimate of 166-day seizure freedom from PGTCS for treatment i (1=LCM and 
2=PBO) in stratum h (1= ≤2 per 28 days Baseline PGTCS frequency and ≥ 4 to <12 years of age, 
2= ≤2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years of age, 3= =≤2 per 28 days 
Baseline PGTCS frequency and ≥18 years of age, 4= >2 per 28 days Baseline PGTCS frequency 
and ≥ 4 to <12 years of age, 5= >2 per 28 days Baseline PGTCS frequency and ≥12 to <18 years 
of age and 6= >2 per 28 days Baseline PGTCS frequency and ≥18 years of age and 
wh={(nh1*nh2)/(nh1+nh2)}/∑
{(nh1*nh2)
6
h=1
/(nh1+nh2)}} 
where nhi is the number of subjects in I treatment group and stratum h.  The variance of d is 
calculated as Var(d)=∑
wh
2
6
h=1
{Var(Sh1)+Var(Sh2)} where Var(Sh1) and Var(Sh2) are the 
Greenwood estimates of variance for Sh1 and Sh2. 
The stratified proportion of subjects remaining seizure free from PGTCS for at least 166 days in 
each treatment group and the associated variance are derived as follows using Mantel Haneszel 
methods: 
The KM estimate for the LCM 166-day seizure-freedom from PGTCS rate is calculated as 
𝑆1=∑
𝑤ℎ
6
ℎ=1
𝑆ℎ1 
The KM estimate for the PBO 166-day seizure-freedom from PGTCS rate is calculated as 
𝑆2=∑
𝑤ℎ
6
ℎ=1
𝑆ℎ2 
The variance is S1 is calculated as Var (𝑆1) =∑
𝑤ℎ
6
6
ℎ=1
𝑉𝑎𝑟(𝑆ℎ1) 
The variance of S2 is calculated as Var (𝑆2) =∑
𝑤ℎ
6
6
ℎ=1
𝑉𝑎𝑟(𝑆ℎ2) 
REDACTED COPY
g ma
PY 
g ma
follow
COP
follow
re free
ACT
re free
ys Base
EDAC
ys Base
freque
RED
freque
R
support any marketing authorization application and any extensions or variations thereof.
or 166
s or
or 166
eizure
y ex
eizure f
eedom 
any
eedom 
ays vs >
nd a
ays vs >
<12 ye
n an
<12 ye
differen
ation
differen
and a co
licat
and a co
ntel Ha
appli
ntel Ha
ws:
n
ws:
edom fr
thori
edom fr
eline P
auth
eline P
ency an
ng a
ency an
ears of 
keting
ears of 
per 28 d
arke
per 28 d
seline P
y ma
seline P
∑
a
∑
{
y
{
6
n
6
h=1
any
h=1
f subjec
port 
f subjec
sup
∑
ent cannot be used to 
w
pp
w2
6
h=1
supp
h=1
es of va
o su
es of va
roporti
sed 
roporti
nt grou
e us
nt grou
KM esti
nno
KM esti
∑
t c
∑6
ca
6
ℎ
ca
ℎ=
a
=
This documen
The K
men
The K
𝑆
m
𝑆


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
In order to assess superiority, 2-sided testing with α=0.05 will be used. The superiority test 
statistic, Q=d2/Var(d) will be assessed by a chi-square distribution with 1 degree of freedom. 
This statistic is referred to as the “row mean score statistic” when using Proc Freq. 
The number and percentage of subjects who experience a PGTCS or censoring and the KM 
seizure-free rate from PGTCS (and 2-sided 95% CI) by Day 166 will be presented by treatment 
group for each stratum and overall. The stratified seizure-freedom rate from PGTCS (and 2-sided 
95% CI) at Day 166 for each treatment group and the difference between treatment groups will 
be presented. A Kaplan-Meier plot will be presented by treatment group for each stratum and 
overall. 
For the gatekeeping strategy, if the primary endpoint is statistically significant at the 5% level, 
then the key secondary efficacy endpoint will also be assessed at the 5% significance level. If the 
primary endpoint fails to reach statistical significance, then the key secondary efficacy endpoint 
will be exploratory only. 
Section 9.2.2.2, Analysis of Percent Change in PGTC seizure frequency from Combined Baseline 
has been removed from the SAP. 
The percent change in log-transformed PGTC seizure frequency during the first 6 weeks of the 
Treatment Period will be analyzed using analysis of covariance, controlling for Baseline seizure 
frequency.  
The percent change in log-transformed PGTC seizure frequency during the Treatment Period 
will be analyzed analysis of covariance, controlling for Baseline seizure frequency.  
All PGTC seizure frequency per 28 days data will be listed. 
Section 8.2.2.2, Time to first PGTCS during the 166-day Treatment Period, has been changed 
from: 
Time to the first PGTC seizure during the 24-week Treatment Period will be evaluated using a 
Cox proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying 
for the subjects’ Baseline PGTC seizure frequency (≤2 per 28 days vs >2 per 28 days in the 
Combined Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 
years of age vs ≥18 years of age). The analysis will use the stratification factors from IRT. If 5 
events or less (ie, less than 6 subjects who had a PGTC seizure) occur in a stratum, then data will 
be pooled by Baseline PGTC seizure frequency for analysis as follows:  
13. If 5 events or less occur in the group of subjects who are ≥12 and <18 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with 
either the group of subjects who are ≥4 to <12 years of age with ≤2 Baseline PGTC seizures 
per 28 days or the group of subjects who are ≥18 years of age with ≤2 Baseline PGTC 
seizures per 28 days, whichever has the smallest number of events. 
14. If 5 events or less occur in the group of subjects who are ≥4 to <12 years of age with ≤2 
Baseline PGTC seizures per 28 days, then this group will be combined for analysis with the 
group of subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 
days. 
REDACTED COPY 
ure fre
COP
ure fre
ling fo
ED C
ling fo
ata wil
CTE
ata wil
uring t
EDA
uring t
e used to support any marketing authorization application and any extensions or variations thereof.
v
5% leve
ons 
5% leve
ce leve
nsio
ce leve
fficacy 
xten
fficacy 
from C
d any
from C
during t
tion 
during t
e, contr
icatio
e, contr
requenc
on ap
requenc
for Bas
ation
for Bas
ll be lis
horiz
ll be lis
the 
au
the 166
uth
166
g the 24
rket
g the 24
on mod
mar
on mod
C seizur
ny m
C seizur
and age
t any
and age
of a
port
of age)
ort 
ge)
than 6 s
upp
than 6 s
ne PGT
to su
ne PGT
r l
ed
r less o
ed t
ess o
PGTC 
e use
PGTC 
This document cannot b
the gro
t be 
the gro
28 day
not 
28 day
seizure
cann
seizure
14.
ent
14. If 5
nt c
If 5


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
15. If 5 events or less occur in the group of subjects who are ≥18 years of age with ≤2 Baseline 
PGTC seizures per 28 days, then this group will be combined for analysis with the group of 
subjects who are ≥12 to <18 years of age with ≤2 Baseline PGTC seizures per 28 days.  
16. Similarly, rules 1 to 3 apply to those age groups within subjects with > 2 Baseline PGTC 
seizures per 28 days. 
The stratified HR will be calculated using the placebo arm as the reference group. 
Additionally, a KM plot for time to first PGTC seizure as well as the KM estimate for the 
median time to first PGTC seizure will be provided. If the median time is not estimable, then the 
25th percentile will be provided.  
Has been changed to: 
Time to the first PGTCS during the 24-week Treatment Period will be evaluated using a Cox 
proportional hazards regression model (Cox, 1972), with an effect for treatment, stratifying for 
the subjects’ Baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days in the Combined 
Baseline Period) and age at informed consent (≥ 4 to <12 years of age, ≥12 to <18 years of age 
vs ≥18 years of age). The analysis will use the stratification factors from IRT and pooled as 
described in Section 4.9.  
The hypothesis for the assessment of the time to first PGTCS is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05. The assumptions of proportional 
hazards will also be checked.  
The stratified HR will be calculated using the placebo arm as the reference group. The SE and 
95% CI for the HR will also be reported.  
Additionally, a KM plot for time to 1st PGTCS as well as the KM estimate for the median time 
to 1st PGTCS and 95% CI will be provided. If the median time is not estimable, then the 25th 
percentile and 95% CI will be provided. The number of 1st PGTCS will be reported by treatment 
group for the Titration Period, first 12 Weeks, and Treatment Period as well as the % of subjects 
who were censored. 
Section 8.3, the following sentence has been added: 
All seizure data recorded during the treatment period will be summarized and listed for the 
seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will 
be performed for the FAS. 
REDACTED COPY 
GT
Y
GT
=0
CO
=0
H
CT
H1
T
1
TE
ndent 
REDA
ndent 
ented
RE
ented
ed to support any marketing authorization application and any extensions or variations thereof.
en the
or va
en the
d using
exten
d using
ment, str
y ex
ment, str
ys in th
d any
ys in th
 ≥12 to
and a
 ≥12 to
from IR
n an
from IR
S is as 
plic
S is as 
: β≠0
thori
: β≠0
t variab
g aut
t variab
d by
ting
d by
ℎ
m
ℎ(
m
(𝑡
ma
𝑡,
ma
, 𝑋
ark
𝑋)
k
)
indepe
rt an
indepe
esting w
ppor
esting w
hecked
supp
hecked
will be
d to 
will be
This document cannot be us
HR w
sed
HR w
ly, a K
be u
ly, a K
GTCS a
not b
GTCS a
entile a
anno
entile a
roup
t ca
roup fo
a
fo
who w
ent
who w
Se
m
Se


