Clinical trial NCT02408549
Conditions: Epilepsy
Keywords: Lacosamide Vimpat Epilepsy Children Primary Generalized Tonic Clonic seizures Idiopathic Generalized Epilepsy Adults
Sponsor: UCB BIOSCIENCES, Inc.
Start date: 2015-08-03; Completion date: 2023-03-30
Enrollment: 239 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Assessment of long-term safety and efficacy of oral lacosamide (LCM) as an adjunctive therapy for uncontrolled primary generalized tonic-clonic seizures (PGTCS) in subjects \>= 4 years of age with idiopathic generalized epilepsy (IGE). This study will enroll subjects from the LCM SP0982 \[NCT02408523\] study.

Detailed description:

Arms: arm 1: Start dose

SP0982 completers at V1:

* LCM 10 mg/kg/day for pediatric subjects weighing \<30 kg
* LCM 8 mg/kg/day for pediatric subjects weighing ≥ 30kg to \<50 kg
* LCM 400 mg/day (200 mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50 kg

SP0982 Baseline failures at V1:

* LCM 2 mg/kg/day for pediatric subjects weighing \<50 kg
* LCM 100 mg/day (50 mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50 kg

Oral solution (pediatric subjects \<50 kg):

* Minimum LCM dose: 4 mg/kg/day
* Maximum LCM dose: 12 mg/kg/day

Tablets (pediatric subjects ≥50kg):

* Minimum LCM dose: 200 mg/day
* Minimum LCM dose: 600 mg/day

Tablets (adult subjects):

* Minimum LCM dose: 200 mg/day
* Maximum LCM dose: 800 mg/day
Interventions: intervention 1: Lacosamide Tablet intervention 2: Lacosamide Oral Solution
Intervention descriptions: intervention 1: * Active substance: Lacosamide
* Pharmaceutical form: Tablet
* Concentration: 50 mg and 100 mg
* Route of Administration: Oral administration intervention 2: * Active substance: Lacosamide
* Pharmaceutical form: Oral solution
* Concentration: 10 mg/ml
* Route of Administration: Oral administration

Protocol documents:
Prot_000.pdf: 
UCB 
 
28 Aug 2020 
Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 1 of 274 
PROTOCOL EP0012 AMENDMENT 5 
AN OPEN-LABEL, MULTICENTER EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF 
LACOSAMIDE AS ADJUNCTIVE THERAPY FOR 
UNCONTROLLED PRIMARY GENERALIZED TONIC-CLONIC 
SEIZURES IN SUBJECTS WITH IDIOPATHIC GENERALIZED 
EPILEPSY 
PHASE 3 
EudraCT Number: 2012-001770-29 
IND Number (tablet): 57939 
IND Number (oral solution): 73809 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
Protocol Amendment 4 
13 Dec 2019 
Substantial 
Protocol Amendment 5 
28 Aug 2020 
Non-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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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 2 of 274 
STUDY CONTACT INFORMATION 
Sponsor 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Sponsor Study Physician 
Name: 
 
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: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Phone: 
 
Email: 
 
 
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28 Aug 2020 
Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Clinical Monitoring Contract Research Organization 
Name: 
Pharmaceutical Research Associates (PRA), Inc. 
Address: 
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
UNITED STATES 
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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28 Aug 2020 
Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
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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 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 13 
3 
STUDY OBJECTIVE(S) ................................................................................................. 16 
3.1 
Primary objective ................................................................................................... 16 
3.2 
Secondary objectives ............................................................................................. 16 
4 
STUDY VARIABLES ..................................................................................................... 16 
4.1 
Safety variables ...................................................................................................... 16 
4.1.1 
Primary safety variables ............................................................................... 16 
4.1.2 
Secondary safety variables ........................................................................... 16 
4.1.3 
Other safety variables .................................................................................. 17 
4.2 
Efficacy variables................................................................................................... 17 
4.2.1 
Primary efficacy variable ............................................................................. 17 
4.2.2 
Secondary efficacy variable ......................................................................... 17 
4.2.3 
Other efficacy variables ............................................................................... 17 
5 
STUDY DESIGN ............................................................................................................. 18 
5.1 
Study description ................................................................................................... 18 
5.1.1 
Study duration per subject ........................................................................... 20 
5.1.2 
Planned number of subjects and site(s) ........................................................ 21 
5.1.3 
Anticipated regions and countries ................................................................ 21 
5.2 
Schedule of study assessments............................................................................... 21 
5.3 
Rationale for study design and selection of dose ................................................... 36 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 37 
6.1 
Inclusion criteria .................................................................................................... 37 
6.2 
Exclusion criteria ................................................................................................... 37 
6.3 
Withdrawal criteria ................................................................................................ 38 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ................ 39 
7 
STUDY TREATMENT(S) .............................................................................................. 40 
7.1 
Description of investigational medicinal product(s) .............................................. 40 
7.2 
Treatment(s) to be administered ............................................................................ 40 
7.2.1 
Treatment Period .......................................................................................... 40 
7.3 
Packaging ............................................................................................................... 42 
7.4 
Labeling ................................................................................................................. 43 
7.5 
Handling and storage requirements ....................................................................... 43 
7.6 
Drug accountability ................................................................................................ 43 
7.7 
Procedures for monitoring subject compliance ...................................................... 44 
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28 Aug 2020 
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Lacosamide 
EP0012 
 
 
 
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7.8 
Concomitant medication(s)/treatment(s) ............................................................... 44 
7.8.1 
Permitted concomitant treatments (medications and therapies) .................. 44 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ................. 45 
7.9 
Blinding.................................................................................................................. 45 
7.10 
Randomization and numbering of subjects ............................................................ 45 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 45 
8.1 
Treatment Period .................................................................................................... 45 
8.1.1 
Visit 1 (Week 0) ........................................................................................... 45 
8.1.2 
Visits 2 to 8 (Weeks 2 to 46, Year 1, excluding Visit 6 and Visit 7) .......... 47 
8.1.3 
Visits 9 and 11 (Weeks 62 and 94, Year 2, excluding Visit 10) .................. 47 
8.1.4 
Visits 12, 13, 14, 15, 16, 17 and X (Weeks 118, 142, 166, 190, 214, 238, 
and X, Years 3 to 5 + Extended Period) ...................................................... 48 
8.1.4.1 
Subjects <18 years ............................................................................. 48 
8.1.4.2 
Subjects ≥18 years ............................................................................. 49 
8.1.5 
Telephone Contact ....................................................................................... 50 
8.1.6 
LCM Solution Dispensation Visit ................................................................ 50 
8.2 
Early Termination Visit ......................................................................................... 50 
8.3 
Termination Visit ................................................................................................... 51 
8.4 
Taper and Safety Follow-Up Period ...................................................................... 53 
8.4.1 
End of Taper Visit ........................................................................................ 53 
8.4.2 
Safety Follow-Up Visit ................................................................................ 54 
8.4.3 
Safety Follow-Up telephone contact ............................................................ 54 
8.5 
Unscheduled Visit .................................................................................................. 54 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 55 
9.1 
Seizure variables .................................................................................................... 55 
9.1.1 
PGTCS ......................................................................................................... 55 
9.1.2 
Absence and myoclonic seizures ................................................................. 56 
9.2 
Health outcome variables ....................................................................................... 56 
9.2.1 
Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) .............................................................................................. 56 
9.2.2 
Pediatric Quality of Life Inventory .............................................................. 56 
9.2.3 
EuroQol-5D-3L Quality of Life Assessment ............................................... 57 
9.2.4 
Healthcare resource use ............................................................................... 57 
9.2.5 
Number of working or school days lost due to epilepsy .............................. 57 
9.2.6 
Number of days with help from a caregiver due to epilepsy ....................... 57 
10 ASSESSMENT OF SAFETY .......................................................................................... 57 
10.1 
Adverse events ....................................................................................................... 57 
10.1.1 
Definitions ................................................................................................... 57 
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Lacosamide 
EP0012 
 
 
 
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10.1.1.1 
Adverse event ..................................................................................... 57 
10.1.1.2 
Serious adverse events ....................................................................... 58 
10.1.1.3 
Adverse events of special interest ...................................................... 59 
10.1.2 
Procedures for reporting and recording adverse events ............................... 60 
10.1.2.1 
Description of adverse events ............................................................ 60 
10.1.2.2 
Rule for repetition of an adverse event .............................................. 61 
10.1.2.3 
Additional procedures for reporting serious adverse events .............. 61 
10.1.3 
Follow up of adverse events ........................................................................ 61 
10.1.4 
Pregnancy ..................................................................................................... 62 
10.1.5 
Suspected transmission of an infectious agent via a medicinal product ...... 63 
10.1.6 
Overdose of investigational medicinal product ........................................... 63 
10.1.7 
Safety signal detection ................................................................................. 63 
10.2 
New seizure types, increase in days with and worsening of days with absence 
or myoclonic seizures ............................................................................................ 63 
10.3 
Laboratory measurements ...................................................................................... 64 
10.3.1 
Evaluation of PDILI ..................................................................................... 64 
10.3.1.1 
Consultation with Medical Monitor and local hepatologist ............... 68 
10.3.1.2 
Immediate action: determination of IMP discontinuation ................. 68 
10.3.1.3 
Testing: identification/exclusion of alternative etiology ................... 69 
10.3.1.4 
Follow-Up evaluation ........................................................................ 70 
10.3.2 
Pregnancy testing ......................................................................................... 71 
10.4 
Other safety measurements .................................................................................... 71 
10.4.1 
Vital signs, body weight and height ............................................................. 71 
10.4.2 
12-lead ECG ................................................................................................ 71 
10.4.2.1 
Overall ECG interpretation ................................................................ 71 
10.4.3 
Assessment of suicidality ............................................................................. 71 
10.4.4 
Physical examination ................................................................................... 72 
10.4.4.1 
Complete physical examination ......................................................... 72 
10.4.4.2 
Brief physical examination ................................................................ 72 
10.4.5 
Neurological examination ............................................................................ 72 
10.4.5.1 
Complete neurological examination .................................................. 73 
10.4.5.2 
Brief neurological examination .......................................................... 73 
10.4.6 
Achenbach CBCL ........................................................................................ 73 
10.4.7 
BRIEF .......................................................................................................... 73 
10.4.8 
Tanner stage ................................................................................................. 74 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 74 
11.1 
Adherence to protocol ............................................................................................ 74 
11.2 
Monitoring ............................................................................................................. 74 
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Lacosamide 
EP0012 
 
 
 
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11.2.1 
Definition of source data .............................................................................. 75 
11.2.2 
Source data verification ............................................................................... 75 
11.3 
Data handling ......................................................................................................... 75 
11.3.1 
Case Report form completion ...................................................................... 75 
11.3.2 
Database entry and reconciliation ................................................................ 76 
11.3.3 
Subject Enrollment log/Subject Identification Code list ............................. 76 
11.4 
Termination of the study ........................................................................................ 76 
11.5 
Archiving and data retention .................................................................................. 76 
11.6 
Audit and inspection .............................................................................................. 77 
11.7 
Good Clinical Practice ........................................................................................... 77 
12 STATISTICS ................................................................................................................... 77 
12.1 
Definition of analysis sets ...................................................................................... 77 
12.1.1 
Enrolled Set .................................................................................................. 77 
12.1.2 
Safety Set ..................................................................................................... 77 
12.1.3 
Full Analysis Set .......................................................................................... 77 
12.2 
General statistical considerations ........................................................................... 78 
12.3 
Planned safety and other analyses.......................................................................... 78 
12.3.1 
Safety analyses ............................................................................................. 78 
12.3.2 
Other analyses .............................................................................................. 78 
12.4 
Planned efficacy analyses ...................................................................................... 78 
12.5 
Handling of protocol deviations............................................................................. 79 
12.6 
Handling of dropouts or missing data .................................................................... 79 
12.7 
Planned interim analysis and data monitoring ....................................................... 79 
12.8 
Determination of sample size ................................................................................. 79 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 79 
13.1 
Informed consent ................................................................................................... 79 
13.2 
Subject identification cards .................................................................................... 80 
13.3 
Institutional Review Boards and Independent Ethics Committees ........................ 80 
13.4 
Subject privacy....................................................................................................... 81 
13.4.1 
Processing of subject health data ................................................................. 81 
13.5 
Protocol amendments ............................................................................................. 82 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 82 
15 REFERENCES ................................................................................................................ 83 
16 APPENDICES ................................................................................................................. 84 
16.1 
Appendix 1: International Classification of Epileptic Seizures (1981) ................. 84 
16.2 
Appendix 2: Patient Weighted Quality Of Life in Epilepsy: QOLIE-31-P 
(Version 2.0, US – English) ................................................................................... 85 
16.3 
Appendix 3: EuroQol-5 Dimension (EQ-5D-3L) Quality of Life Assessment ..... 95 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
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16.4 
Appendix 4: Protocol Amendment 1 ..................................................................... 98 
16.5 
Appendix 5: Protocol Amendment 2 ................................................................... 168 
16.6 
Appendix 6: Protocol Amendment 3 ................................................................... 207 
16.7 
Appendix 7: Protocol Amendment 4 ................................................................... 233 
16.8 
Appendix 8: Protocol Amendment 5 ................................................................... 267 
16.9 
Appendix 9: Contraception Table ........................................................................ 272 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 273 
18 SPONSOR DECLARATION ........................................................................................ 274 
 
