Clinical trial NCT02408523
Conditions: Epilepsy
Keywords: Lacosamide Vimpat Epilepsy Children Primary Generalized Tonic Clonic seizures Idiopathic Generalized Epilepsy Adults
Sponsor: UCB BIOSCIENCES, Inc.
Start date: 2015-04-01; Completion date: 2019-06-01
Enrollment: 242 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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 documents:
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.
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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:
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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
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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 
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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
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07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
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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
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07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
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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
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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
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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
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Lacosamide
SP0982
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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
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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
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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
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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]).
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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 
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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 
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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)
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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 
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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 
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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 
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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). 
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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.
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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.
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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
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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). 
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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.
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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.
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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
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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 
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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.
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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
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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 
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07
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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
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07
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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.
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07
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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. 
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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
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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 
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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
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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.
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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)
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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).
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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.
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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.
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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.
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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%).
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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 
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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.
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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 
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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.
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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 
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Final Clinic 
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Safety 
Follow-up 
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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 
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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.
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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.
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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 
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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.
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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
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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.
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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
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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)
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Urine pregnancy test (for women of childbearing potential)
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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)
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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
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UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 59 of 267
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Socio-professional data
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AE reporting
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Concomitant medications and AEDs 
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Withdrawal criteria
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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)
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UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 60 of 267
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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
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UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 61 of 267
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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
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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 
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Withdrawal criteria
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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)
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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
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UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 64 of 267
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Concomitant medications and AEDs 
•
Withdrawal criteria
•
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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.
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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
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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
•
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relative to the Prospective Baseline
•
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•
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
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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 
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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 
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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 
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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
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07 Nov 2017
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Lacosamide
SP0982
Confidential
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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
−
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•
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.
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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.
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07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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).
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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.
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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.
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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 
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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).
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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, 
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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.
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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 
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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.
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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.
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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.
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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.
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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.
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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 
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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.
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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.
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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, 
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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
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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 
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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:
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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
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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. 
•
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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
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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 
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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).
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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.
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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.
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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.
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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.
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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 
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•
50% response for days with absence seizures during the 24-week Treatment Period; a 
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•
50% response for days with myoclonic seizures during the 24-week Treatment Period; a 
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•
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.
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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.
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Clinical Study Protocol
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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.
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Clinical Study Protocol
Lacosamide
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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.
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07 Nov 2017
Clinical Study Protocol
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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.
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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 
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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 
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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
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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
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___
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__
__
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 
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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). 
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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). 
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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.
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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
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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
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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.
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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 
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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 
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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.
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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:
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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.
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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
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TCe
V3
TCf
V4
V5
V6
V7
V8
V9/
ETg
End of
Taperh
Final 
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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
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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.
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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.
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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
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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. 
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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.
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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
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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
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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
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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
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UCB
07 Nov 2017
Clinical Study Protocol
Lacosamide
SP0982
Confidential
Page 154 of 267
Figure 5-2: SP0982 overall schematic diagram
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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
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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.
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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.”
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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).
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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) 
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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. 
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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 
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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).
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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 
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Final 
Clinic Visit
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2 weeks
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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.
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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 
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increase
(dose increase after 
back-titration step)
Min
Max
Min
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<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
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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).
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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.
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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.
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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.
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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
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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
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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
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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)
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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
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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:
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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:
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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 
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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
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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)
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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 
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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])
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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)
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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
•
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•
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.
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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
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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
•
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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
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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.
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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.
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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 
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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
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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 
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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).
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UCB
07 Nov 2017
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Lacosamide
SP0982
Confidential
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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.
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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.
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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.
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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.
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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 
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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.
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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.
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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:
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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.
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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
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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
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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:
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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 
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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]).
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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
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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 
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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 
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•
50% response for days with absence seizures during the 24-week Treatment Period; a 
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•
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
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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)
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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.
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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
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Urinalysis will be required for subjects ≥5 years of age only.
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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
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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 
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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, 
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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
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*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.
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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)
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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 
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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.
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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:
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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. 
•
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<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]).
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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.
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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.
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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.
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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).
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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.
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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.
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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 
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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 
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UCB
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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.
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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
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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.
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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:
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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).
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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).
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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 
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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.
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Lacosamide
SP0982
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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 
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Clinical Study Protocol
Lacosamide
SP0982
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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.
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SP0982
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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.
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Lacosamide
SP0982
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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.”
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Lacosamide
SP0982
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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:
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Lacosamide
SP0982
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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]).
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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 
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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) 
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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
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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
•
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Baseline
Other safety variables are:
•
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•
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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
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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 
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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.
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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.
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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
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V4
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V6
V7
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Study week
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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/
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Visit
Study week
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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. 
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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.
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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)
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No
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No
AED=antiepileptic drug
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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
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1
1
2
Yes
1
2
3
Yes
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0
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3
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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
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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.
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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.
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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:
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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.
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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 
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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
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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 
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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 
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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.
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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 
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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.
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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.
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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.
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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
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07
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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.
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ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Approval Date 
(dd-mon-yyyy
(HH:mm))
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This document cannot be used to support any marketing authorization application and 
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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
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neralize
tion 
neralize
17
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17
not be used to support any mar
01
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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 
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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 
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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 
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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 
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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 
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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 
 
 
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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 
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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 
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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 
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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 
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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.  
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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 
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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 
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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). 
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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. 
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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 
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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.  
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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 
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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 
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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 
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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.  
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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. 
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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 
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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 
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UCB 
 
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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). 
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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 
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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: 
   
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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. 
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Statistical Analysis Plan 
 
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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. 
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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
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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 
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UCB 
 
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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.  
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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 
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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=∑
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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 
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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 
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𝑆2=∑
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6
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𝑆ℎ2 
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6
6
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𝑉𝑎𝑟(𝑆ℎ1) 
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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 
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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
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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 
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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% 
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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 =  
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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 
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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 
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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  
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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 
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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. 
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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. 
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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. 
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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 
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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 
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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 
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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 
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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 
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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.  
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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. 
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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 
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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 
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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} 
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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 
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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.  
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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. 
 
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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 
 
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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. 
 
 
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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 = _____ 
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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 =        _____ 
 
 
 
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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) 
  
  
____ 
 
 
 
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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 
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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 
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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 
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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 
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UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
Hepatitis fulminant 
Hepatitis toxic 
Non-alcoholic steatohepatitis 
Blood bilirubin abnormal 
Blood bilirubin increased 
Hyperbilirubinaemia 
 
 
 
 
 
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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. 
 
 
 
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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 
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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 
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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.  
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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. 
 
 
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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) 
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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 
 
 
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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 
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and Pe
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Days w
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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 
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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 
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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. 
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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.  
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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. 
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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: 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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: 
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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 
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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 
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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.  
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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) 
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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 
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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 
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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:  
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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: 
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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 
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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. 
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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 . 
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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 
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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) 
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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. 
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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. 
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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: 
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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 
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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
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od rela
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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 
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support any marketing authorization application and any extensions or variations thereof.
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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 
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ting authorization application and any extensions or variations thereof.
rst 6
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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
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days, 1
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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 
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used to support any marketing authorization application and any extensions or variations thereof.
for 
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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
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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.  
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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 
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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. 
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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. 
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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
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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 
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UCB 
 
28 Mar 2019 
Statistical Analysis Plan 
 
SP0982 
ℎ(𝑡, 𝑋) = ℎ0(𝑡)exp(∑𝛽𝑗𝑋𝑗
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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. 
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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. 
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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. 
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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 
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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.  
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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: 
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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 
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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 
 
 
 
 
 
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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. 
 
 
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof.


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