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Section 8.3.1.2 Days with seizures per 28 days, the following sentence was added to the 2nd to 
last paragraph: 
PCH will be calculated for the 6-week Titration Period, first 12 weeks of the Treatment Period 
and the 24-week Treatment Period. 
Section 8.3.1.3, Seizure-free status, was modified from: 
Refer to Section 8.2.1.1 for PGTC seizure-free status. 
A subject will have seizure freedom (seizure free status=yes) for all generalized seizure types for 
the applicable Treatment Period if the subject completed the Treatment Period and reported zero 
generalized seizures for all days during the Treatment Period when the number of seizures was 
available, and had <10% of days during the Treatment Period with seizure data reported as “not 
done”. 
Has been changed to: 
A subject will have seizure-free status for PGTCS=yes for the Treatment Period if the subject 
completed the Treatment Period (with a minimum 166 days) and reported zero PGTCS or “not 
done” for all days during the Treatment Period. If the subject is exited from the study due to the 
125th event occurring reporting zero PGTCS or “not done” for all days and duration of the 
Treatment Period is < 166 days, then the subject has not achieved seizure-free status for PGTCS.  
A subject will have seizure free status=yes for all generalized seizure types for the applicable 
Treatment Period if the subject completed the Treatment Period and reported zero generalized 
seizures for all days during the Treatment Period when the number of generalized seizures was 
available, and had <10% of days during the Treatment Period with seizure data reported as “not 
done”. 
Seizure-free statuses will be calculated for 6-week Titration Period, first 12 weeks of the 
Treatment Period and the 24-week Treatment Period. 
Section 8.3.1.4, Responder status – reduction in PGTCS frequency, has been changed from: 
Response to treatment regarding PGTC seizure frequency will be based on the percent change in 
seizure frequency, calculated as described in Section 8.3.1.1. A responder is defined as a subject 
experiencing ≥50% reduction in PGTC seizure frequency per 28 days from the Combined 
Baseline to the period of interest (first 12 weeks of the Treatment Period or the 24-week 
Treatment Period).  
Has been changed to: 
Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.3.1.1 . A 50% responder is defined as a subject experiencing ≥50% 
reduction in PGTCS frequency per 28 days from the Combined Baseline to the period of interest 
(6-week Titration Period, first 12 weeks of the Treatment Period or the 24-week Treatment 
Period). A 75% responder is defined as a subject experiencing ≥75% reduction in PGTCS 
frequency per 28 days from Combined Baseline to the period of interest (6-week Titration 
Period, first 12 weeks of the Treatment Period or the 24-week Treatment Period). 
Section 8.3.1.5 PGTCS worsening, is new: 
REDACTED COPY 
ot a
Y
ot a
genera
COP
genera
reatm
D CO
reatm
riod w
TED
riod w
he Trea
ACT
he Trea
ed fo
RE
ed fo
be used to support any marketing authorization application and any extensions or variations thereof.
es for 
vari
es for 
ed zero
or v
ed zero
ures w
ons o
ures w
orted a
nsion
orted a
nt Perio
d an
nt Perio
orted ze
and
orted ze
ited fro
ion a
ited fro
all days
catio
all days
ieved s
pplic
ieved s
alized s
n ap
alized s
ment Per
ation
ment Per
when th
rizat
when th
atment
thor
atment
or 6
ting
or 6-
ng
-w
g
w
eatmen
ket
eatmen
–
m
– redu
y ma
redu
ding PG
t any
ding PG
ted as d
port 
ted as d
uction 
uppo
uction 
od of in
o sup
od of in
).
d
).
anged t
use
anged t
This document cannot 
e to trea
ot be
e to trea
bed in
not
bed in
uction 
can
uction 
(6
en
(6-
nt
-wee
nt c
wee
Peri
men
Peri
fr
m
fr


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Seizure worsening is defined as a subject experiencing ≥50% increase in PGTCS frequency per 
28 days from Combined Baseline to the period of interest (6-week Titration Period, first 12 
weeks of the Treatment Period or the 24-week Treatment Period). 
Section 8.3.1.6 Responder status – reduction in days with absence seizures, is new: 
Response to treatment for absence seizures per 28 days will be based on the percent change in 
days with absence seizures, calculated as described in Section 8.3.1.2. A 50% responder is 
defined as a subject experiencing ≥50% reduction in days with absence seizures per 28 days 
from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of 
the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in days with absence seizures per 28 days from the Prospective 
Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment 
Period or the 24-week Treatment Period). 
Section 8.3.1.7 Responder status – reduction in days with myoclonic seizures, is new: 
Response to treatment for myoclonic seizures per 28 days will be based on the percent change in 
days with myoclonic seizures, calculated as described in Section 8.3.1.2. A 50% responder is 
defined as a subject experiencing ≥50% reduction in days with myoclonic seizures per 28 days 
from the Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of 
the Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in days with myoclonic seizures per 28 days from the Prospective 
Baseline to the period of interest (6-week Titration Period, first 12 weeks of the Treatment 
Period or the 24-week Treatment Period). 
Section 8.3.2.1, Percent Change in PGTCS frequency per 28 days from Combined Baseline, is 
new: 
Descriptive statistics will be provided on the percent change in PGTCS frequency for the first 6 
weeks of (entire Titration Period), first 12 weeks of, and the entire Treatment Period.   
All PGTCS frequency per 28 days data will be listed. 
Section 8.3.2.2 Reduction in days with seizures per 28 days was changed from: 
The following data will be summarized with descriptive statistics only: 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days compared to the 
Prospective Baseline 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline 
REDACTED COPY
d). A
PY 
d). A
nic seiz
OPY
nic seiz
on Per
D CO
on Per
CS freq
ACT
CS freq
d on
R
d on
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
eks of 
var
eks of 
a subjec
or v
a subjec
pective
ons 
pective
eatmen
nsio
eatmen
es, is ne
ny e
es, is ne
on the
nd a
on the
1.2
an
1.2. A 
and
. A 
yocloni
tion 
yocloni
Titrati
icatio
Titrati
75% re
pplic
75% re
zures p
n app
zures p
riod, fir
tion 
riod, fir
quency 
thor
quency 
n the p
eting
n the p
st 12 w
arket
st 12 w
ys data 
y ma
ys data 
days w
t any
days w
be sum
ppor
be sum
with ab
o su
with ab
Baseline
d to
Baseline
hange 
use
hange 
ment Pe
t be 
ment Pe
ercent c
nno
ercent c
relativ
can
relativ

e

P
nt
P


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
the Prospective Baseline 
All seizure days data for absence and myoclonic seizures will be listed. 
Has been changed to: 
The following data will be summarized with descriptive statistics only: 
 Change in days with absence seizures per 28 days during the Treatment Period relative to the 
Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the first 12 weeks of the 
Treatment Period relative to the Prospective Baseline 
 Percent change in days with absence seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
 Change in days with myoclonic seizures per 28 days during the Treatment Period relative to 
the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the first 6 weeks of the 
Treatment Period (Titration Period) relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the first 12 weeks of the 
Treatment Period relative to the Prospective Baseline 
 Percent change in days with myoclonic seizures per 28 days during the Treatment Period 
relative to the Prospective Baseline 
All seizure days data for absence and myoclonic seizures will be listed. 
Section 8.3.2.3, Seizure-free status, was modified from: 
The following seizure-free status (yes/no) summaries will be provided: 
 Seizure-free status (yes, no) for PGTC seizures for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTC seizures for the 24-week Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
Has been changed to: 
The following seizure-free status (yes/no) summaries will be provided: 
REDACTED COPY
28 da
PY 
28 da
er 28 
TED 
er 28 
onic s
EDA
onic s
od) re
RE
od) re
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
od rela
xtens
od rela
first 6 w
d any
first 6 w
seline
and
seline
ng the 
tion 
ng the 
ays dur
appl
ays dur
days d
izati
days d
seizure
aut
seizure
elative 
ting a
elative 
clonic 
arket
clonic 
he Pros
mar
he Pros
ith myo
any
ith myo
ive Bas
ort a
ive Bas
or abse
supp
or abse
izure
d to s
izure-f
s
f-f-f-
seizur
used
seizur
e-
b
-free 
be 
free 
izure
nno
izure f
Seiz
t ca
Seiz
T
n
T