LIST OF TABLES 
Table 5‒1: Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit) .............................. 23 
Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 
(Treatment Period, ET Visit, Termination Visit, and Unscheduled Visit 
for subjects <18 years at enrollment).................................................................... 28 
Table 5‒3: Schedule of study assessments for Years 3 through 5 for EP0012 
(Treatment Period, ET Visit, Termination Visit, and Unscheduled Visit 
for subjects ≥18 years at enrollment) .................................................................... 32 
Table 5-4:Schedule of study assessments (Taper Period and Safety Follow-Up 
Period) ................................................................................................................... 35 
Table 7‒1: Minimum and maximum LCM dose during the Treatment Period ...................... 41 
Table 7‒2: Lacosamide dosing for subjects requiring taper ................................................... 42 
Table 10‒1: 
Anticipated serious adverse events for the epilepsy population .................. 59 
Table 10‒2: 
Laboratory tests ............................................................................................ 64 
Table 10‒3: 
Required investigations and follow up for PDILI ....................................... 66 
Table 10‒4: 
PDILI laboratory measurements .................................................................. 69 
Table 10‒5: 
PDILI information to be collected ............................................................... 70 
Table 5-4:Schedule of study assessments (Taper Period and Safety Follow-Up 
Period) ................................................................................................................. 270 
Table 5-4:Schedule of study assessments (Taper Period and Safety Follow-Up 
Period) ................................................................................................................. 270 
 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug(s) 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AV 
atrioventricular 
bid 
twice daily 
BMI 
body mass index 
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 
CPM 
Clinical Project Manager 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EDC 
electronic data capture 
EI-AED 
enzyme-inducing antiepileptic drug 
EQ-5D-3L 
3-level EuroQol-5 Dimension Quality of Life Assessment 
ES 
Enrolled Set 
ET 
Early Termination 
GCP 
Good Clinical Practice 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGE 
idiopathic generalized epilepsy 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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IRB 
Institutional Review Board 
IRT 
interactive response technology 
iv 
intravenous 
LCM 
lacosamide 
LFT 
liver function test 
MAO-A 
monoamine oxidase A 
MAP 
managed access program 
PDILI 
potential drug-induced liver injury 
PedsQL™ 
Pediatric Quality of Life Inventory 
PGTCS 
primary generalized tonic-clonic seizure(s) 
PK 
pharmacokinetic 
PS 
Patient Safety 
QOLIE-31-P 
Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SFU 
Safety Follow Up 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEAEs 
treatment-emergent adverse events 
TMF 
trial master file 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
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Lacosamide 
EP0012 
 
 
 
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1 
SUMMARY 
This Phase 3, multicenter, open-label extension study is designed to assess the long-term 
safety and efficacy of oral lacosamide (LCM, VIMPAT®; SPM 927; previously referred to as 
harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, ADD 234037) as an 
adjunctive therapy for uncontrolled primary generalized tonic-clonic seizures (PGTCS) in 
subjects ≥4 years of age with idiopathic generalized epilepsy (IGE). This study will enroll 
subjects who have completed the LCM SP0982 study. In addition, subjects who completed 
the SP0982 Prospective Baseline Period and met all entry criteria except the minimum 
PGTCS criteria required for randomization into SP0982 may choose to enter EP0012 
(eligible Baseline failures and completers are defined in Section 5.1). It is estimated that up to 
250 subjects across approximately 150 to 180 sites will be enrolled in EP0012. 
Once 125 subjects have had a second PGTCS in SP0982, that study will have met its 
protocol-defined stopping criteria and all subjects will transition into EP0012 or taper off 
study medication. Subjects who completed SP0982 will start at Visit 1 on a dose of 
LCM 10mg/kg/day for pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric 
subjects weighing ≥30kg to <50kg, and LCM 400mg/day (200mg twice daily [bid]) for adult 
subjects (≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who are eligible 
Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day for 
pediatric subjects weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects (≥18 
years of age) or pediatric subjects weighing ≥50kg.  
Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility 
based on tolerability is allowed. Investigators will assess whether a subject would tolerate a 
further LCM 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 target dose of 
4mg/kg/day (oral solution) or 200mg/day (tablets) within 14 days after Visit 1.  
At any time during the course of the study if it becomes apparent that a subject is unable to 
attain at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then 
the subject must enter the Taper Period and be withdrawn from the study. 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased 
in steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must 
remain on the dose for ≥7 days before a subsequent dose escalation.  
EP0012 will consist of a Treatment Period, an up to 4-week Taper Period, and a 30-day 
Safety Follow-Up Period. During the Treatment Period, Visit 2 will occur 2 weeks after Visit 
1, and Visit 3 will occur 4 weeks later (Week 6). Clinical visits will then occur every 8 weeks 
for the first year, and every 16 weeks in the second year. For subjects who continue in the 
study after Year 2, visits will occur every 24 weeks thereafter until the end of the study. From 
Year 2 (Visit 11) to 3 onwards, pediatric subjects weighing <50kg will return to the clinic for 
an additional Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of 
LCM solution; LCM usage will be reviewed and empty LCM bottles will be returned. 
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EP0012 
 
 
 
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A telephone contact will occur every 8 weeks if no clinic visit is scheduled. The study 
duration and the total number of clinic visits will vary for each subject. Treatment will 
continue until LCM is approved for use in the subject’s country for the treatment of PGTCS 
in subjects with IGE, or until UCB has determined that the clinical development program for 
the indication will be formally discontinued, or until UCB decides to close the study. 
At the completion of the study, investigators should discuss treatment options with the 
subject and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. 
Taper of LCM may not be required for some subjects who complete the study depending on 
the treatment option selected by the investigator in consultation with the subject and/or their 
parent(s)/legal representative(s).  
The primary study objective is to assess the safety and tolerability of LCM as an adjunctive 
therapy for uncontrolled PGTCS in subjects with IGE during long-term exposure. Secondary 
objectives are to assess the efficacy of adjunctive LCM therapy during long-term exposure 
for the treatment of uncontrolled PGTCS in subjects with IGE, and to allow subjects who 
have completed SP0982 and eligible Baseline failures from SP0982 to receive LCM. 
The primary safety variables are adverse events (AEs), subject withdrawals due to AEs, 
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. Secondary safety variables 
are percentage of treatment-emergent marked abnormalities in hematology and chemistry 
parameters; percentage of treatment-emergent marked abnormalities in 12-lead 
electrocardiograms (ECGs); and percentage of treatment-emergent marked abnormalities in 
vital sign measurements (ie, blood pressure [BP] and pulse rate). Other safety variables 
include changes in hematology, chemistry, and urinalysis parameters, changes in 12-lead 
ECGs, and changes in in vital sign measurements (ie, BP and pulse rate), including height 
and weight and physical (including neurological) examination findings.  In addition, for 
pediatric subjects <18 years of age, safety will be evaluated using behavioral assessments 
(Achenbach Child Behavior Checklist [CBCL]), and cognitive function assessments 
(Behavior Rating Inventory of Executive Function®/Behavior Rating Inventory of Executive 
Function-Preschool Version® [BRIEF®/BRIEF-P®]). The seizure efficacy variables are 
evaluations of seizure frequency, based on information included in subject diaries. The health 
outcome variables, including the Patient Weighted Quality of Life in Epilepsy Inventory-
Form 31 (QOLIE-31-P), the Pediatric Quality of Life Inventory™ (PedsQL™), the 3-level 
EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L), healthcare resource use, the 
number of working or school days lost by subjects due to epilepsy, and the number of days 
with help from a caregiver due to epilepsy will be assessed for the first 2 years of treatment. 
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 
unknown origin.  
Generalized seizures are those in which the first clinical changes indicate initial involvement 
of both brain hemispheres. Consciousness typically is impaired and this impairment may be 
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EP0012 
 
 
 