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Seizure-free status (yes, no) for PGTCS for the first 6 weeks of the Treatment Period 
(Titration Period) 
 Seizure-free status (yes, no) for PGTCS for the first 12 weeks of the Treatment Period  
 Seizure-free status (yes, no) for PGTCS for the 24-week Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the first 6 weeks of the 
Treatment Period (Titration Period) 
 Seizure-free status (yes, no) for all generalized seizure types for the first 12 weeks of the 
Treatment Period  
 Seizure-free status (yes, no) for all generalized seizure types for the 24-week Treatment 
Period  
Section 8.3.2.4, Responder status – reduction in PGTCS frequency 
The number and percentage of responders will be summarized with descriptive statistics only for 
the following periods of interest: 
 PGTC seizures during the first 12 weeks of the Treatment Period 
 PGTC seizures during the 24-week Treatment Period 
A histogram of ≥50%, ≥75% and 100% responder status for PGTC seizure frequency during the 
first 12 weeks and the 24-week Treatment Period by treatment group will be provided. 
Has been changed to: 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 
6 weeks (Titration Period) compared to the Combined Baseline 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the first 
12 weeks of the Treatment Period compared to the Combined Baseline 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency during the 
Treatment Period compared to the Combined Baseline 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 
6 weeks (Titration Period) compared to the Combined Baseline 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the first 
12 weeks of the Treatment Period compared to the Combined Baseline 
 Percentage of subjects with at least a 75% reduction in PGTCS frequency during the 
Treatment Period compared to the Combined Baseline 
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for PGTCS 
frequency during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment 
Period by treatment group will be provided. 
Section 8.3.2.5, Responder status – reduction in days with absence seizures, is new: 
The following data will be summarized with descriptive statistics only: 
REDACTED COPY 
tatus f
OPY
tatus f
d by tr
D CO
d by tr
with d
DAC
with d
t least
RE
t least
R
support any marketing authorization application and any extensions or variations thereof.
e
atmen
ion
atmen
riptive 
d any
riptive 
iod
tion
iod
for PG
n app
for PG
reatmen
tion 
reatmen
descript
utho
descript
st a 50%
ing a
st a 50%
pared t
ketin
pared t
h at lea
mar
h at lea
ent Per
ny m
ent Per
cts with
ort a
cts with
d comp
ppo
d comp
This document cannot be used to 
of subje
to su
of subje
Titratio
ed to
Titratio
entage o
e use
entage o
2 weeks
t be 
2 weeks
Perce
nno
Perce
Tr
an
Tr
A his
men
A his
fre
m
fre


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the first 6 
weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the first 
12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure days during the 
Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the first 6 
weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the first 
12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure days during the 
Treatment Period compared to the Prospective Baseline 
 A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in 
days with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 
24-week Treatment Period by treatment group will be provided. 
Section 8.3.2.6, Responder status – reduction in days with myoclonic seizures 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline  
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
first 12 weeks of the Treatment Period compared to the Prospective Baseline  
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days during the 
Treatment Period compared to the Prospective Baseline  
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
first 6 weeks of the Treatment Period (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure days during the 
Treatment Period compared to the Prospective Baseline 
Section 8.4.2.1, QOLIE-31-P variables, the following paragraph was added: 
QOLIE-31-P data, for a specific visit may have a status of Abandoned if the subject doesn’t 
complete the questionnaire. If the subject has duplicate QOLIE-31-P data for the same visit, 
where one record is deemed as Abandoned and one record is deemed as Completed, the 
Completed data will be used in the analysis and not the Abandoned record. All recorded QOLIE-
31-P data will be listed. 
Section 8.4.2.1, QOLIE-31-P variables, the following sentence was added to the 2nd paragraph: 
REDACTED COPY 
ith
Y
ith
ptive s
OPY
ptive s
educti
ED C
educti
itration
CTED
itration
a 50%
DAC
a 50%
eriod 
RED
eriod 
ting authorization application and any extensions or variations thereof.
rst 6
varia
rst 6
e
o
e
ng the f
ons 
ng the f
ys durin
exte
ys durin
er statu
nd a
er statu
riod), f
n an
riod), f
ed.
tio
ed.
yocloni
plica
yocloni
st
n
statistic
n app
atistic
ion in m
atio
ion in m
on Perio
oriza
on Perio
% reduct
auth
% reduct
compa
ng au
compa
be used to support any marke
t a 50%
ketin
t a 50%
the Pro
mark
the Pro
h at leas
any m
h at leas
atment P
rt an
atment P
cts with
uppo
cts with
the Tre
o sup
the Tre
f subje
ed to
f subje
t Period
use
t Period
annot 
.4.2.1, 
t be
.4.2.1, 
IE
an
IE-
nn
-31
nno
31
nt c
P
mplete
t can
mplete
This documen
where
ent 
where
Com
me
Com


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The means of the QOLIE-31-P total score, subscale scores and health status item score will be 
plotted by visit. 
Section 8.4.2.2, PedsQL variables, the following sentence was added: 
The means of the PedsQL subscale scores and total score will be plotted by visit. 
Section 8.4.2.3, EQ-5D-3L quality of life variables, the following sentence was added: 
The mean of the EQ-5D-3L VAS will be plotted by visit.  For the EQ-5D-3L, the percentage of 
subjects reporting a level within each dimension will be plotted in a histogram. 
Section 10.1.2, Analysis of exposure variables, the 2nd paragraph was changed from: 
Treatment duration will be summarized with the number and percentage of subjects with 
treatment duration by 3 Week categories: 1-21 days, 22–42 days, 43–63 days, 64–84 days, 
85-105 days, 106–126 days, 127-147 days, 148-168 days, and > 168 days. Furthermore, the 
subject years exposed will be presented for the entire Treatment Period. 
 
Has been changed to: 
Treatment duration will be summarized with the number and percentage of subjects with 
treatment duration by 3 Week categories: 1 to 21 days, 22 to 42 days, 43 to 63 days, 64 to 84 
days, 85 to 105 days, 106 to 126 days, 127 to 147 days, 148 to 168 days, and > 168 days. 
Furthermore, the subject years exposed will be presented for the entire Treatment Period. 
If actual dosing information is presented, the LCM dose categories for oral solution are as 
follows: 0mg/kg/day/Unknown, >0 to <4mg/kg/day, ≥4mg/kg/day to <8mg/kg/day, and ≥8mg/kg 
day.  The LCM dose categories for tablets are as follows: 0mg/day/Unknown, >0 to 
<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and ≥800mg/day. 
Section 10.2, Adverse events, the following paragraphs were modified from: 
 Incidence of other significant TEAEs (See Section 12.2 for details). 
The following summary will be presented by actual dose at onset (Placebo oral solution, 
0mg/kg/day, >0 to <4mg/kg/day, ≥4 to <8mg/kg/day, ≥8 to <12mg/kg/day, >12mg/kg/day, 
Placebo tablets, 0mg/day, >0 to <200mg/day, ≥200 to <300mg/day, ≥300 to <400mg/day and 
≥400mg/day). AEs of pediatric subjects weighing <50kg randomized to LCM but where no LCM 
was taken will be summarized in the 0mg/kg/day column; AEs of adult subjects and pediatric 
subjects weighing ≥50kg randomized to LCM but where no LCM was taken will be summarized 
in the 0mg/day column. AEs of unknown dosing are not summarized but those taken where LCM 
dose is 0mg/kg/day or 0mg/day are in the applicable column.  AEs of unknown dosing are those 
with UNK as the dose or known dosing and partial AE start or stop dates. 
 Incidence of TEAEs by actual dose at onset  
Subject data listings will be presented for the following: 
 Subjects experiencing TEAEs 
 Subjects experiencing Serious TEAEs 
 Subjects experiencing TEAEs leading to discontinuation 
REDACTED COPY
, 22 
PY 
, 22 
days, 1
COPY
days, 1
present
D CO
present
e LCM
CTED
e LCM
mg/kg
DACT
mg/kg
blets ar
REDA
blets ar
≥400
RE
≥400
e used to support any marketing authorization application and any extensions or variations thereof.
f 
r
f 
with 
sion
with 
–
e
–84 da
tens
84 da
rthermo
exte
rthermo
percenta
licati
percenta
o 42 da
pplic
o 42 da
148 to 
n ap
148 to 
nted for
tion
nted for
M dose 
oriza
M dose 
g/day, ≥
utho
g/day, ≥
re as fo
g aut
re as fo
0 to <60
ting 
0 to <60
lowing 
arke
lowing 
t TEAE
y m
t TEAE
l be pre
rt an
l be pre
/kg/day
port
/kg/day
day, >0
supp
day, >0
of ped
to s
of ped
e summ
ed to
e summ
hing ≥5
use
hing ≥5
This document cannot b
/day co
be u
/day co
0mg/kg
not b
0mg/kg
UNK a
anno
UNK a
Inci
nt c
Inci
Sub
me
Sub