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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 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 PGTCS in IGE is complex because the patient population is heterogeneous, as 
PGTCS 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 antiepileptic drugs (AEDs) and vagus nerve stimulation. 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 (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 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 also 
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. 
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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 PGTCS, the efficacy and tolerability profiles for LCM were evaluated in a series of 
animal models followed by a Phase 2 pilot study of patients with IGE and uncontrolled 
PGTCS. 
Lacosamide demonstrated significant seizure protection in animal models of seizures and 
epilepsy mimicking generalized epilepsy in humans. Of particular relevance for the PGTCS 
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 and increased spike and wave discharges in the WAG/R and 
Genetic Absence Epilepsy Rats from Strasbourg models of absence epilepsy. 
SP0961, the Phase 2, multicenter, open-label pilot study designed to assess the safety of 
adjunctive LCM (400mg/day) for uncontrolled PGTCS in subjects aged 16 to 65 years with 
IGE, is complete. The results of this pilot study showed reductions in PGTCS 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, cannot be distinguished 
between the drug versus 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. 
SP0982 is a Phase 3, double-blind, randomized, placebo-controlled, parallel-group, 
multicenter study designed to evaluate the efficacy and safety of LCM for uncontrolled 
PGTCS in subjects ≥4 years of age with IGE. 
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The current study (EP0012) will assess the long-term safety, tolerability, and efficacy of 
LCM and will enroll subjects who have completed SP0982 as well as eligible Baseline 
failures from SP0982. At the completion of the study, investigators should discuss treatment 
options with the subject and/or legal representative to best manage the subject's epilepsy. 
3 
STUDY OBJECTIVE(S) 
3.1 
Primary objective 
The primary objective is to assess the safety and tolerability of LCM as an adjunctive therapy 
for uncontrolled PGTCS in subjects with IGE during long-term exposure. 
3.2 
Secondary objectives 
The secondary objectives are: 
• To assess the efficacy of adjunctive LCM therapy during long-term exposure for the 
treatment of subjects with IGE experiencing uncontrolled PGTCS 
• To allow subjects who have completed SP0982 and eligible Baseline failures from 
SP0982 to receive LCM 
4 
STUDY VARIABLES 
4.1 
Safety variables 
4.1.1 
Primary safety variables 
The primary safety variables are: 
• The incidence of TEAEs over the duration of the Treatment Period. 
• Subject withdrawals due to TEAEs 
• Incidence of new appearance of absence and/or myoclonic seizures during the Treatment 
Period 
• An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with absence 
seizures per 28 days compared to the Prospective Baseline 
• An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days compared to the Prospective Baseline 
• At least 50% worsening in days with absence seizures 
• At least 50% worsening in days with myoclonic seizures 
4.1.2 
Secondary safety variables 
Secondary safety variables are: 
• Percentage of treatment-emergent marked abnormalities in hematology and chemistry 
parameters 
• Percentage of treatment-emergent marked abnormalities in 12-lead ECGs 
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• Percentage of treatment-emergent marked abnormalities in vital sign measurements (ie, 
BP and pulse rate) 
4.1.3 
Other safety variables 
• Changes in hematology, chemistry, and urinalysis parameters 
• Changes in 12-lead ECGs 
• Changes in vital sign measurements (ie, BP and pulse rate), including weight and height 
and physical (including neurological) examination findings 
• Achenbach CBCL1½-5 or CBCL/6-18 (for pediatric subjects only) 
• Cognitive function assessment BRIEF/BRIEF-P (for pediatric subjects only) 
4.2 
Efficacy variables 
4.2.1 
Primary efficacy variable 
No primary efficacy variables are defined for this study. 
4.2.2 
Secondary efficacy variable 
The secondary efficacy variable is: 
• Percent change in PGTCS frequency per 28 days from Combined Baseline, where 
Combined Baseline is defined as the combined 12-week Historical Baseline and 4-week 
Prospective Baseline periods immediately prior to randomization in the parent study 
(SP0982) 
4.2.3 
Other efficacy variables 
The other efficacy variables are: 
• Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
• Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline 
• Change in days with absence seizures per 28 days relative to the Prospective Baseline 
• Percent change in days with absence seizures per 28 days relative to the Prospective 
Baseline 
• At least a 50% reduction in PGTCS frequency compared to the Combined Baseline 
• At least a 50% reduction in myoclonic seizure days compared to the Prospective Baseline 
• At least a 50% reduction in absence seizure days compared to the Prospective Baseline 
• Seizure-free status (yes/no) for PGTCS 
• Seizure-free status (yes/no) for all generalized seizure types 
• 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 
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≥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 for the first 2 years of treatment  
• Change from Baseline in the EQ-5D-3L visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age) for the first two 
years of treatment 
• Healthcare resource use: medical procedures, hospitalizations, and healthcare provider 
visits for the first 2 years of treatment. 
• Number of working or school days lost by subject due to epilepsy for the first two years 
of treatment. 
• Number of days with help from a caregiver due to epilepsy for the first two years of 
treatment 
5 
STUDY DESIGN 
5.1 
Study description 
This is a multicenter, open-label extension study to assess the long-term safety, tolerability 
and change in seizure frequency associated with long-term adjunctive oral LCM for 
uncontrolled PGTCS in subjects ≥4 years of age with IGE. This study will enroll consenting 
subjects, or subjects whose legal representatives have given consent, who have completed the 
LCM SP0982 study (or have left the primary study at the time of the 125th event, whichever 
came first) as well as eligible Baseline failures from SP0982. Then, some subjects who 
tapered in SP0982 after the 125th event may enter EP0012 for the Safety Follow-Up only 
(ICF to be signed beforehand). Up to 250 subjects from 150 to 180 study sites are planned to 
be enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, study completers from SP0982 who are eligible for inclusion in EP0012, SP0982 
Safety Follow-Up subjects, and Other are defined as: 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry 
criteria except the minimum PGTCS criteria required for randomization (Baseline 
failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) 
of SP0982 and experienced ≥2 PGTCS during that time or  
Subjects who experience a second PGTCS after the first 6 weeks of the Treatment Period of 
SP0982 
SP0982 completers 
• Subjects who experience <2 PGTCS within the 24-week Treatment Period of SP0982  
• Subjects who were ongoing in SP0982 when the 125th event occurred 
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SP0982 Safety Follow-Up subjects 
• Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up Visit only  
Other 
• Subjects that enrolled in EP0012 that did not fall into the above categories 
Randomized subjects meeting SP0982 exit criteria and subjects who completed SP0982 will 
start at Visit 1 on a dose of LCM 10mg/kg/day for pediatric subjects weighing <30kg, LCM 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 400mg/day (200mg 
bid) for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who 
are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day 
for pediatric subjects weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects 
(≥18 years of age) or pediatric subjects weighing ≥50kg. In addition, once 125 subjects have 
had a second PGTCS in SP0982 (ie, the 125th event has occurred), that study will have met its 
protocol-defined end. All subjects ongoing in SP0982 will transition into EP0012 for further 
long-term treatment or for a Safety Follow-Up. 
Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility 
based on tolerability is allowed. Investigators will assess whether a subject would tolerate a 
further LCM 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 target dose of 
4mg/kg/day (oral solution) or 200mg/day (tablets) within 14 days after Visit 1.  
At any time during the course of the study if it becomes apparent that a subject is unable to 
attain at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then 
the subject must enter the Taper Period and be withdrawn from the study. 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased 
in steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must 
remain on the dose for ≥7 days before a subsequent dose escalation.  
The LCM dose may be increased or decreased at the investigator’s discretion after the subject 
receives the first dose of LCM in the study (see Table 7‒1). Baseline failures must complete 
Week 1 of dosing before LCM may be increased or decreased. The maximum dose for 
pediatric subjects weighing <50kg is 12mg/kg/day (oral solution). The maximum dose for 
pediatric subjects weighing ≥50kg is 600mg/day (tablets) and for adult subjects is 800mg/day 
(tablets).  
A clinic visit (scheduled or unscheduled) is required if:  
• The dose is increased for the first time to any dose above 10mg/kg/day for pediatric 
subjects weighing <50 kg. One week after the first time the dose is increased, an 
unscheduled telephone contact must be conducted to ensure that the dose is well tolerated. 
• The dose is increased for the first time to any dose above LCM 400mg/day for all adult 
subjects or pediatric subjects weighing ≥50kg. One week after the first time the dose is 
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Clinical Study Protocol 
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increased, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
EP0012 will last at least 2 years and consist of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final 
Clinic Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria. 
Eligible Baseline failures from SP0982 who choose to enter this study will undergo a 
complete Visit 1. Visit 2 will occur 2 weeks after Visit 1 and Visit 3 will occur 4 weeks later 
(Week 6). Clinic visits will then occur every 8 weeks for the first year, and every 16 weeks in 
the second year. For subjects who continue in the study after Year 2, visits will occur every 
24 weeks thereafter until the end of the study. From Year 2 (Visit 11) to 3 onwards, pediatric 
subjects weighing <50kg will return to the clinic for an additional Dispensation Visit 12 
weeks after each 24-weekly visit, for the dispensation of LCM solution; LCM usage will be 
reviewed and empty LCM bottles will be returned.  
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone 
contacts will be used to obtain information regarding concomitant medication use, and assess 
withdrawal criteria and AEs, as well as to ensure subjects are compliant with LCM 
administration and diary completion.  
Subjects and/or their caregiver will be dispensed a seizure diary to record all types of 
seizures, concomitant AEDs, and other pertinent health status information. Subjects must 
bring their diary to each visit. Baseline seizure frequency and type will be verified by a 
reliably documented seizure history collected (eg, in a seizure diary during SP0982). 
New concomitant AEDs may be introduced to optimize treatment, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication 
in the subject’s country. New AEDs should be added only when the subject has not optimally 
or adequately responded to a maximum tolerated dose of LCM. Concomitant AEDs may be 
carefully tapered and discontinued to achieve LCM monotherapy, if clinically appropriate. 
The Medical Monitor must be consulted prior to initiation of concomitant AED withdrawal. 
At the completion of the study, investigators should discuss treatment options with the 
subject and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. 
Taper of LCM (Taper Visit and SFU) may not be required for some subjects who leave the 
study depending on the treatment option selected by the investigator in consultation with the 
subject and/or their parent(s)/legal representative(s).  
5.1.1 
Study duration per subject 
For adult subjects, treatment will continue for at least 2 years.  Once 2 years of participation 
are reached, adult subjects will continue to participate until 1 of the 2 following conditions 
are met.  
• LCM is approved for use for the treatment of PGTCS in subjects with IGE in the 
subject’s country for or until the latest approval is granted either by EMA, FDA, or 
PMDA.  
• For pediatric subjects, treatment will continue until 1 of the following 2 conditions are 
met: 
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− up to 5 years of participation or  
− until the approval of the extension of indication to cover the target age group is 
granted  
Adult and pediatric subjects are completers if they continue in the study for the maximum 
duration in their respective region. 
The following study periods are defined: 
• A Treatment Period lasting for at least 5 years (238 weeks) for the population less than 
18 years old at enrollment and will be shorter for adults leaving the study when the 
PGTCS indication approvals are being obtained during the course of the study.  
• An up to 4-week Taper Period and a 30-day Safety Follow-Up Period.  
− Subjects continuing LCM treatment with commercially available LCM will transition 
to a dose determined by the investigator and do not have to perform the tapering 
(Taper Visit and SFU). 
− Subjects tapering off LCM will do so over a period of up to 4 weeks (see taper 
schedule, Table 7‒2). 
− An End of Taper Visit (latest 3 days after the final dose) will occur after the final 
LCM dose for subjects who taper off LCM. 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 same design will 
apply to some of the subjects tapered in SP0982 at the time of the 125th event and who 
entered EP0012 for the Safety Follow-Up Visit only and to subjects who entered 
EP0012 for a Safety Follow-up Visit after discontinuing SP0982 due to the study 
stopping. 
The end of the study is defined as the date of the last visit/telephone contact of the last subject 
in the study. 
Subjects who entered EP0012 as <18 years and become adults (≥18 years) during the study, 
will remain in the study for at least 5 years (238 weeks).  
5.1.2 
Planned number of subjects and site(s)  
Up to 250 subjects across 150 to 180 international sites are planned to be enrolled in this 
study. 
5.1.3 
Anticipated regions and countries 
This 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 for treatment Years 1 to 2 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) is provided in Table 5‒1. An additional schedule 
of study assessments for treatment Years 3 to 5 (Treatment Period, Early Termination [ET] 
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Visit, Termination Visit, and Unscheduled Visit) is provided in Table 5‒2 for subjects 
<18 years and Table 5‒3 for subjects ≥18 years. The schedule of study assessments for the 
Taper Period and Safety Follow-Up Visit (including subjects who tapered in SP0982 after the 
125th event consented to enter EP0012 for the Safety Follow-up only) is provided in Table 5-
4. 
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Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) 
  
Treatment Perioda 
 
Unscheduledb 
Duration 
Open-label: at least 2 years 
 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitc 
V1 
V2 
V3 
V4 
V5 
V6** 
V7** 
V8 
Telephone 
Contactd 
V9 
V10** 
V11 
ET 
Visite 
Termination 
Visitf 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
NA 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID card dispensing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications and 
AED(s) 
X* 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Medical history/Epilepsy history 
update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (complete)g 
X* 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Physical exam (brief)h 
 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
Neurological exam (complete)i 
X* 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Neurological exam (brief)j 
 
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 
X 
Body weight and heightm 
X* 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Tanner Stagen 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Laboratory testso 
X* 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
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Clinical Study Protocol 
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EP0012 
 
 
 
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Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) 
  
Treatment Perioda 
 
Unscheduledb 
Duration 
Open-label: at least 2 years 
 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitc 
V1 
V2 
V3 
V4 
V5 
V6** 
V7** 
V8 
Telephone 
Contactd 
V9 
V10** 
V11 
ET 
Visite 
Termination 
Visitf 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
NA 
Endocrinologyp 
X* 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy testq 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Call IRT 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
C-SSRSr 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
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 
Dispense LCM 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
LCM review/return 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Withdrawal criteria 
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 
EQ-5D-3L 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
QOLIE-31-P/PedsQLs 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Achenbach CBCLt 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
BRIEF-P/BRIEFu 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Healthcare resource use 
X* 
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 
X 
 
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Clinical Study Protocol 
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Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) 
  
Treatment Perioda 
 
Unscheduledb 
Duration 
Open-label: at least 2 years 
 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitc 
V1 
V2 
V3 
V4 
V5 
V6** 
V7** 
V8 
Telephone 
Contactd 
V9 
V10** 
V11 
ET 
Visite 
Termination 
Visitf 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
NA 
Days with help from a caregiver 
due to epilepsy 
X* 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; 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; EQ-5D-3L=3-level EuroQol-5 Dimension Quality of Life Assessment; ET=early termination; exam=examination; ID=identification; 
IRT=interactive response technology; LCM=lacosamide; NA=not applicable; PedsQL=Pediatric Quality of Life Inventory; QOLIE-31-P=Patient Weighted 
Quality of Life in Epilepsy Inventory-Form 31; V=Visit 
Note: For subjects who have completed SP0982, assessments marked (*) should have already been completed during the last visit of the previous protocol and do 
not need to be repeated at Visit 1; for eligible Baseline failures from SP0982, a full Visit 1 is required including all scheduled tasks and procedures. 
Note: Visit 6, Visit 7 and Visit 10 (**) assessments will not be performed according to Protocol Amendment 3. 
a 
The duration of the Treatment Period will continue for at least 2 years and vary by subject age group and is defined in Section 5.1.1.  
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks including Week 30 and Week 38 during the study, except during weeks in which a clinic visit is planned (eg, 
Week 62). Therefore, telephone contacts in Year 2 are scheduled for Week 54, Week 70, Week 78, and Week 86. 
e 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-4. For subjects who continue on commercial LCM, the early Termination Visit is the last visit in the study.  
 
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f 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate (see Table 5‒2). For 
subjects who will not continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For 
subjects who continue on LCM, the Termination Visit is the last visit in the study. 
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 assessment of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function. 
j 
The brief neurological examination will include selected assessment 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) a 12-lead ECG (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 
Height will be recorded at Visits 1 and 9, and at the ET and Termination Visit. 
n 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
o 
Urinalysis will be required for all subjects. 
p 
If the patient was treated in SP0982, endocrinology should be done if age was <18 years at SP0982 Visit 1. If the patient was a Baseline failure in SP0982, 
endocrinology should be done if age is <18 years at EP0012 Visit 1. 
q 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion. 
r 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3).  
s 
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 PedsQL 
form appropriate for each subject’s age should be completed, with the following exception: if a subject ages up to the next form of the PedsQL within 1 year 
after the Baseline assessment of the primary study, the form that was used at the Baseline assessment should be completed for 1 year after the Baseline 
assessment, and subsequently the form consistent with his/her age at the time of assessment should be completed. For each version of the PedsQL subjects 
must have at least 1 year of data before transitioning to the next age range (see Section 9.2.1).  
t 
The Achenbach CBCL: CBCL/1½-5 for children 18 months to 5 years and 11 months of age and CBCL/6-18 for children ≥6 years to <18 years of age; to be 
completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). The version of the Achenbach CBCL appropriate to each 
subject’s age should be administered with the following exception: for subjects who completed the CBCL/1½-5 at the Baseline assessment of the previous 
study and turn 6 years of age within 1 year after the Baseline assessment of the primary study, the CBCL/1½-5 should be completed for 1 year after the 
Baseline assessment of the primary study, and subsequently the CBCL/6-18 should be completed. The Achenbach CBCL will only be administered in 
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countries where a validated translated version is available. For each version of the CBCL, subjects must have at least 1 year of data before transitioning to 
the next age range. The Achenbach CBCL should be completed by the same parent/legal representative, if possible (see Section 10.4.6).  
u 
The BRIEF-P should be used for subjects who are <5 years of age at Visit 1, and the BRIEF should be used for subjects who are ≥5 years of age at Visit 1. 
For each developmentally appropriate version of the BRIEF, subjects must have at least 1 year of data before transitioning to the next age range (see 
Section 10.4.7). 
 
 
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Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit for subjects <18 years 
at enrollment) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 + Extended Period 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17 
Vxf 
ET Visitg 
Term Visith 
LCM Solution 
Dispensation 
Visiti 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
X 
 
 
 
NA 
Concomitant medications and 
AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam (complete)j 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Neurological exam (brief)k 
 
X 
 
X 
 
X 
X 
X (even 
visit only) 
X 
X 
 
 
12-lead ECGl 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Vital signs (BP and pulse) 
including orthostatic 
assessmentsm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body weight and heightn 
 
X 
X 
X 
X 
X 
X 
X (even 
visits only) 
X 
X 
 
 
Tanner Stageo 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Laboratory tests 
 
X 
 
X 
 
X 
Xp 
Xp 
X 
X 
 
 
Endocrinologyq 
 
 
 
 
 
 
 
 
X 
X 
 
 
Pregnancy testr 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit for subjects <18 years 
at enrollment) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 + Extended Period 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17 
Vxf 
ET Visitg 
Term Visith 
LCM Solution 
Dispensation 
Visiti 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
X 
 
 
 
NA 
Call IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRSs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM 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 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Achenbach CBCLt 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
BRIEFu 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; 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; ET=early termination; exam=examination; IRT=interactive response technology; LCM=lacosamide; NA=not applicable; 
Term=Termination; V=Visit; Vx=Visit X 
Note: Subjects who turn 18 years during the course of this study will be considered as pediatrics, however these subjects will not need to complete the 
Achenbach CBCL and BRIEF assessments.  
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a 
The duration of the Treatment Period will vary by subject age group and is defined in Section 5.1.1. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
physical or neurological examination, ECG, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned 
(eg, Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. If the subject remains in the study beyond Week 238, telephone contacts will 
continue at 8-week intervals. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
f 
Subjects may require additional routine visits (Visit X) if the study is still ongoing at Week 238 for the respective subject. Vx visits are to be performed 
every 24 weeks. Additional routine visits should be scheduled and performed in accordance with footnote ‘b’ to avoid visit window deviations. Assessments 
must be performed in accordance with Table 5‒3. 
g 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-4. For subjects who continue on commercial LCM, the early Termination Visit is the last visit in the study.  
h 
A Termination Visit must be completed for all subjects who complete the study. This can be performed in alignment of the date of the last scheduled visit if 
appropriate. For subjects who will not continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; 
see Table 5-4. For subjects who continue on LCM, the Termination Visit is the last visit in the study.  
i 
Dispensation Visit will occur 12 weeks after each 24-weekly visit from Year 2 (Visit 11) to Year 3 onwards and will be for the purpose of dispensing LCM 
solution for pediatric subjects <50kg. 
j 
The complete physical examination will include cardiac and respiratory function via auscultation and review of all body systems. 
k 
The brief neurological examination will include selected assessment of general neurological status, reflexes, muscle strength, and coordination/cerebellar 
function. 
l 
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) a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
m 
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
n 
Height will be recorded at Visits 12, 14, 16, Visit X (even visits), and at the ET and Termination Visit. 
o 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
p 
Laboratory tests are applicable for combined the last scheduled visit/Termination Visit. If the last scheduled visit is not the Termination Visit, laboratory 
tests are not required. 
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q 
If the patient was treated in SP0982, endocrinology should be done if age was <18 years at SP0982 Visit 1. If the patient was a Baseline failure in SP0982, 
endocrinology should be done if age is <18 years at EP0012 Visit 1. 
r 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion. 
s 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3).  
t 
The Achenbach CBCL: CBCL/6-18 for children ≥6 years to <18 years of age; to be completed by the parent(s)/legal representative(s) (estimated completion 
time 45 minutes). For each version of the CBCL, subjects must have at least 1 year of data before transitioning to the next age range. The Achenbach CBCL 
should be completed by the same parent/legal representative, if possible (see Section 10.4.6).  
u 
The BRIEF should be used for subjects who are ≥5 years of age. For each developmentally appropriate version of the BRIEF, subjects must have at least 
1 year of data before transitioning to the next age range (see Section 10.4.7). 
 
 
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Table 5‒3: 
Schedule of study assessments for Years 3 through 5 for EP0012 
(Treatment Period, ET Visit, Termination Visit, and Unscheduled Visit for 
subjects ≥18 years at enrollment) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of 
study 
Year 3 
Year 4 
Year 5 +Extended Period 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17 
Vxe 
ET Visitf 
Term Visitg 
LCM Solution 
Dispensation 
Visit 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
X 
 
 
 
NA 
Concomitant 
medications 
and AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory 
testsh 
 
X 
 
X 
 
X 
Xi 
Xi 
X 
X 
 
 
Pregnancy 
testj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense 
subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary 
return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Call IRT 
 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
 
X 
Dispense 
LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM 
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 
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AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; IRT=interactive 
response technology; LCM=lacosamide; NA=not applicable; Term=Termination; V=Visit; Vx=Visit X 
a 
The duration of the Treatment Period will vary by patient age group and is defined in Section 5.1.1. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
physical or neurological examination, ECG, vital signs, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric 
AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned (eg, 
Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, Week 
174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230.  If the subject remains in the study beyond Week 238, telephone contacts will 
continue at 8-week intervals. 
e 
Vx visits are to be performed every 24 weeks. When subjects leave the study, investigators should discuss treatment options with the subject and/or legal 
representative to best manage the subject's epilepsy. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. For subjects who will not continue on LCM, this visit will be 
followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on commercial LCM, the early 
Termination Visit is the last visit in the study. Investigators should discuss treatment options with the subject and/or legal representative to best manage the 
subject's epilepsy.  
g 
A Termination Visit must be completed for all subjects who complete the Treatment Period (Week 238 or extended treatment period). This can be performed 
in alignment of the date of the last scheduled visit if applicable. For subjects who will not continue on commercial LCM, this visit will be followed by LCM 
taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on LCM, the Termination Visit is the last visit in the 
study. A Termination Visit is to be done if the subject is leaving the study prior to Week 238 following the approval of the PGTCS indication in their 
respective region/country as follows: for US subjects, when the US approval is obtained; for EU subjects, if the EU approval is obtained; and for all other 
adults at the approval of the PGTCS indication in Japan (last targeted approval). When subjects leave the study, investigators should discuss treatment 
options with the subject and/or legal representative to best manage the subject's epilepsy.  
h 
Laboratory tests include chemistry, hematology and, urinalysis. 
i 
Laboratory tests are applicable for the combined last scheduled visit/Termination Visit. If the last scheduled visit is not the Termination Visit, laboratory 
tests are not required. 
j 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion. 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Table 5-4:Schedule of study assessments (Taper Period and Safety Follow-
Up Period)  
 
Assessment 
 
Taper Perioda 
(up to 4 weeks) 
Safety Follow-Up Periodb 
End of Taper Visit 
(maximum 3 days 
after the last dose)c 
 
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) 
X 
X 
 
Neurological exam (brief) 
X 
X 
 
12-lead ECGd 
X 
Xe 
 
Vital signs (BP and pulse) including 
orthostatic assessments 
X 
X 
 
Body weight  
X 
X 
 
Laboratory tests: 
 
 
 