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC 
and PTs. 
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in 
Section 12.5. 
Has been changed to: 
 Incidence of other significant TEAEs (See Section 12.2.1  for details) 
 Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 12.2.2 for 
details) 
To assess TEAEs related to epilepsy, PTs will be identified by ongoing manual medical review.  
The following PTs (including those identified from continuing medical review) will be 
summarized: petit mal epilepsy, myoclonus, and myoclonic epilepsy. 
 Incidence of TEAEs of interest related to epilepsy by 3-month exposure period of TEAE 
onset 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2. AEs of unknown dosing are those with no known dose or known dosing and 
partial AE start or stop dates. 
 Incidence of TEAEs by actual dose at onset  
Subject data listings will be presented for the following: 
 Subjects experiencing adverse events on the ES 
 Subjects experiencing Serious TEAEs on the SS 
 Subjects experiencing TEAEs leading to discontinuation on the SS 
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC 
and PTs. 
A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in 
Section 12.5. 
Section 10.3, clinical laboratory evaluations, the following paragraphs were modified from: 
Markedly abnormal (MA) values indicate significant deviations from the expected range of 
age-appropriate values. Marked laboratory abnormalities observed post-Baseline during the 
Treatment Period but not present at Baseline are considered treatment emergent. MA values for 
serum chemistry and hematology laboratory parameters are provided in UCB conventional 
(traditional) and standard units. The definition of MA values for hematology and chemistry 
values can be found in Section 12.3. 
The number and percentage of subjects with at least 1 treatment-emergent markedly abnormal 
(TEMA) value will be summarized by visit for each laboratory parameter (hematology and 
clinical chemistry) with markedly abnormal criteria specified. TEMA values are those that are 
observed during the defined treatment period at scheduled or unscheduled visits and were not 
observed at any visit during the Baseline period. A table summarizing the number of subjects 
meeting the potential drug induced liver injury criteria will also be presented. 
REDACTED COPY 
llowin
D CO
llowin
n the E
CTE
n the E
AEs on
EDA
AEs on
adin
RE
adin
used to support any marketing authorization application and any extensions or variations thereof.
for 
va
for 
cal rev
ions
cal rev
ill be 
ensio
ill be 
e perio
any 
e perio
dosing 
n an
dosing 
n dose o
ation
n dose o
ng:
ati
ng:
ES
ho
ES
n the SS
auth
n the SS
ng to di
ting
ng to di
showi
arke
showi
quired 
t any
quired 
labora
supp
labora
mal (MA
d to 
mal (MA
e value
sed
e value
This document cannot be 
Period b
be us
Period b
hemistry
ot be
hemistry
iona
nnot
ional) 
ot
l) 
ues can
can
ues can
The
ent
The n
t
n
(TE
me
(TE


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The NCI CTC criteria can be found in Section 12.4 .  The number and percentage of subjects 
with treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher (hematology 
and clinical chemistry) will be summarized by treatment group, laboratory parameter, and visit 
for the Treatment Period. Treatment emergent abnormalities of grade 2 or higher are those that 
were observed during the Treatment Period at scheduled visits and not reporting a grade 2 or 
higher abnormality during the Baseline Period.  
Has been changed to: 
Treatment-emergent markedly abnormal (TEMA) values indicate significant deviations from the 
expected range of age-appropriate values. TEMA laboratory abnormalities results are those that 
are observed post-Baseline during the Treatment Period but are not present at Baseline. TEMA 
values for serum chemistry and hematology laboratory parameters are provided in UCB 
conventional (traditional) and standard units. The definition of MA values for hematology and 
chemistry values can be found in Section 12.3. The number and percentage of subjects with at 
least 1 TEMA value will be summarized by scheduled visit, Last Visit, minimum and maximum 
post-Baseline values obtained during the Treatment Period for each laboratory parameter 
(hematology and clinical chemistry) with markedly abnormal criteria specified. TEMA values 
are those that are observed during the defined treatment period at scheduled or unscheduled visits 
and were not observed at any visit during the Baseline period.  
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria will also be presented. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC) 
can be found in Section 12.4. The number and percentage of subjects with treatment emergent 
laboratory abnormalities of NCI CTC grade 2 or higher (hematology and clinical chemistry) will 
be summarized by treatment group, laboratory parameter, and visit for the Treatment Period. 
Treatment emergent abnormalities of grade 2 or higher are those that were observed during the 
Treatment Period at scheduled visits and not reporting a grade 2 or higher abnormality during the 
Baseline Period. All treatment emergent laboratory abnormalities of NCI CTC grade 2 or higher 
will be presented in a subject number listing. 
Section 10.4.1, Vital Signs, the following sentence was inserted: 
All TEMA results summarized will be presented in a subject number listing. 
Section 10.4.2.2, Analysis of ECG parameters, was modified from: 
Absolute values and change from Baseline of ECG parameters will be summarized using 
descriptive statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-
Baseline values obtained during the Treatment Period, and in each of the age groups. 
Unscheduled ECG assessments during the study will not be presented in by-visit summaries, but 
will be considered when determining the last visit, minimum, and maximum post-Baseline 
values during the Treatment Period. If repeat measurements are taken at a particular visit, then 
the average value is used in summaries and the original values are listed. 
The number and percentage of subjects who met each of the treatment-emergent abnormality 
criteria specified in Section 12.3.4 will be presented within the specified age groups. For each 
parameter, the number and percentage of subjects with an abnormality (ie subjects who met any 
of the criteria specific to their age) will be summarized for heart rate, PR interval and QRS 
REDACTED COPY
the p
OPY 
the p
inolog
TED 
inolog
and pe
ACTE
and pe
rade 2 
DAC
rade 2 
aborat
RED
aborat
gr
R
gr
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.
m the
var
m the
ose that
or v
ose that
e. TEM
ons 
e. TEM
UCB
sio
UCB
ematolo
xten
ematolo
f subje
y ext
f subje
nimum
any 
nimum
oratory
nd a
oratory
a speci
n an
a speci
schedu
tion 
schedu
potentia
app
potentia
gy Crite
izati
gy Crite
ercenta
horiz
ercenta
2 or hig
auth
2 or hig
tory pa
g au
tory pa
rade 2 o
eting
rade 2 o
and no
arke
and no
mergent 
ma
mergent 
number 
any m
number 
 the fo
ort a
 the fo
mmarize
supp
mmarize
Analysis
d to s
Analysis
es and 
used
es and 
statisti
be u
statisti
e values
ot b
e values
heduled
anno
heduled
ll be co
t can
ll be co
values
ent 
values
the 
me
the 