 
Chemistry/hematology 
X 
Xe 
 
 
Endocrinology 
 
Xe 
 
 
Urine pregnancy testf 
X 
X 
 
Contact IRT 
X 
 
 
Subject diary return/reviewg 
X 
 
 
LCM review/return 
X 
 
 
Withdrawal criteria 
X 
 
 
AE reporting 
X 
X 
X 
C-SSRSh 
X 
X 
 
Healthcare resource usei 
X 
X 
 
Work/school days lost due to epilepsyi 
X 
X 
 
Days with help from a caregiver due to 
epilepsyi 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; IRT=interactive response technology; LCM=lacosamide; TC=telephone contact 
Note: The schedule of study assessments for the Taper Period and Safety Follow-Up Visit includes some of the 
subjects who tapered in SP0982 after the 125th event who consented to enter EP0012 for the Safety Follow-Up 
only. 
a 
Subjects who will not continue on LCM must complete an End of Taper Visit and a Safety Follow-Up 
Period; see Table 5-4. For subjects who continue on commercial LCM, the (Early) Termination Visit is the 
last visit in the study. 
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b 
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 Visit. 
c 
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 7‒2. 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 place at the ET or Termination Visit. 
d 
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) a 12-lead 
ECG (2 interpretable recordings) approximately 20 to 30 minutes apart must be performed. 
e 
The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, 
or endocrinology) or reading (ECG) at the previous clinic visit. 
f 
Pregnancy tests will be performed for female subjects of childbearing potential only. A urine pregnancy test 
will be performed. 
g 
The last subject diary will be returned at the End of Taper Visit. 
h 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3). 
i 
Healthcare resource use, work/schools days lost due to epilepsy, and days with help from a caregiver due to 
epilepsy will be assessed only for patients completing the study after ≤2 years. These assessments are not 
applicable for patients tapering down or performing the SFU-visits during Years 3, 4 or 5). 
5.3 
Rationale for study design and selection of dose 
Clinical experience has shown that up to 30% of patients with PGTCS who are treated with 
currently available AEDs have inadequate seizure control or poor drug tolerability. Thus, 
there is a significant unmet medical need for new treatment options in this patient population.  
The efficacy, safety, and tolerability of LCM as an adjunctive therapy have been 
demonstrated in the partial-onset seizure population. The approach for further LCM 
development is to evaluate the use of adjunctive LCM for the treatment of uncontrolled 
PGTCS in patients with IGE.  
The goal of the Phase 3 LCM PGTCS program is to provide clinical evidence of the efficacy 
and safety of LCM as an adjunctive therapy for uncontrolled PGTCS in subjects with IGE as 
the basis for approval of this indication. SP0982 is a double-blind, randomized, placebo-
controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety of 
LCM for uncontrolled PGTCS in subjects ≥4 years of age with IGE. EP0012 will provide 
continued availability of LCM to subjects who have completed SP0982 and eligible Baseline 
failures from SP0982. 
For adult subjects (≥18 years of age), 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 PGTCS 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 PGTCS with IGE. The maximum dose of LCM 800mg/day is the highest 
dose that has been used in previous clinical studies. Dose selection in EP0012 is based on the 
primary study (SP0982). During EP0012, investigators will be allowed to increase or 
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decrease the dose of LCM to optimize tolerability and seizure reduction for each subject. 
Lacosamide doses may be increased up to a maximum of LCM 12mg/kg/day (oral solution) 
for pediatric subjects weighing <50kg. The maximum dose for pediatric subjects (<18 years 
of age) ≥50kg is 600mg/day (tablets) and for adult subjects is 800mg/day (tablets).  
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 for the open-label extension study (EP0012) must 
be 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 must have completed or be an eligible Baseline failure from the parent study 
(SP0982), as defined in Section 5.1. Note: Other subjects screened for SP0982 may be 
considered for roll-over to EP0012 if the investigator considers that the subject could 
benefit from treatment with open-label LCM and based on prior discussion with and 
approval from the UCB Study Physician or representative. 
3. Subject/legally acceptable representative considered as reliable and capable of adhering to 
the protocol (eg, able to understand and complete diaries and questionnaires), visit 
schedule, and medication intake according to the judgment of the investigator. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject is receiving any investigational drugs or using any experimental devices in 
addition to LCM. 
2. Subject meets the withdrawal criteria for SP0982 or is experiencing an ongoing serious 
adverse event (SAE). 
3. Subject has an active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide 
Severity Rating Scale (C-SSRS). The subject should be referred immediately to a Mental 
Healthcare Professional. 
4. 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 all subjects who entered EP0012 directly 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. 
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Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be 
repeated once for confirmation. 
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 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Investigators should contact the Medical Monitor whenever possible to discuss the 
withdrawal of a subject in advance. All subjects discontinuing treatment with LCM for any 
reason should taper as described in Section 7.2. All subjects who withdraw due to an AE 
must be followed until resolution of the event or until the event is considered stable. 
Subjects must be withdrawn from the study if any of the following events occur: 
1. Tapered subjects from SP0982 who enter EP0012 after the 125th event will be withdrawn 
at the enrollment visit and enter directly into the Safety Follow-Up Period without and ET 
Visit being performed in EP0012.  
2. The subject develops second or third degree atrioventricular (AV) block. 
3. The subject becomes pregnant, as evidenced by a positive pregnancy test. 
4. The sponsor or a regulatory agency requests withdrawal of the subject. 
5. The subject is unwilling or unable to continue, or the legal representative is unwilling or 
unable to allow the subject to continue in the study. 
6. In the case of liver function test (LFT) results of transaminases (ALT and/or aspartate 
AST) ≥3x ULN to <5xULN and total bilirubin ≥2xULN or transaminases (AST and/or 
ALT) ≥5xULN, LCM must be immediately discontinued, and the subject withdrawn from 
the study. The LFTs will be repeated as soon as possible, and in no case more than 
1 week later. 
7. Subject ≥6 years of age has actual suicidal ideation since last visit 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. 
8. Subject is unable to tolerate at least the minimum LCM target dose of 4mg/kg/day (oral 
solution) or 200mg/day (tablets). 
Subjects may be withdrawn from the study if any of the following events occur: 
• The subject requires a medication that is not permitted (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. 
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• 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. 
• Discontinuation criteria for potential drug-induced liver injury (PDILI) are described in 
Section 6.3.1. 
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. 
After the decision to withdraw the subject, the investigator will provide the subject with 
information about available alternative treatments. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with PDILI must be assessed to determine if investigational medicinal product 
(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%). 
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume 
IMP administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 10.3.1.2.1 are followed. 
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 10.3.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. See 
Section 6.3 for when and how to discontinue subjects from the IMP. See Section 8.2 for the 
procedures to be performed at the time of discontinuation. 
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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 CRF must 
document the primary reason for IMP discontinuation. 
7 
STUDY TREATMENT(S) 
7.1 
Description of investigational medicinal product(s) 
Investigational medicinal product (IMP) will be provided as LCM oral solution (LCM 
10mg/mL) and LCM tablets (LCM 50mg and LCM 100mg). 
The oral solution formulation contains 10mg/mL of drug substance and is colorless to pale 
yellow in appearance. 
The tablet formulation will be supplied in doses of 50mg and 100mg. The 50mg tablets are 
light pink, oval, film-coated tablets debossed with “SP” on 1 side and “50” on the other. The 
100mg tablets are dark yellow, oval, film-coated tablets debossed with “SP” on 1 side and 
“100” on the other. 
7.2 
Treatment(s) to be administered 
Lacosamide will be orally administered bid (at approximately 12-hour intervals in the 
morning and in the evening) in 2 equally divided doses (oral solution for pediatric subjects 
weighing <50kg or tablets for adult subjects [≥18 years of age] and pediatric subjects 
[<18 years of age] weighing ≥50kg); during the study, subjects who initially started on oral 
solution may transfer to tablets at the investigator’s discretion.  
Tablets must not be broken. In rare cases where uneven dosing (e.g., 350mg/day, 
450mg/day, 550mg/day, etc) is medically needed, although the interactive response 
technology (IRT) will not dispense the exact dose, please contact the Medical Monitor for 
additional instructions. 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]). 
During the study, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction for each subject, within the dose range described 
in Table 7‒1.  
7.2.1 
Treatment Period 
At Visit 1, subjects who completed SP0982 will start on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg 
to <50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start 
at Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and 
LCM 100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects 
weighing ≥50kg.  
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Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility 
based on tolerability is allowed. Investigators will assess whether a subject would tolerate a 
further LCM 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 target dose of 
4mg/kg/day (oral solution) or 200mg/day (tablets).  
Subjects who tapered in SP0982 after the 125th event will enroll at Visit 1 and proceed 
directly to the Safety Follow-up Period without receiving LCM.  
At any time during the course of the study if it becomes apparent that a subject is unable to 
attain at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then 
the subject must enter the Taper Period and be withdrawn from the study. 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased 
in steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must 
remain on the dose for ≥7 days before a subsequent dose escalation.  
Table 7‒1 provides the minimum and maximum LCM dose during the Treatment Period. 
Table 7‒1: 
Minimum and maximum LCM dose during the Treatment Period 
Formulation 
Minimum LCM dose 
Maximum LCM dose 
Oral solution (pediatric subjects <50 kg) 
4mg/kg/day 
12mg/kg/day 
Tablets (pediatric subjects ≥50kg) 
200mg/day 
600mg/day 
Tablets (adult subjects) 
200mg/day 
800mg/day 
LCM=lacosamide  
The LCM dose may be adjusted at the investigator’s discretion after the subject receives the 
first dose of LCM in the study. Baseline failures must complete Week 1 of dosing before 
LCM may be increased or decreased. The maximum dose for pediatric subjects weighing 
<50kg is 12mg/kg/day (oral solution). The maximum dose for pediatric subjects weighing 
≥50kg is 600mg/day (tablets) and for adult subjects is 800mg/day (tablets).  
A clinic visit (scheduled or unscheduled) is required if:  
• The dose is increased for the first time to any dose above 10mg/kg/day for pediatric 
subjects weighing <50kg. One week after the first time the dose is increased, an 
unscheduled telephone contact must be conducted to ensure that the dose is well tolerated. 
• The dose is increased for the first time to any dose above LCM 400mg/day for all adult 
subjects or pediatric subjects weighing ≥50kg. One week after the first time the dose is 
increased, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
Subjects withdrawing from the study must complete the ET Visit and (if they do not proceed 
with commercially available LCM)  an up to 4-week taper followed by an End of Taper Visit 
(see taper schedule, Table 7‒2). Following the End of Taper Visit, there will be a 30-day 
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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. A slow 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. In case of an emergency, a faster taper is permitted after discussion 
with the Medical Monitor, whenever possible.  
At the completion of the Treatment Period, investigators should discuss treatment options 
with the subject and/or their parent(s)/legal representative(s) to best manage the subject’s 
epilepsy. Taper of LCM may not be required for some subjects who complete the study 
depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent(s)/legal representative(s). 
Subjects completing the Treatment Period and not continuing with commercially available 
LCM must complete the Termination Visit and also undergo taper, followed by an End of 
Taper Visit (see taper schedule, Table 7‒2), and a 30-day Safety Follow-Up Period.  
The following table summarizes the recommended LCM dose taper: 
Table 7‒2: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
4mg/kg/day 
2mg/kg/day 
NA 
NA 
NA 
800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
NA 
300mg/day 
200mg/day 
100mg/day 
NA 
NA 
200mg/day 
100mg/day 
NA 
NA 
NA 
ET=early termination; LCM=lacosamide; NA=not applicable 
Note: The oral solution is dosed as mg/kg/day and tablets are dosed as mg/day. 
aSubjects will begin taper on ET/Termination Visit. 
7.3 
Packaging 
Lacosamide (tablets and oral solution) 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 
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storage. Oral solution will be packaged in amber polyethylene terephthalate bottles. Tablets 
will be supplied in high-density polyethylene bottles with child proof polypropylene screw 
caps. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice 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 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 Handing 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 the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including 
empty containers)/partially used, unused, damaged, and/or expired IMP must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB Standard 
Operating Procedures (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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7.7 
Procedures for monitoring subject compliance 
At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP 
bottles. 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-PGTCS.  
7.8 
Concomitant medication(s)/treatment(s) 
All concomitant medication and treatment must be recorded in the appropriate study 
documents (eg, eCRF and source document). 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
Female subjects not surgically sterile or 2 years postmenopausal should practice 1 highly 
effective method of contraception (according to 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. Recommended contraception methods for subjects on 
enzyme-inducing antiepileptic drugs (EI-AEDs) or not on EI-AEDs are detailed in 
Section 16.7. Subjects on EI-AEDs who do not use one of the highly effective contraception 
methods recommended for this group may practice 2 combined methods of contraception (ie, 
combined hormonal contraception plus barrier method with spermicidal agent). 
The initiation of felbamate treatment while participating in EP0012 is prohibited. 
The use of neuroleptics except for clozapine is allowed. The use of barbiturates and narcotic 
analgesics is also allowed. Stable use of benzodiazepines is allowed as concomitant AEDs, 
but intermittent use is only allowed as rescue medication for epilepsy indications (maximum 
1 dose per week). 
During the Treatment Period, new concomitant AEDs may be introduced, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication 
in the subject’s country. For example, a new AED may be added when the subject has not 
optimally or adequately responded (lack of efficacy or tolerance) to LCM. Concomitant 
AEDs may be carefully tapered and discontinued to achieve LCM monotherapy, if clinically 
appropriate. The Medical Monitor must be consulted prior to initiation of concomitant AED 
withdrawal. 
 
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7.8.2 
Prohibited concomitant treatments (medications and therapies) 
The following medications/therapies are prohibited during the course of this study: 
• Clozapine 
• MAO-A inhibitors 
• Vigabatrin 
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 
This is an open-label study; there will be no blinding. 
7.10 
Randomization and numbering of subjects 
This is an open-label study and subjects will not be randomized to any treatment groups. The 
unique identification number assigned to subjects during the previous SP0982 study will be 
used to identify subjects and to maintain subject confidentiality throughout the current study. 
An IRT will be used to assign the applicable LCM treatment. Further instructions will be 
provided in the IRT manual.  
8 
STUDY PROCEDURES BY VISIT 
Prior to any study activities, the subject or legal representative will be asked to read and sign 
an Informed Consent form that has been approved by an IRB/IEC and that complies with 
regulatory requirements. The subject or legal representative will be given adequate time to 
consider any information concerning the study, given to them by the investigator or designee. 
As part of the informed consent procedure, the subject or legal representative will be given 
the opportunity to ask the investigator any questions regarding potential risks and benefits of 
participation in the study. Additionally, if applicable (according to the subject’s age and local 
requirements), the subject will sign an IRB/IEC Assent form. 
All visits occur at the end of the respective week in the study and a window of ±7 days 
relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a 
Telephone Contact every 8 weeks if no clinic visit is scheduled. 
A detailed schedule of study assessments for treatment Years 1 to 2 is provided in Table 5‒1, 
for treatment Years 3 to 5 in Table 5‒2, Table 5‒3 and for the Taper Period and Safety 
Follow-Up Period in Table 5-4.  
8.1 
Treatment Period 
8.1.1 
Visit 1 (Week 0) 
The following tasks and procedures are to be performed at this visit (for subjects who have 
completed SP0982, assessments marked [*] should have already been completed during the 
last visit of the previous protocol and do not need to be repeated at Visit 1; for eligible 
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Baseline failures from SP0982, a full Visit 1 is required including all scheduled tasks and 
procedures). Tapered subjects from SP0982 will enter EP0012 for the Safety Follow-Up only 
and will be withdrawn at Visit 1 once Visit 1 assessments have been performed. Details of 
the Safety Follow-Up are provided in Section 8.4.2 and Section 8.4.3. 
• Written Informed Consent/Assent 
• Inclusion/exclusion criteria 
• Subject identification card dispensed 
• Concomitant medications and AEDs* 
• Medical history/epilepsy history update 
• Physical examination (complete)* 
• Neurological examination (complete)* 
• ECG (12-lead) assessment* 
• Vital signs (pulse rate, BP) including orthostatic assessments* 
• Body weight and height* 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]).* Baseline failures from SP0982 
may have an additional urine pregnancy test at V1 of EP0012, at the investigator’s 
discretion. 
• Contact IRT 
• Dispense subject diary 
• Dispense LCM 
• Assess withdrawal criteria* 
• AE reporting* 
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
• Healthcare resource use* 
• Work/school days lost due to epilepsy* 
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• Days with help from a caregiver due to epilepsy* 
8.1.2 
Visits 2 to 8 (Weeks 2 to 46, Year 1, excluding Visit 6 and Visit 7) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (brief, Visit 2, 3, 4, and 5; complete, Visit 8) 
• Neurological examination (brief, Visit 2, 3, 4, and 5; complete, Visit 8) 
• ECG (12-lead) assessment (Visit 2, 4, and 8 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight (Visit 4, and 8 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 8 only) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) [Visit 2, 5, and 8 only], and a urine pregnancy test [for women 
of childbearing potential])  
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 5 and 8) (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
(Visit 5 and 8 only) 
• Achenbach CBCL for subjects <18 years of age (Visit 5 and 8 only) 
• BRIEF for subjects <18 years of age (Visit 5 and 8 only) 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
8.1.3 
Visits 9 and 11 (Weeks 62 and 94, Year 2, excluding Visit 10) 
The following tasks and procedures are to be performed at these visits: 
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• Concomitant medications and AEDs  
• Physical examination (brief, Visit 9; complete, Visit 11) 
• Neurological examination (brief, Visit 9; complete, Visit 11) 
• ECG (12-lead) assessment (Visit 9 and 11) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 9 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 11 only) 
• 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]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 9 and 11) (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
(Visit 9 and 11 only) 
• Achenbach CBCL for subjects <18 years of age (Visit 9 and 11 only) 
• BRIEF for subjects <18 years of age (Visit 9 and 11 only) 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
8.1.4 
Visits 12, 13, 14, 15, 16, 17 and X (Weeks 118, 142, 166, 190, 214, 
238, and X, Years 3 to 5 + Extended Period) 
8.1.4.1 
Subjects <18 years 
The following tasks and procedures are to be performed at these visits (Visit X [Vx] visits are 
to be performed every 24 weeks): 
• Concomitant medications and AEDs 
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• Physical examination (complete, Visit 13, 15, 17, and odd numbered visits thereafter) 
• Neurological examination (brief, Visit 12, 14, 16, 17, and even numbered visits 
thereafter) 
• ECG (12-lead) assessment (Visit 13, 15, 17, and odd numbered visits thereafter) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 12, 14, 16, and even numbered visits thereafter) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 13, 15, 17, and odd numbered visits 
thereafter) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 
17/Termination Visit. If Visit 17 is not the Termination Visit, laboratory tests are not 
required. Laboratory tests are not performed at Visit 13 and 15 according to Protocol 
Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects ≥6 years to <18 years of age (Visit 13, 15, 17, and odd 
numbered visits thereafter) 
• BRIEF for subjects ≥5 to <18 years of age (Visit 13, 15, 17, and odd numbered visits 
thereafter) 
8.1.4.2 
Subjects ≥18 years 
The following tasks and procedures are to be performed at these visits, additional routine 
visits (Visit X) can be done after Visit 17 (Vx visits are to be performed every 24 weeks) with 
assessments described in Table 5‒3. 
• Concomitant medications and AEDs 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 
17/Termination Visit. If Visit 17 is not the Termination Visit, laboratory tests are not 
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required. Laboratory tests are not performed at Visit 13 and 15 according to Protocol 
Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
8.1.5 
Telephone Contact  
Telephone contacts are required at Week 30 and Week 38 and every 8 weeks during Year 2 
to Year 5, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, 
telephone contacts in Year 2 are scheduled for Week 54, Week 70, Week 78, and Week 86. 
Telephone contacts in Years 3 to 5 are scheduled for: Year 3 - Week 102, Week 110, Week 
126, Week 134; Year 4 - Week 150, Week 158, Week 174, Week 182; Year 5 - Week 198, 
Week 206, Week 214, Week 222, Week 230, Week 238, and every 8 weeks during the 
Extended Period. 
The investigator or designee should contact the subject by telephone. During the telephone 
contact the following assessments will be performed: 
• Concomitant medications and AEDs 
• Assess withdrawal criteria 
• AE reporting 
The investigator will also ensure subjects are compliant with LCM administration and diary 
completion during the telephone contact. 
8.1.6 
LCM Solution Dispensation Visit 
From Year 3 onwards, pediatric subjects weighing <50kg will return to the clinic for an 
additional Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of 
LCM solution; LCM usage will be reviewed, and empty LCM bottles will be returned. 
8.2 
Early Termination Visit 
Subjects withdrawing from the study will complete the ET Visit, and LCM will be tapered 
over a period of up to 4 weeks if not continuing with commercially available LCM (see taper 
schedule, Table 7‒2). 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
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• Physical examination (complete), excluding subjects ≥18 years after the first 2 years 
• Neurological examination (brief), excluding subjects ≥18 years after the first 2 years 
• ECG (12-lead) assessment, excluding subjects ≥18 years after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments, excluding subjects ≥18 
years after the first 2 years 
• Body weight and height, excluding subjects ≥18 years after the first 2 years 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study), excluding subjects ≥18 years after the first 2 
years 
• C-SSRS assessment (for subjects ≥6 years of age), excluding subjects ≥18 years after the 
first 2 years 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the ET Visit for subjects early terminating 
the study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
8.3 
Termination Visit 
A Termination Visit will be completed by subjects who complete the Treatment Period and 
meet 1 of the following conditions:   
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1. The subject chooses to transition to commercial LCM. 
2. The subject chooses not to continue treatment with LCM.   
Subjects not continuing treatment with LCM will complete the Termination Visit, and LCM 
will be tapered over a period of up to 4 weeks (see taper schedule, Table 7‒2). Subjects who 
continue treatment with commercial LCM must also complete the Termination Visit. 
Taper of LCM is not required for subjects who leave the Termination Visit and transition to 
commercial LCM. Subjects transitioning to commercial LCM will do so immediately and 
will continue at a dose determined by the investigator.  In this instance, the Termination Visit 
will serve as the subject's last visit in the study.   
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Physical examination (complete), excluding subjects ≥18 years after the first 2 years 
• Neurological examination (complete) Note: Complete neurological exam to be performed 
for subjects terminating the study during Years 1-2, for all subjects and brief exam for 
subjects <18 years terminating during Years 3-5. Neurological exam is excluded for 
subjects ≥18 years after the first 2 years. 
• ECG (12-lead) assessment, excluding subjects ≥18 years after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments excluding subjects 
≥18 years after the first 2 years 
• Body weight and height, excluding subjects ≥18 years after the first 2 years 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study), excluding subjects ≥18 years after the first 2 
years 
• C-SSRS assessment (for subjects ≥6 years of age), excluding subjects ≥18 years after the 
first 2 years 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary for subjects undergoing taper 
• Subject diary return/review 
• Dispense LCM for subjects undergoing taper 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
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• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the Termination Visit for subjects 
terminating the study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
8.4 
Taper and Safety Follow-Up Period 
8.4.1 
End of Taper Visit 
An End of Taper Visit will occur after the final LCM dose for subjects who taper off LCM. 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Physical examination (complete) 
• Neurological examination (brief) 
• ECG (12-lead) assessment 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and a urine pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Subject diary return/review 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
The following assessments are only applicable at the End of Taper Visit for subjects 
terminating/early terminating the study during the first 2 years (see Section 4.2.3): 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
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Subjects who were already tapered in SP0982 after the 125th event occurred do not need to 
undergo the End of Taper Visit assessments in EP0012 as the assessments were performed in 
SP0982. 
8.4.2 
Safety Follow-Up Visit 
Following the End of Taper Visit, the subject will return 2 weeks after the last dose of study 
drug for a Safety Follow-Up Visit (including subjects tapered in SP0982 after the 125th event 
occurs who enter EP0012 only for a Safety Follow-Up Visit). During the Safety Follow-Up 
Visit, the following assessments will be performed: 
• Concomitant medications and AEDs 
• Physical examination (complete) 
• Neurological examination (brief)  
• ECG (12-lead) assessment (only required for subjects with an abnormal reading at the 
previous clinic visit) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight  
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, [only required for subjects with an abnormal value at the 
previous clinic visit], and a urine pregnancy test [for women of childbearing potential]) 
• AE reporting 
The following assessments are only applicable at the Safety Follow-Up Visit for subjects 
terminating/early terminating the study during the first 2 years (see Section 4.2.3): 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
8.4.3 
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. During the Safety Follow-Up telephone contact, the following 
assessments will be performed: 
• Concomitant medications and AEDs  
• AE reporting 
8.5 
Unscheduled Visit 
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. A clinic visit (scheduled or unscheduled) is required the first time the dose is 
increased above the dose of 10mg/kg/day (oral solution) for pediatric subjects weighing 
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<50kg or 400mg/day (tablets) for adult and pediatric subjects ≥50kg. One week after the first 
time the dose is increased above the dose of 10mg/kg/day or 400mg/day, an unscheduled 
telephone contact must be conducted to ensure that the dose is well tolerated. Similarly, a 
clinic visit (scheduled or unscheduled) is required for pediatric subjects weighing <50 kg the 
first time the dose is increased to 11mg/kg/day, or 12mg/kg/day, and all adult subjects or 
pediatric subjects weighing ≥50kg the first time the dose is increased to LCM 500mg/day, 
LCM 600mg/day, LCM 700mg/day, and LCM 800mg/day. One week after the first time the 
dose is increased to 11mg/kg/day, or 12mg/kg/day for pediatric subjects <50kg, and 
LCM 500mg/day, LCM 600mg/day, LCM 700mg/day, or LCM 800mg/day for all adult 
subjects or pediatric subjects weighing ≥50kg, an unscheduled telephone contact must be 
conducted to ensure that the dose is well tolerated. 
During an Unscheduled Visit the following assessments are required: 
• Concomitant medications and AEDs  
• Physical examination (brief) during the first 2 years, excluding subjects ≥18 years after 
the first 2 years 
• Neurological examination (brief) during the first 2 years, excluding subjects ≥18 years 
after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments, excluding subjects ≥18 
years after the first 2 years 
• Contact IRT 
• Subject diary return/review 
• Assess withdrawal criteria 
• AE reporting 
If Unscheduled Visit is due to a psychiatric AE, then the C-SSRS is required. 
In addition to the required assessments listed above, further assessments can be completed as 
needed and may include ECG, laboratory tests, etc. 
9 
ASSESSMENT OF EFFICACY 
9.1 
Seizure variables 
Subjects will keep a diary to record all seizure activity from Visit 1 until the end of study 
participation. Efficacy variables will be assessed using the seizure count information recorded 
on the subject diaries. The subject should be reminded to bring the diary to each clinic visit. 
Should an adverse event involving a seizure be reported, it must be consistent with the 
seizure information (including specific type of seizure) reported in the seizure diary. 
9.1.1 
PGTCS 
The following information will be recorded as applicable: 
• Seizure type 
• Number of PGTCS 
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If more than one PGTCS occurs on a single day, each seizure should be counted separately, 
provided there is a complete recovery of consciousness between seizures. 
9.1.2 
Absence and myoclonic seizures 
In the subject diary, the following information will be recorded: 
• 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.  
9.2 
Health outcome variables 
Health outcome variables will be evaluated during the first 2 years of treatment. 
9.2.1 
Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) 
The QOLIE-31-P Version 2 (see Section 16.2) 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). 
9.2.2 
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 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 HRQoL is measured for pediatric subjects ≤4 years of age. The PedsQL 
appropriate for each subject’s age should be completed, with the following exception: if a 
subject ages up to the next form of the PedsQL within 1 year after the Baseline assessment of 
the primary study, the form that was used at the Baseline assessment should be completed for 
1 year after the Baseline assessment, and subsequently the form consistent with his/her age at 
the time of assessment should be completed. 
For each version of the PedsQL, subjects must have at least 1 year of data before 
transitioning to the next age range. 
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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. 
9.2.3 
EuroQol-5D-3L Quality of Life Assessment  
The EQ-5D-3L (EuroQol Group, 2011) (see Section 16.3) 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 VAS, anchored 
at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the 
bottom. 
9.2.4 
Healthcare resource use 
Healthcare resource use will include concomitant medical procedures, hospitalizations, and 
healthcare provider visits during the first 2 years of treatment. 
9.2.5 
Number of working or school days lost due to epilepsy 
The number of working or school days lost by the subject due to epilepsy will be recorded, as 
applicable during the first 2 years of treatment. 
9.2.6 
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 during the first 2 years of treatment. 
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 this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
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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 
investigational product was taken but specific study procedures were conducted. This 
includes all AEs not present prior to the initial visit and all AEs that recurred or worsened 
after the initial visit. 
Signs or symptoms of the condition/disease for which the investigational product is being 
studied should be recorded as AEs only if their nature changes considerably or their 
frequency or 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.  
Should an AE involving a seizure be reported, it must be consistent with the seizure 
information (including specific type of seizure) reported in the seizure diary. 
10.1.1.2 
Serious adverse events 
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, but are not limited to, 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 he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization 
criteria. However, emergency room visits that do not result in admission to the hospital 
would not qualify for this criteria and, instead, should be evaluated for 1 of the other 
criteria in the definition of serious [eg, life-threatening adverse experience, important 
medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or 
manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For 
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example, if a subject has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. 
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.) 
If commercial LCM is given during hospitalization, this needs to be recorded on the CRF. 
10.1.1.2.1 
Anticipated serious adverse events 
The following Anticipated SAEs are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure.  
This list does not change the investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 10.1.2. 
Table 10‒1: Anticipated serious adverse events 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 
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 beats/min) 
• Syncope or loss of consciousness (other than seizure related) 
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• Serious suspected multiorgan hypersensitivity reactions.  
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US Food and 
Drug Administration: 
An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) 
combined with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ 
Eosinophils % ≥10% 
◦ 
Eosinophils absolute ≥0.5G/L 
◦ 
Neutrophils absolute <1.5G/L 
◦ 
Platelets ≤100G/L 
◦ 
ALT ≥2xULN 
◦ 
AST ≥2xULN 
• Emergence of non-pre-existing 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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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 IMP), 
up to 30 days from the end of the study for each subject, and to also inform participating 
subjects of the need to inform the investigator of any SAE within this period. Serious AEs 
that the investigator thinks may be associated with the IMP must be reported to UCB 
regardless of the time between the event and the end of the study. 
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure. 
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 10.3.1.4. 
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If an AE is still ongoing at the end of the study for a subject, follow up should be provided 
until resolution/stable level of sequelae is achieved, or until the investigator no longer deems 
that it is clinically significant, or until the subject is lost to follow up. If no follow up is 
provided, the investigator must provide a justification. The follow up will usually be 
continued for 30 days after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the 
Patient Safety (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 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, 
UCB will ask the investigator or designee to contact the subject and his partner to request 
consent 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/contract research organization (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 
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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. 
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 CRF, 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 SAE or nonserious AE. These events are only considered AEs or SAEs 
if there are associated clinical signs and symptoms or if the act of taking the excess medicine 
itself is an AE or SAE (eg, suicide attempt). 
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 
New seizure types, increase in days with and worsening of 
days with absence or myoclonic seizures 
Incidence of new seizure types, increase in absence seizure days or myoclonic seizure days 
per 28 days during the Treatment Period, and 50% worsening in days with absence seizures 
or myoclonic seizures per 28 days during the Treatment Period will be assessed using the 
seizure count information recorded on the subject diaries (see Section 9.1). 
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10.3 
Laboratory measurements 
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, 
Table 5‒2, Table 5‒3 and Table 5-4. A central laboratory will perform the routine analysis of 
blood and urine specimens. Pregnancy testing will also be performed (see Section 10.3.2). 
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 
Endocrinology 
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 
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 
 