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
interval. Subject numbers for those with treatment-emergent abnormal ECG values will be listed 
by abnormality criteria. Treatment-emergent abnormal results for a subject are those that are 
observed during the defined treatment period at scheduled or unscheduled visits and were not 
observed at any visit during the Baseline period. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
Has been changed to 
For quantitative ECG measurements (heart rate, PR interval, QRS interval, QT interval, RR 
Interval and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
statistics of the actual values and change from Baseline will be summarized using descriptive 
statistics for the scheduled visits, overall, Last Visit, minimum and maximum post-Baseline 
values obtained during the Treatment Period, and in each of the TEMA ECG criteria age 
categories. Last visit is the value from the last post baseline visit during the Treatment Period. 
Repeated or unscheduled ECG assessments during the study will not be presented in by-visit 
summaries, but will be considered when determining the last visit, minimum, and maximum 
post-Baseline values during the Treatment Period. If repeat measurements are taken at a 
particular visit, then the average value is used in summaries and the original values are listed. 
The number and percentage of subjects who met each of the TEMA criteria specified in 
Section 12.3.4 will be presented within the specified age groups. For each parameter, the number 
and percentage of subjects with an abnormality (ie subjects who met any of the criteria specific 
to their age) will be summarized for heart rate, PR interval, QRS interval, QT interval and 
corrected QT intervals by scheduled visit and Last Visit during the Treatment Period. Repeated 
or unscheduled ECG assessments during the study will not be presented in by-visit summaries, 
but will be considered when determining the last visit values during the Treatment Period. 
Subject numbers for those with TEMA ECG values will be listed by abnormality criteria. TEMA 
results for a subject are those that are observed during the defined treatment period at scheduled 
or unscheduled visits and were not observed at any visit during the Baseline period. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
Section 10.4.4.1, New Seizure Type, was modified from: 
The incidence of new seizure types i.e. those not experienced in the Prospective Baseline but 
experienced during the Treatment Period as recorded in the diary will be summarized. 
Has been changed to: 
The number and percentage of subjects with seizure types present or absent in the Treatment 
Period vs whether the seizure type was present or absent in Combined Baseline will be tabulated. 
The number and percentage of subjects with seizure types present or absent in the Treatment 
Period vs whether the seizure type was present or absent in Seizure History (including Combined 
Baseline) will be tabulated. 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period with absence or myoclonic seizure type, respectively, 
indicated by the Seizure History Classification but not experienced in the Combined Baseline as 
recorded in the diary will be summarized.  
REDACTED COPY
of th
PY 
of th
d age g
OPY
d age g
ie subj
D CO
ie subj
, PR i
TED 
, PR i
nd La
ACTE
nd La
g the s
DAC
g the s
ning th
RED
ning th
A
R
A E
R
E
ng authorization application and any extensions or variations thereof.
R 
o
R 
mmary 
ns or
mmary 
scriptiv
sions
scriptiv
t
e
t-Basel
ensi
Basel
riteria 
exte
riteria 
Treatm
ny e
Treatm
present
d any
present
nimum
and 
nimum
ements
on a
ements
the ori
atio
the ori
 TEMA
pplic
 TEMA
groups
n app
groups
bjects w
tion 
bjects w
interva
izati
interva
ast Visi
horiz
ast Visi
study w
auth
study w
he last 
ng au
he last 
This document cannot be used to support any market
ECG v
eting
ECG v
e observ
arke
e observ
ot obser
ma
ot obser
uantita
t any
uantita
Seizure
supp
Seizure
new sei
d to s
new sei
ring the
sed 
ring the
hanged
be u
hanged
mber a
not 
mber a
od vs w
ann
od vs w
The num
nt ca
The num
Perio
men
Perio
B
m
B


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period but not experienced in the Combined Baseline or indicated 
in Seizure History Classification will also be summarized. 
The number and percentage of subjects with new absence or myoclonic seizure types in the 
Treatment Period, with absence or myoclonic, respectively, indicated by the Seizure History 
Classification but not experienced in the Combined Baseline Period or subjects with ≥50% 
worsening in days with absence or myoclonic seizures, respectively, will be summarized.  
Section 10.4.8.2, Analysis of Achenbach variables, the following sentence was added: 
The means of the calculated T-score will be plotted by visit. 
Section 10.4.9.1, BRIEF-P scores, the following sentence was added: 
The means of the BRIEF-P assessment data will be plotted by visit. 
Section 10.4.9.2, BRIEF scores, the following sentence was added: 
The means of the BRIEF assessment data will be plotted by visit. 
Section 12.2.1, Other Significant AEs, the table has been update with the latest criteria. Liver 
injury related criteria has been moved to the table in Section 12.2.2. 
Section 12.2.2, AEs for Potentially Drug Induced Liver Injury, this table is newly added. 
Section 12.3.4, Table 11, ECGs – Abnormality Criteria, categories for QT, QTc(F), and QTc(B) 
have been updated. 
Section 12.5, Registry Required Tables, the list of tables required has been updated. 
Section 12.6, Additional Subgroups to be programmed in ADSL, is newly added.  
13.4 
Amendment 4 
13.4.1 
Rationale for the amendment 
A Type C Meeting request was submitted to FDA on Dec 12, 2018 to IND 057939 Sequence No. 
1268 cross-reference IND 068407 and IND 073809.  Included in the package was the SP0982 
SAP Amendment 3.  A Type C Written Response dated 4Mar2019 was received which prompted 
this amendment.  Other items were clarified or added. 
13.4.2 
Modification and changes 
At the request of FDA, the following items were added or clarified: 
 New sensitivity analysis of the primary endpoint was added involving dropouts after 1st 
PGTCS 
 Clarification regarding the checking of the proportional hazards assumption was added 
 Variables and analyses involving reduction and increase in seizure frequency, responder 
status and worsening for absence and myoclonic seizures were added 
 Analyses involving post-treatment vital sign and QTc measurements were added 
The following items were clarified: 
 Stratum pooling algorithm 
REDACTED COPY
r Inj
PY 
r Inj
iteria,
COP
iteria,
e list of
ACTE
e list of
be pro
EDA
be pro
ed to support any marketing authorization application and any extensions or variations thereof.
ith the 
on a
ith the 
2.2.2.
catio
2.2.2.
ury, this
pplic
ury, this
, catego
on a
, catego
of table
horiz
of table
ogramm
aut
ogramm
amend
arke
amend
submit
ny m
submit
8407 a
t any
8407 a
ype
po
ype C
ort
C W
r items
upp
r items
difica
d to s
difica
This document cannot be us
of FDA
used
of FDA
ew sens
t be 
ew sens
PGTC
not 
PGTC

c

Cl
an
Cl

n



UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 Algorithm for identifying rescue medications 
The following items were added: 
 A new listing of rescue medications 
 References specific to the Cox proportional hazards analysis 
 Additional analyses using the Development subgroup 
 New variable identifying Asian sites 
13.4.2.1 
Specific changes 
The information below was revised from: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Amendment #2 
14 Mar 2017 
Amendment #3 
4 Jan 2019 
Has been revised to: 
SAP/Amendment Number Date 
Final SAP 
09 Aug 2016 
Amendment #1 
24 Feb 2017 
Amendment #2 
14 Mar 2017 
Amendment #3 
4 Jan 2019 
Amendment #4 
26 Mar 2019 
Section 3.2.5, the 3rd paragraph was changed from: 
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the 
CRF, although rescue benzodiazepines will also be identified programmatically as any 
benzodiazepines taken intermittently for 1 day at any frequency. Rescue medication is defined as 
the intermittent use of benzodiazepines (limited to 2 doses per 28 days) for epilepsy indications 
if established at least 28 days prior to Visit 1.  Lifetime benzodiazepines are defined as 
benzodiazepines taken in the subject’s history and stopped at least 28 days prior to Visit 1. 
Has been revised to: 
Benzodiazepines taken for rescue will be flagged with “RESCUE” in the indication field on the 
CRF, although rescue AEDs will also be identified programmatically as any AED taken 
intermittently for 1 or 2 days, at any frequency, with an epilepsy or seizure related indication. 
Rescue medication is defined as the intermittent use of benzodiazepines (limited to 2 doses per 
28 days) for epilepsy indications if established at least 28 days prior to Visit 1.  Lifetime 
benzodiazepines are defined as benzodiazepines taken in the subject’s history and stopped at 
least 28 days prior to Visit 1. 
Section 3.9, the changes to protocol-defined analyses has been changed from: 
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for 
PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. 
REDACTED COPY 
2019
DAC
2019
chan
RE
chan
used to support any marketing authorization application and any extensions or variations thereof.
nged fr
ting 
nged fr
ll be fla
arke
ll be fla
pin
m
pines w
ma
es w
ttently 
any m
ttently 
odiazep
rt an
odiazep
days pr
ppor
days pr
n in the
supp
n in the
to:
d t
to:
nes tak
use
nes tak
This document cannot be
ugh res
be u
ugh res
tently f
ot b
tently f
ue med
nno
ue med
8 days) 
t ca
8 days) 
benzo
ment 
benzo
lea
me
lea


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The analysis of the key secondary endpoint has been clarified to assess the seizure-free rate using 
an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates within each 
stratum. The extended Mantel-Haenszel technique is a randomization-based nonparametric 
method that provides a more robust method to assess seizure freedom. 
Has been revised to: 
For the key secondary efficacy variable, the Protocol Section 4.1.2 says that seizure freedom for 
PGTCS during the 24-week Treatment Period, will be estimated using Kaplan-Meier analysis. 
Also, Protocol Section 13.3.2.1 states that the key secondary efficacy variable will be analyzed in 
the same manner as the primary endpoint using the FAS and that the percentage of seizure-free 
subjects at 24 weeks will be estimated from the KM estimates of time to first seizure. The 
analysis of the key secondary endpoint has been clarified to assess the seizure-free rate at 24 
weeks using an extended Mantel-Haenszel technique which combines Kaplan-Meier estimates 
within each stratum. The extended Mantel-Haenszel technique is a randomization-based 
nonparametric method that provides a more robust method to assess seizure freedom. Thus, the 
key secondary efficacy variable will not be analyzed in the same manner as the primary efficacy 
endpoint; the other secondary efficacy variable, time to first PGTCS, will be analyzed in the 
same manner as the primary efficacy endpoint. 
Section 4.9, the stratum pooling algorithm has been updated from: 
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age 
at informed consent categories will be summed.   
 If 2 of the age at informed consent categories combined have < 3 total events, then all age 
categories are combined for the analysis.  
 If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events 
or less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥18 years of age is the category with the smallest number of events that are 2 events or 
less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥12 and <18 years of age is the category with the smallest number of events that are 2 
events or less, it should be combined with the strata with the 2nd smallest number of events. 
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to 
determine stratum pooling. 
Has been revised to: 
For the subjects with Baseline PGTCS frequency ≤2 per 28 days, the events for each of the 3 age 
at informed consent categories will be summed.  For categories with < 3 total events, the 
combining should occur as follows: 
 If 2 of the age at informed consent categories combined have < 3 total events, then all age 
categories are combined for the analysis.  
 If ≥4 to <12 years of age is the category with the smallest number of events that are 2 events 
or less, it should be combined with the ≥12 and <18 years of age category. 
REDACTED COPY 
Y
2 per 2
OPY
2 per 2
ories c
CTED
ories c
sis. 
DAC
sis. 
tegory
RED
tegory
h t
R
h t
any marketing authorization application and any extensions or variations thereof.
zed in
var
zed in
e-
o
-free
or v
free
The
ns
The
rate at 
sio
rate at 
Meier es
ten
Meier es
ation
y ext
ation-
x
-b
xt
b
re freed
any 
re freed
er as th
nd a
er as th
, will b
n an
, will b
from:
plica
from:
28 day
n app
28 day
combin
oriza
combin
y with 
g au
y with 
the ≥12
eting
the ≥12
ory with
mark
ory with
with the
y m
with the
This document cannot be used to support 
age is t
rt an
age is t
ld be c
port
ld be c
Baseli
sup
Baseli
poolin
d to 
poolin
sed to:
used
sed to:
ubjects 
t be 
ubjects 
rmed co
not 
rmed co
mbining
cann
mbining

e

If 2
nt 
If 2


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
 If ≥18 years of age is the category with the smallest number of events that are 2 events or 
less, it should be combined with the ≥12 and <18 years of age category. 
 If ≥12 and <18 years of age is the category with the smallest number of events that are 2 
events or less, it should be combined with the strata with the 2nd smallest number of events. 
Repeat the algorithm for combining strata for the subjects who did not have events if there are 
categories with < 3 total non-events. 
For the subjects with Baseline PGTCS frequency >2 per 28 days, repeat the same exercise to 
determine stratum pooling for both events and non-events. 
For each primary efficacy endpoint sensitivity analysis which uses stratum pooling, the pooling 
of the strata should be reassessed since the event distribution for the specific sensitivity may be 
different than the distribution in the primary efficacy endpoint analysis.  
Section 6.6, the following sentence was added at the end of this section: 
AEDs flagged as rescue medications will also be listed in subject data listings. 
Section 8.1.2, the 2nd paragraph was revised from: 
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
) 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The 
assumptions of proportional hazards will also be checked. 
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. 
The SE and 95% CI for the HR will also be reported. 
Has been revised to: 
The hypothesis for the assessment of primary efficacy variable (time to event) is as follows: 
H0: β=0 
Versus 
H1: β≠0 
where β is the coefficient of an independent variable representing the treatment effect in the 
model. The hazard function is represented by 
REDACTED COPY 
H
TE
H1
TE
1: β≠
TED 
: β≠
ent var
DACT
ent var
nted by
REDA
nted by
y marketing authorization application and any extensions or variations thereof.
he pooli
ons 
he pooli
ivity m
nsio
ivity m
istings.
d an
istings.
(time t
catio
(time t
≠0
riz
≠0
riable r
utho
riable r
y
𝑋
k
𝑋)
ke
)
o support any
=
et
= ℎ
depende
any m
depende
ng will
rt an
ng will
nal haz
ppor
nal haz
ratio (H
o sup
ratio (H
t cannot be used 
CI for t
d to 
CI for t
sed to:
use
sed to:
thesis f
t be
thesis f
This document 
ersus
nt ca
ersus


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
𝑝
𝑗=1
) 
where xj is the collection of independent variables and h0(t) is the baseline hazard at time t. For 
the null hypothesis, the testing will be 2-sided with an α=0.05; the p-value will be presented. The 
assumptions of proportional hazards will also be assessed graphically (e.g. log (log S) plot vs 
time, empirical score process) for any departure; non-proportionality is not expected when using 
a stratified Cox model. Depending on the departure from proportional hazards, a sensitivity 
analysis (e.g. piecewise proportional hazards, time-varying coefficient, restricted mean survival) 
may be performed. 
The stratified hazard ratio (HR) will be calculated using the placebo arm as the reference group. 
The 95% CI for the HR will also be reported. 
Section 8.1.4, the following sensitivity analysis was clarified from: 
 Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events) through 
each subject’s first 166 days of treatment, on the FAS. 
Was revised to: 
 Repeat the primary efficacy analysis using all PGTCS data (ie, all reported events after the 
date of the 125th event) through each subject’s first 166 days of treatment, on the FAS. 
Section 8.1.4, the following sensitivity analysis was added: 
 Repeat the primary efficacy analysis using the FAS, except all subjects who prematurely 
discontinue after their 1st PGTCS will be analyzed as treatment failures. 
Section 8.2.2.2, the following sentence was clarified from: 
The assumptions of proportional hazards will also be checked.  
Was revised to: 
The assumptions of proportional hazards will also be checked using the same approach as for the 
primary efficacy endpoint. 
Section 8.3, was revised from: 
All seizure data recorded during the treatment period will be summarized and listed for the 
seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will 
be performed for the FAS. 
Was revised to: 
All seizure data recorded during the treatment period will be summarized and listed for the 
seizure related other efficacy variables. Analyses of seizure-related other efficacy variables will 
be performed for the FAS. For absence seizure analyses, this analysis population will be further 
restricted to the subset of subjects who reported a history of absence seizures or reported absence 
seizures during baseline or the 24-week treatment period.  For myoclonic seizure analyses, this 
analysis population will be further restricted to the subset of subjects who reported a history of 
myoclonic seizures or reported myoclonic seizures during baseline or the 24-week treatment 
period. 
REDACTED COPY 
TCS 
PY
TCS 
irst 16
OPY
irst 16
was ad
D C
was ad
ing th
CTE
ing th
ll be a
DAC
ll be a
ce wa
RE
ce wa
ed to support any marketing authorization application and any extensions or variations thereof.
g 
i
g 
rvival)
or va
rvival)
erence 
nsio
erence 
eported
nd a
eported
ata (ie, 
pplic
ata (ie, 
66 days
n app
66 days
added:
ation
added:
he FAS
horiz
he FAS
analyze
utho
analyze
as clarif
ing a
as clarif
ards wi
rket
ards wi
onal haz
t any
onal haz
p
ed from
supp
ed from
ecorded
d to 
ecorded
This document cannot be us
other e
sed
other e
ed for th
be us
ed for th
ised to
ot b
ised to
seizure
cann
seizure
seizure 
nt c
seizure 
be pe
men
be pe
re
m
re