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; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid stimulating hormone; WBC=white blood cell 
10.3.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI 
events must be reported as an AE and reported to the study site and sponsor within 24 hours 
of learning of their occurrence. Any PDILI event that meets the criterion for potential Hy’s 
Law must be reported as an AE of special interest (see Section 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 10.3.1.1). 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 
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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 10.3.1.4). 
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 CRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider 
changing any medically required concomitant medication known to be hepatotoxic to a 
suitable alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 10.3.1.2.1 are met, rechallenge with IMP may be appropriate.  
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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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 
≥2xULNb 
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 10.3.1.3); 
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 10.3.1.2). 
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 10.3.1.3). 
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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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 10.3.1.1. 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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10.3.1.1 
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 10.3.1.3) and SAE report (if 
applicable). 
10.3.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring. The immediate action is 
dependent on the laboratory values and symptoms of hepatitis or hypersensitivity and ranges 
from continuation of IMP (followed by immediate investigation) to immediate and permanent 
discontinuation (see Section 6.3.1 and Table 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. 
10.3.1.2.1 
IMP restart/rechallenge (if applicable) 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur. 
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 10‒3), but for whom an alternative diagnosis 
is confirmed, can rarely restart IMP. Rechallenge with IMP can occur only if ALL of the 
following requirements are met: 
• The results of additional testing and monitoring described in Section 10.3.1.3 and 
Section 10.3.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory 
parameters and any associated symptoms (ie, a subsequent alternative diagnosis fully 
explains the hepatic findings).  
• No alternative treatment options are available to the subject. 
• The subject has shown clear therapeutic benefit from the IMP. 
• Subject’s ALT or AST elevations do not exceed ≥3xULN. 
• Subject’s total bilirubin is <1.5xULN. 
• Subject has no signs or symptoms of hypersensitivity.  
• The rechallenge is approved by the UCB responsible physician and a hepatologist. The 
hepatologist must be external to UCB. It is recommended that the hepatologist be a local 
hepatology expert or the hepatologist treating the subject. 
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Subject agrees to the investigator-recommended monitoring plan. 
10.3.1.3 
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 CRF. 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: 
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 
Differential count, hematocrit, hemoglobin, platelet count, RBC and WBC 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Albumin, AST, ALT, ALP, GGT, serum CPK, and LDH to evaluate possible 
muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
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ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma glutamyl transferase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RBC=red blood 
cell count; RNA=ribonucleic acid; ULN=upper limit of normal; WBC=white blood cell count 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
The following additional information is to be collected: 
Table 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 
10.3.1.4 
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. 
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10.3.2 
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, Table 5‒3 
and Table 5-4.  
10.4 
Other safety measurements 
10.4.1 
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, Table 5‒3 and Table 5-4. 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 schedule of study assessments in Table 5‒1, 
Table 5‒2, Table 5‒3 and Table 5-4.  
10.4.2 
12-lead ECG 
Standard 12-lead ECGs will be performed according to the schedule of study assessments in 
Table 5‒1, Table 5‒2, Table 5‒3 and Table 5-4.  
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), a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
10.4.2.1 
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 6.3). 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. 
10.4.3 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia 
University Medical Center, 2008). This scale will be used for screening as well as to assess 
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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, Table 5‒3 
and Table 5-4.  
The C-SSRS will be completed for subjects who are ≥6 years of age. The “Since Last Visit” 
version of the C-SSRS should be used. If a subject becomes 6 years of age during the study, 
the "Already Enrolled" version of the C-SSRS should be used once, followed by the “Since 
Last Visit” version 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. 
10.4.4 
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, Table 5‒3 and Table 5-4. Clinically significant physical examination findings are 
to be reported as AEs. 
10.4.4.1 
Complete physical examination 
The complete physical examination will include cardiac and respiratory function via 
auscultation and review of all body systems.  
10.4.4.2 
Brief physical examination 
The brief physical examination will include review of the following body systems: 
• Cardiovascular 
• Pulmonary 
• Abdominal (hepato-gastrointestinal) 
• Dermatologic 
10.4.5 
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, Table 5‒3 and Table 5-4. 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 
PGTCS. 
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10.4.5.1 
Complete neurological examination 
The complete neurological examination will include selected assessment of mental status, 
sensory systems, motor functions, cranial nerves, reflexes, and coordination/cerebellar 
function. 
10.4.5.2 
Brief neurological examination 
The brief neurological examination will include selected assessments of: general neurological 
status, reflexes, muscle strength and coordination/cerebellar function. 
10.4.6 
Achenbach CBCL 
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. 
The Achenbach CBCL consists of the CBCL/1½ -5 for children <5 years and 11 months of 
age, and the CBCL/6-18 for children ≥6 years to <18 years of age. These are to be completed 
by the parent(s)/legal representative(s). The completion of the Achenbach CBCL will require 
approximately 45 minutes. The version of the Achenbach CBCL appropriate to each subject’s 
age should be administered with the following exception: for subjects who completed the 
CBCL/1½-5 at the Baseline assessment of the previous study and turn 6 years of age within 
1 year after the Baseline assessment of the primary study, the CBCL/1½-5 should be 
completed for 1 year after the Baseline assessment of the primary study, and subsequently the 
CBCL/6-18 should be completed. The Achenbach CBCL will only be administered in 
countries where a validated translated version is available. For each version of the CBCL, 
subjects must have at least 1 year of data before transitioning to the next age range. 
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. 
10.4.7 
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 or 
BRIEF appropriate for each subject’s age should be completed, with the following exception: 
For subjects who completed the BRIEF-P at the Baseline assessment of the previous study 
and turn 5 years of age within 1 year after the Baseline assessment of the primary study, the 
BRIEF-P should be completed for 1 year after the Baseline assessment of the primary study, 
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and subsequently the BRIEF should be completed. The BRIEF-P and BRIEF will be 
administered according to the tabular schedules of study procedures (Section 5.2). The 
BRIEF-P and BRIEF will be used only in countries where a translated scale is available. For 
each developmentally appropriate version of the BRIEF subjects must have at least 1 year of 
data before transitioning to the next age range. 
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.  
10.4.8 
Tanner stage 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study, according to the schedule of study assessments 
in Table 5‒1 and Table 5‒2. The investigator or qualified designee will evaluate the subject’s 
sexual development using the 3-item 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 the evaluation of Tanner Stage (ie, those subjects who are pubescent 
at Visit 1 or who will enter puberty during the course of the study). 
11 
STUDY MANAGEMENT AND ADMINISTRATION 
11.1 
Adherence to protocol 
The investigator should not deviate from the protocol. In medical emergencies, the 
investigator may use his/her medical judgment and may remove a study participant from 
immediate hazard before notifying UCB (or its representative) and the IRB/IEC in writing 
regarding the type of emergency and the course of action taken. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the 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 
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data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study 
participant). Monitoring visits will provide UCB (or designee) with the opportunity to 
evaluate the progress of the study, verify the accuracy and completeness of eCRFs, ensure 
that all protocol requirements, applicable authorities’ regulations, and investigator’s 
obligations are being fulfilled, and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 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. 
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. 
11.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During 
monitoring visits, reported data are reviewed with regard to being accurate, complete, and 
verifiable from source documents (eg, subject files, recordings from automated instruments, 
tracings [ECG], x-ray films, laboratory notes). All data reported on the eCRF should be 
supported by source documents, unless otherwise specified in Section 11.2.1. 
11.3 
Data handling 
11.3.1 
Case Report form completion 
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. 
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Detailed instructions will be provided in the eCRF completion guidelines. 
11.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning 
checks will be used in addition to manual review to check for discrepancies and to ensure 
consistency of the data. This study will be 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. 
11.3.3 
Subject Enrollment log/Subject Identification Code list 
The subject’s enrollment will be recorded in the Subject 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. 
11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at 
a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
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. 
11.5 
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 investigational product. These 
documents should be retained for a longer period, however, if required by the applicable 
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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 (TMF). 
11.6 
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 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 
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). 
11.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt 
action by UCB to secure compliance. Continued noncompliance may result in the termination 
of the site’s involvement in the study. 
12 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the 
Statistical Analysis Plan (SAP). 
12.1 
Definition of analysis sets 
12.1.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have a signed Informed Consent/
Assent form. 
12.1.2 
Safety Set 
The Safety Set (SS) consists of all enrolled subjects who received at least 1 dose of LCM 
during EP0012. 
12.1.3 
Full Analysis Set 
The Full Analysis Set is a subset of the SS and consists of all subjects with seizure diary data 
for at least 1 day during EP0012. 
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12.2 
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 (SD), median, 
minimum, and maximum. 
12.3 
Planned safety and other analyses 
12.3.1 
Safety analyses 
The incidence of all TEAEs, treatment emergent SAEs and TEAEs leading to premature 
discontinuation from study drug will also be summarized descriptively. Additional 
summaries will be provided by maximum intensity and relationship to study drug. All tables 
of TEAEs will include Medical Dictionary for Regulatory Activities primary System Organ 
Class and Preferred Term. Further details on the analysis of each variable will be given in the 
SAP.  
Incidence of new seizure types, increase in days with absence seizure or myoclonic seizures 
per 28 days during the Treatment Period, and 50% worsening in days with absence seizures 
or myoclonic seizures per 28 days during the Treatment Period will be summarized. 
Laboratory measurements as described in Section 10.3 and other safety measurements as 
described in Section 10.4 will be presented. 
12.3.2 
Other analyses 
Details of further analyses will be provided in the SAP. 
12.4 
Planned efficacy analyses 
Seizure data will be summarized from diary assessments. The percent change from the 
combined Baseline Period in PGTCS frequency per 28 days will be summarized. Response, 
defined as at least a 50% reduction in PGTCS frequency per 28 days compared to the 
combined Baseline Period, and freedom from PGTCS during the study will also be presented 
descriptively. 
Days with myoclonic or absence seizures are more clinically relevant endpoints; therefore, 
change in and percent change in days with myoclonic and/or absence seizures will be 
summarized. The percentage of subjects with 50% reduction in days with absence and/or 
myoclonic seizures per 28 days compared to the Prospective Baseline will be presented. 
Subjects who were seizure-free from all generalized seizures will also be tabulated. 
Descriptive statistics including number of subjects, mean, SD, median, minimum, and 
maximum will be used to summarize continuous data including seizure frequencies per 
28 days and days with seizures per 28 days. Frequency counts will be used to display 
categorical data, where appropriate. 
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12.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for 
identifying important protocol deviations and the classification of important protocol 
deviations will be defined within the project Data Cleaning Plan. To the extent feasible, rules 
for identifying protocol deviations will be defined without review of the data and without 
consideration of the frequency of occurrence of such deviations. Whenever possible, criteria 
for identifying important protocol deviations will be implemented algorithmically to ensure 
consistency in the classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process 
prior to database lock. 
12.6 
Handling of dropouts or missing data 
All data will be used to their maximum possible extent, but without any imputations for 
missing data for any parameter, unless otherwise specified in the SAP. 
12.7 
Planned interim analysis and data monitoring 
No interim analysis or Data Monitoring Committee is planned. However, data may be 
reported prior to the completion of this study to support annual reports, regulatory 
submissions, and publications. 
12.8 
Determination of sample size 
The sample size of this open-label extension study will be determined by the parent SP0982 
study, where approximately 200 subjects are planned to be randomized.  
SP0982 is an event-driven study. Up to 250 subjects may be enrolled to meet the required 
number of events. Baseline failures from SP0982 will also be eligible for EP0012, which may 
increase the sample size. 
13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
Informed consent 
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, the 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 
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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 US must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent/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. 
13.2 
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 him/her at all times. 
13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local 
regulations, ICH-GCP, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki. 
The investigator/UCB 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. 
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 
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original approval, it may be possible for the investigator to obtain an expedited review by the 
IRB/IEC as allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the 
investigator will be responsible for submitting periodic progress reports to the IRB/IEC 
(based on IRB/IEC requirements), at intervals appropriate to the degree of subject risk 
involved, but no less than once per year. The investigator should provide a final report to the 
IRB/IEC following study completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as 
specified by the applicable regulatory requirements in each concerned country. Where 
applicable, investigators are to provide the sponsor (or its representative) with evidence of 
such IRB/IEC notification. 
13.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned during the previous SP0982 study. 
The investigator agrees that representatives of UCB, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the subject’s primary medical records that directly concerns this study (including, 
but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries 
for hospital admissions occurring during a subject’s study participation, and autopsy reports 
for deaths occurring during the study). 
13.4.1 
Processing of subject health data 
The processing of the subject personal health data in this study is allowed for the purpose of 
scientific research to evaluate the efficacy and the safety of the tested drug, in accordance 
with legal requirements from: 
• the laws governing the conduct of clinical studies (ie, the provisions of the French Public 
Health Code and the EU clinical trial regulation 536/2014 which requires sponsors to 
collect and analyze such data before they are submitted to health authorities) 
• the EU regulation 1235/2010 on pharmacovigilance which requires follow-up and 
reporting of adverse events of medicinal products to the health authorities, and any other 
applicable law 
This means that after the end of the study the subject coded personal data will be retained for 
at least 25 years to ensure the validity of the research. 
The subjects will be informed that the Sponsor is legally entitled and obliged to keep, retain, 
and use your medical data to ensure the quality of scientific results and to comply with legal 
or judicial retention periods. 
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13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and 
must be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to 
being implemented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable. 
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15 
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. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed on 10 Apr 2012.  
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
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. Basic information on how to use the EQ-5D-3L instrument. 
EQ-5D-3L User guide. Version 4.0. Apr 2011. 
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. 
Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev. 2000;22:75-80.Herman 
ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4. 
ILAE, 1989; 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. 
Jallon P, Latour P. Epidemiology of Idiopathic Generalized Epilepsies. Epilepsia. 
2005;46(Suppl 9):S10–4.  
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. doi: 
10.1212/WNL.0b013e31822cfc90. 
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5:693-722. 
Verrotti 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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16 
APPENDICES 
16.1 
Appendix 1: 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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16.4 
Appendix 4: Protocol Amendment 1 
Rationale for the amendment 
The primary purpose of this substantial amendment follows the amendment made to the 
SP0982 protocol, which is to identify significant changes to the study design and the 
inclusion of pediatric subjects (≥4 to 12 years of age). 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• Duration of this study (EP0012) has been clarified as at least 2 years. 
• Lacosamide plasma concentration analysis has been removed as it provides limited ability 
to interpret compliance and to perform an accurate PK modeling. 
• Clarification on subjects being able to participate in a substudy at some sites, without 
being withdrawn from EP0012. 
• For pediatric subjects <50kg, a Dispensation Visit has been added 12 weeks after each 
24-weekly visit from Year 3 onwards, in order to dispense LCM solution. 
• The use of concomitant medications and treatments has been clarified. 
• Behavior Rating Inventory of Executive Function Preschool Version® (BRIEF-P®) has 
been added. 
• Socio-professional data assessment has been removed in this study. 
• Permitted and prohibited concomitant treatments have been clarified to be consistent with 
SP0982.  
• In order to optimize study operations, ECGs will be evaluated locally and not centrally. 
• Other changes made in this amendment are to provide clarification or are administrative 
in nature. 
Specific changes 
Change #1 
Title page: 
IND Number: 57939 
Has been changed to: 
IND Number (tablet): 57939 
IND Number (oral solution): 73809 
The information below was revised to include Protocol Amendment 1 and the type of 
protocol amendment: 
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Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
 