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Section 8.3.1.1, the following text was removed: 
The percent change in log-transformed (PCHL) PGTCS frequency per 28 days from the 
Combined Baseline (CB) to the appropriate analysis period (T) is defined as: 
PCHL = [(ln(SFT) – ln(SFCB)) / ln(SFCB)] x 100 
where SFT corresponds to the 28-day PGTCS frequency during the relative period and SFCB 
corresponds to the 28-day Combined Baseline PGTCS frequency. 
Section 8.3.1.2, paragraphs 3, 4, and 5 were revised from: 
The percent change (PCH) in days with absence seizures per 28 days from the appropriate 
Baseline (B) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DB) / DB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DB corresponds to the number of days with absence seizures per 28 days 
during the Baseline Period. If DB is zero, then PCH will be missing and any such subjects will 
be excluded from the percent change summary. PCH will be calculated for the 6-week Titration 
Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period. 
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from 
the appropriate Baseline Period will be calculated. 
Were revised to: 
The percent change (PCH) in days with absence seizures per 28 days from the Prospective 
Baseline (B) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DB) / DB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DB corresponds to the number of days with absence seizures per 28 days 
during the Prospective Baseline Period. If DB is zero, then PCH will be missing and any such 
subjects will be excluded from the percent change summary. PCH will be calculated for the 6-
week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment Period. 
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from 
the Prospective Baseline Period will be calculated. 
Section 8.3.1.8, Variable: Days with absence and myoclonic seizures – worsening is new: 
Safety of the LCM treatment will be based on the percent change in days with absence seizure 
per 28 days and days with myoclonic seizure per 28 days. The increase in days with absence 
seizures per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, 
>50 to 75%, and >75% for the Treatment Period. The increase in days with myoclonic seizures 
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 
75%, and >75% for the Treatment Period. 
Section 8.3.1.9, Variable: Absence and myoclonic seizure frequencies per 28 days is new: 
In order to account for potential differences in the durations of the study periods for individuals, 
absence and myoclonic seizure data will be normalized to 28 days. 
REDACTED COPY 
th 
Y
th 
ence se
CTED
ence se
eriod 
DACT
eriod 
marketing authorization application and any extensions or variations thereof.
ate
s
ate
ays d
y ex
ays dur
x
ur
eizures 
any
eizures 
d any s
nd a
d any s
ted for
n an
ted for
reatme
tion
reatme
oclonic
plica
oclonic
seizures
oriza
seizures
(T) is 
utho
(T) is 
of days
ketin
of days
 to the 
mark
 to the 
not be used to support any 
Period
y m
Period
m the p
t any
m the p
t 12 we
ort a
t 12 we
change
supp
change
eline P
to su
eline P
 Variab
sed 
 Variab
he LCM
be u
he LCM
ays and
ot b
ays and
This document can
res per 
anno
res per 
0 to 75
t can
0 to 75
per 28
ent 
per 28
75%
me
75%


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The 28-day absence SF will be calculated for the Prospective Baseline and Treatment Periods as: 
SF =  
(# absence seizures in the relative period/# days in relative period with evaluable absence seizure 
data)*28 
The PCH in Absence seizure frequency per 28 days from the Prospective Baseline (PB) to the 
appropriate analysis period (T) is defined as: 
PCH = [(SFT – SFPB) / SFPB] x 100 
where SFT corresponds to the 28-day absence seizure frequency during the relative period and 
SFPB corresponds to the 28-day Prospective Baseline absence frequency; if subjects had no 
absence seizures in Prospective Baseline, then PCH cannot be calculated. PCH is calculated for 
6-week Titration Period, first 12 weeks of the Treatment Period and the 24-week Treatment 
Period. 
SF and PCH are calculated for subjects with myoclonic seizures using the same algorithm 
described above. 
Section 8.3.1.10, Variable: Responder status – reduction in absence and myoclonic seizure 
frequencies is new: 
Response to treatment will be based on the percent change in absence and myoclonic seizure 
frequencies, calculated as described in Section 8.3.1.9. A 50% responder is defined as a subject 
experiencing ≥50% reduction in absence (or myoclonic) seizure frequency per 28 days from the 
Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the 
Treatment Period or the 24-week Treatment Period). A 75% responder is defined as a subject 
experiencing ≥75% reduction in absence (or myoclonic) seizure frequency per 28 days from 
Prospective Baseline to the period of interest (6-week Titration Period, first 12 weeks of the 
Treatment Period or the 24-week Treatment Period). 
Section 8.3.1.11, Variable: Absence and myoclonic seizure frequency - worsening is new: 
Safety of the LCM treatment will be based on the percent change in absence seizure frequency 
per 28 days and myoclonic seizure frequency per 28 days. The increase in absence seizure 
frequency per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, 
>50 to 75%, and >75% for the Treatment Period. The increase in myoclonic seizure frequency 
per 28 days from Prospective Baseline will be categorized as >0 to 25%, >25 to 50%, >50 to 
75%, and >75% for the Treatment Period. 
Section 8.3.2.5, the following last bullet was changed from: 
A histogram of ≥50%, ≥75%, and 100% (seizure freedom) responder status for reduction in days 
with absence seizures during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week 
Treatment Period by treatment group will be provided. 
Was revised to: 
A histogram of ≥50% and ≥75% responder status for reduction in days with absence seizures 
during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by 
treatment group will be provided. 
REDACTED COPY
hange
OPY 
hange
.1.9
CO
.1.9
OP
myoclo
ED C
myoclo
st (6
CTE
st (6-
TE
-w
E
w
ent Pe
DAC
ent Pe
nce (or
REDA
nce (or
in
RE
inte
RE
te
e used to support any marketing authorization application and any extensions or variations thereof.
od and
s or
od and
had no
ions
had no
calcu
ensio
calcula
o
la
k Trea
xten
k Trea
he same
d an
he same
nce and
ation
nce and
e in abs
app
e in abs
A 50%
ion a
A 50%
onic) se
zatio
onic) se
week T
oriza
week T
eriod). 
utho
eriod). 
r myoc
g au
r myoc
erest (6
ting
erest (6
atment 
rket
atment 
nce and
y ma
nce and
will be
t any
will be
c seizur
port 
c seizur
from Pr
uppo
from Pr
5% for 
o sup
5% for 
Prospe
d to
Prospe
% for th
used
% for th
This document cannot b
3.2.5, th
be u
3.2.5, th
ogram 
nnot
ogram 
h absen
can
h absen
Treatm
ent c
Treatm
Wa
me
Wa


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Section 8.3.2.6, the following bullet was inserted: 
A histogram of ≥50% and ≥75% responder status for reduction in days with myoclonic seizures 
during the first 6 weeks (Titration Period), first 12 weeks, and the 24-week Treatment Period by 
treatment group will be provided. 
Section 8.3.2.7, Analysis: Percent change in absence and myoclonic seizure frequency per 28 
days from Prospective Baseline is new: 
Descriptive statistics will be provided on the percent change in absence and myoclonic seizure 
frequencies for the first 6 weeks of (entire Titration Period), first 12 weeks of, and the entire 
Treatment Period.   
All absence and myoclonic seizure frequency per 28 days data will be listed. 
Section 8.3.2.8, Analysis: Responder status – reduction in absence and myoclonic seizure 
frequency is new: 
The following data will be summarized with descriptive statistics only: 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in absence seizure frequency during 
the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure frequency 
during the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency 
during the first 6 weeks (Titration Period) compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency 
during the first 12 weeks of the Treatment Period compared to the Prospective Baseline 
 Percentage of subjects with at least a 75% reduction in absence seizure frequency during 
the Treatment Period compared to the Prospective Baseline 
Percentage of subjects with at least a 75% reduction in myoclonic seizure frequency during the 
Treatment Period compared to the Prospective Baseline 
REDACTED COPY 
ctio
Y
ctio
mpare
OPY
mpare
% redu
D CO
% redu
eriod c
TED
eriod c
ast a 50
DAC
ast a 50
e Trea
REDA
e Trea
l
R
l
marketing authorization application and any extensions or variations thereof.
re 
a
re 
re
or
re
nic seiz
exten
nic seiz
nce seiz
n an
nce seiz
pective 
ation
pective 
in myo
plica
in myo
ed to th
app
ed to th
uction 
ation
uction 
compa
rizat
compa
0% red
utho
0% red
atment 
g au
atment 
east 
ketin
east a 5
ing
a 5
red to t
arke
red to t
t be used to support any
with at l
ny m
with at l
Period
t any
Period
bjects w
ppo
bjects w
eks (Tit
sup
eks (Tit
ge of su
ed to
ge of su
the firs
used
the firs
rcentag
t be 
rcentag
This document canno
the fir
not 
the fir

c

Pe
an
Pe


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Section 10.2, the following TEAE summary was added: 
 Incidence of common TEAEs for EU labeling (above or equal to reporting threshold of 1% 
(prior to rounding) of subjects in the total LCM group) and occurring >1% than in the 
placebo group 
Section 10.4.4.4, Increase in absence seizure frequency is new: 
Response to treatment regarding absence seizures will also be based on the percent change in the 
absence seizure frequency per 28 days, calculated as described in Section 8.3.1.9 . The number 
and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% to 75%, 
and >75% in absence seizure frequency per 28 days during the Treatment Period compared to the 
Prospective Baseline Period will be presented.  
Section 10.4.4.5, Increase in myoclonic seizure frequency is new: 
Response to treatment regarding myoclonic seizures will also be based on the percent change in 
the myoclonic seizure frequency per 28 days, calculated as described in Section 8.3.1.9. The 
number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, >50% 
to 75%, and >75% in myoclonic seizure frequency per 28 days during the Treatment Period 
compared to the Prospective Baseline Period will be presented.  
References were revised from: 
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 
1972;34(2):187-220.  
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of 
lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. 
Epilepsia. 2007;48(S6):77-78.  
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the 
analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301. 
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered 
analysis of variance. Biometrika. 1976;63:655-60. 
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive 
lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-
controlled study. Epilepsy & Behavior. 2010; 19: 352-8. 
Was revised to the following: 
Allison, PD. Survival Analysis Using SAS®: A Practical Guide. 2nd ed. Cary: SAS Institute; 
2010 
Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, et al. Adjunctive 
lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-
controlled study. Epilepsy & Behavior. 2010; 19: 352-8. 
Collett D. Modelling survival data in medical research. 3rd ed. London: CRC Press; 2015 
Cox DR. Regression models and life-tables. J R Stat Soc Series B Methodol. 
1972;34(2):187-220.  
REDACTED COPY 
at Soc
COP
at Soc
Landin
CTE
Landin
ects w
DAC
ects w
R
R
R
ting authorization application and any extensions or variations thereof.
e
a
e
er 
a
er 
75%,
or va
75%,
ared to 
ns or
ared to 
he perce
ny ex
he perce
ecti
an
ection
ny
on
5%, >2
and 
5%, >2
ing the 
on a
ing the 
c Serie
n ap
c Serie
ngham 
horiz
ngham 
with pri
utho
with pri
e used to support any marke
Rando
keting
Rando
Methods
arke
Methods
. On cl
ny m
. On cl
rika. 19
t any
rika. 19
hukla R
ppor
hukla R
imary g
supp
imary g
pilepsy
to s
pilepsy
the fol
sed
the fol
This document cannot b
D. Surv
be u
D. Surv
on V, D
cann
on V, D
amotri
nt c
amotri
cont
men
cont


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
French JA, Temkin NR, Hammer AE, VanLandingham KE. Time to nth seizure analysis of 
lamotrigine as adjunctive therapy in subjects with primary generalized tonic-clonic seizures. 
Epilepsia. 2007;48(S6):77-78.  
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods for the 
analysis of multicentre trials. Stat Methods Med Res. 2005;14:281-301. 
Marcus R, Peritz E, Gabriel KR. On closed testing procedure with special reference to ordered 
analysis of variance. Biometrika. 1976;63:655-60. 
SAS®/Stat 9.4: User’s Guide. Cary: SAS Institute Inc; 2015 
Section 12.3.3, Table 10 was updated with the post-treatment vital sign abnormalities requested 
in the Type C Written Response. 
Section 12.3.4, Table 11 was updated with the post-treatment QTc abnormalities requested in the 
Type C Written Response. 
Appendix 5: Registry Required Tables was revised from: 
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or 
Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the 
CSR required Tables. 
Disposition and Discontinuation Reasons by Development 
Discontinuation due to AEs 
Demographics by Development 
Baseline Characteristics by Development 
LCM Overall Exposure by Development 
Study Medication Duration by Development 
Incidence of TEAEs by Development – Overview 
Incidence of TEAEs by Development 
Incidence of Serious TEAEs by Development 
Incidence of Non-serious TEAEs  
Incidence of TEAEs by Relationship and Development 
Incidence of TEAEs Leading to Discontinuation by Development 
Incidence of Serious TEAEs by Relationship  
Incidence of Non-serious TEAEs by Relationship  
Incidence of Fatal TEAEs by Relationship  
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects 
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship 
Was revised to: 
REDACTED COPY
pment
OPY 
pment
nt
D
nt
ment
RE
ment
used to support any marketing authorization application and any extensions or variations thereof.
reques
ons o
reques
es requ
exten
es requ
, clinic
n an
, clinic
produc
ation
produc
t
opmen
arket
opmen
ment 
y ma
ment –
elopme
t any
elopme
AEs by
ppor
AEs by
rious T
o sup
rious T
AEs by
ed t
AEs by
This document cannot be 
f TEAE
be us
f TEAE
ce of S
not b
ce of S
dence 
cann
dence 
Incide
ent 
Incide
In
m
In


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
The following is the list of tables required for Article 41 (EudraCT), clinicaltrials.gov and/or 
Article 46 (European Pediatric Regulation). These tables will be produced at the same time as the 
CSR required Tables. 
Disposition and Discontinuation Reasons by Development 
Discontinuation due to AEs 
Demographics by Development 
Baseline Characteristics by Development 
ILAE Seizure Classification History by Development 
Classification of Epileptic Syndrome by Development 
AEDs and Benzodiazepines at Study Entry by Development 
Summary of Time to Second PGTCS by Development 
Proportion of Subjects with Seizure Freedom at Day 166 by Development 
PGTCS Frequency Observed Results and Percent Changes from Combined Baseline by 
Development 
Absence Seizure Frequency Observed Results and Percent Changes from Prospective Baseline 
by Development 
Myoclonic Seizure Frequency Observed Results and Percent Changes from Prospective Baseline 
by Development 
Responder Status for PGCTS by Development 
Responder Status for Absence Seizure Frequency by Development 
Responder Status for Myoclonic Seizure Frequency by Development 
Seizure-free Status for PGTCS by Development 
Days with Absence Seizures Observed Results and Percent Changes from Prospective Baseline 
by Development 
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective 
Baseline by Development 
Increase in Absence Seizure Frequency During the Treatment Period Compared to Prospective 
Baseline by Development 
Responder Status and Seizure Worsening for Days with Absence Seizures by Development 
Days with Myoclonic Seizures Observed Results and Percent Changes from Prospective 
Baseline by Development 
Increase in Days with Myoclonic Seizures During the Treatment Period Compared to 
Prospective Baseline by Development 
Increase in Myoclonic Seizure Frequency During the Treatment Period Compared to Prospective 
Baseline by Development 
Responder Status and Seizure Worsening for Days with Myoclonic Seizures by Development 
REDACTED COPY
cent
PY 
cent
s and 
ED C
s and 
pment
DAC
pment
re Fre
RE
re Fre
cannot be used to support any marketing authorization application and any extensions or variations thereof.
ent
nd
ent
ombine
on a
ombine
Change
pplic
Change
Percen
ation
Percen
ntnt
equenc
ing a
equenc
ure Fre
rket
ure Fre
y Deve
y ma
y Deve
Observ
t any
Observ
Absen
supp
Absen
opment
to s
opment
sence S
sed
sence S
Develo
be us
Develo
der Sta
not b
der Sta
ys with 
cann
ys with 
This documen
Baselin
nt c
Baselin
Inc
me
Inc
P


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Incidence of Absence Seizure Emergence or Worsening by Development 
Incidence of Myoclonic Seizure Emergence or Worsening by Development 
Seizure-free Status for All Generalized Seizure Types by Development 
Study Medication Duration by Development 
Cumulative Study Medication Duration by Development 
Study Medication Daily Dosing by Development 
Incidence of TEAEs by Development – Overview 
Incidence of TEAEs by Development 
Incidence of Serious TEAEs by Development 
Incidence of Non-serious TEAEs  
Incidence of TEAEs by Relationship and Development 
Incidence of TEAEs Leading to Discontinuation by Development 
Incidence of Serious TEAEs by Relationship  
Incidence of Non-serious TEAEs by Relationship  
Incidence of Fatal TEAEs by Relationship  
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects 
Incidence of Non-serious TEAEs Above Reporting Threshold of 5% of Subjects by Relationship 
12-Lead ECG Summary by Development 
Treatment-Emergent Abnormal 12-Lead ECG Findings for Subjects by Development 
Section 12.6 was revised from: 
The following subgroup variable will also be programmed: 
Subjects enrolled at Japanese study sites (Japanese, non-Japanese) 
Was revised to: 
The following subgroup variable will also be programmed: 
Subjects enrolled at Japanese study sites (Japanese, non-Japanese) 
Subjects enrolled at Asian study sites (Asian, non-Asian) – Asian sites are those in Taiwan, 
South Korea, China and Japan 
 
 
 
 
 
REDACTED COPY 
rting T
ED C
rting T
Reporti
ACTE
Reporti
ment
RED
ment
R
ad
R
ad
o support any marketing authorization application and any extensions or variations thereof.
Thresh
zatio
Thresh
ting Th
thori
ting Th
d ECG
eting
d ECG
le will 
ny m
le will 
se stud
ort a
se stud
This document cannot be used to
group v
d to s
group v
led at J
used
led at J
nrolled
be u
nrolled
Korea, C
not b
Korea, C


UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.


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