Has been changed to: 
 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
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: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Phone: 
 
Fax: 
 
Has been changed to: 
Clinical Project Manager  
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
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GERMANY 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Phone: 
 
Fax: 
 
Change #4 
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 (24h) 
Fax 
Europe and Rest of the World (except Japan): +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 (except Japan): DSICT.-@ucb.com 
Change #5 
LIST OF ABBREVIATIONS 
The following abbreviation has been added: 
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VAS 
visual analogue scale 
Change #6 
Section 1 SUMMARY 
Paragraphs 1 through 8 
This is a Phase 3, multicenter, open-label extension study designed to assess the long-term 
safety and efficacy of oral lacosamide (LCM, VIMPAT®; SPM 927; previously referred to as 
harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, AD 234037) as an 
adjunctive therapy for uncontrolled primary generalized tonic-clonic (PGTC) seizures in 
subjects with idiopathic generalized epilepsy (IGE). This study will enroll subjects who have 
completed the LCM SP0982 study. In addition, subjects who completed the SP0982 
Prospective Baseline Period and met all entry criteria except the minimum PGTC seizure 
criteria required for randomization into SP0982 may choose to enter EP0012 (eligible 
Baseline failures and completers are defined in Section 5.1). It is estimated that 
approximately 200 subjects across approximately 150 sites will be enrolled in EP0012. 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 400mg/day (200mg 
twice daily [bid]); subjects who are eligible Baseline failures from SP0982 will start at Visit 1 
on a dose of LCM 100mg/day (50mg bid). Investigators will be allowed to increase or 
decrease the dose of LCM to optimize tolerability and seizure reduction in a range from 
LCM 100mg/day to 800mg/day.  
EP0012 will last up to approximately 6 years and consists of a Treatment Period and an End 
of Study Period lasting up to 5 weeks. During the Treatment Period, Visit 2 will occur 
2 weeks after Visit 1, and Visit 3 will occur 4 weeks later (Week 6). Visits will then occur 
every 8 weeks for the first year, every 4 months in the second year, and every 6 months 
thereafter until the end of the study. A telephone contact will occur every 8 weeks if no clinic 
visit is scheduled. The study duration and the total number of clinic visits will vary for each 
subject. Treatment will continue until LCM is commercially available in the subject’s country 
for the treatment of PGTC seizures in subjects with IGE, or until UCB has determined that 
the clinical development program for the indication will be formally discontinued, or until the 
sponsor decides to close the study. 
Upon study completion, subjects must either transition to commercial LCM or taper off study 
drug. Subjects continuing treatment with commercial LCM will transition at their current 
dose. Subjects tapering off LCM will do so at a recommended decrease rate of 
LCM 200mg/day per week, unless the investigator feels that safety concerns require a more 
rapid withdrawal of LCM. 
Have been changed to: 
This Phase 3, multicenter, open-label extension study is designed to assess the long-term 
safety and efficacy of oral lacosamide (LCM, VIMPAT®; SPM 927; previously referred to as 
harkoseride; (R) 2 acetamido-N-benzyl-3-methoxypropionamide, ADD 234037) as an 
adjunctive therapy for uncontrolled primary generalized tonic-clonic (PGTC) seizures in 
subjects ≥4 years of age with idiopathic generalized epilepsy (IGE). This study will enroll 
subjects who have completed the LCM SP0982 study. In addition, subjects who completed 
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the SP0982 Prospective Baseline Period and met all entry criteria except the minimum PGTC 
seizure criteria required for randomization into SP0982 may choose to enter EP0012 (eligible 
Baseline failures and completers are defined in Section 5.1). It is estimated that 
approximately 200 subjects across approximately 150 sites will be enrolled in EP0012. 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg 
to <50kg, and LCM 400mg/day (200mg twice daily [bid]) for adult subjects (≥18 years of 
age) or pediatric subjects weighing ≥50kg. Subjects who are eligible Baseline failures from 
SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing 
<50kg, and LCM 100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. 
Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility 
based on tolerability is allowed. Investigators will assess whether a subject would tolerate a 
further LCM 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 target dose of 
4mg/kg/day (oral solution) or 200mg/day (tablets) within 14 days after Visit 1.  
At any time during the course of the study if it becomes apparent that a subject is unable to 
attain at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then 
the subject must enter the Taper Period and be withdrawn from the study. 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased 
in steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who 
have dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) 
before a subsequent dose adjustment. 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4 week Taper 
Period, and a 30-day Safety Follow-Up Period. During the Treatment Period, Visit 2 will 
occur 2 weeks after Visit 1, and Visit 3 will occur 4 weeks later (Week 6). Clinical visits will 
then occur every 8 weeks for the first year, and every 16 weeks in the second year. For 
subjects who continue in the study after Year 2, visits will occur and every 24 weeks 
thereafter until the end of the study. From Year 3 onwards, pediatric subjects weighing <50kg 
will return to the clinic for an additional Dispensation Visit 12 weeks after each 24-weekly 
visit, for the dispensation of LCM solution; LCM usage will be reviewed and empty LCM 
bottles will be returned.  
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. The study 
duration and the total number of clinic visits will vary for each subject. At selected sites, 
subjects may also be able to participate in a substudy without withdrawing from EP0012. 
Treatment will continue until LCM is approved for use in the subject’s country for the 
treatment of PGTC seizures in subjects with IGE, or until UCB has determined that the 
clinical development program for the indication will be formally discontinued, or until UCB 
decides to close the study. 
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At the completion of the study, investigators should discuss treatment options with the 
subject and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. 
Taper of LCM may not be required for some subjects who complete the study depending on 
the treatment option selected by the investigator in consultation with the subject and/or their 
parent(s)/legal representative(s). 
Paragraph 10, third sentence:  
In addition, for pediatric subjects <18 years of age, safety will be evaluated using behavioral 
assessments (Achenbach Child Behavior Checklist [CBCL]), and cognitive function 
assessments (Behavior Rating Inventory of Executive Function® [BRIEF®]).  
Has been changed to: 
In addition, for pediatric subjects <18 years of age, safety will be evaluated using behavioral 
assessments (Achenbach Child Behavior Checklist [CBCL]), and cognitive function 
assessments (Behavior Rating Inventory of Executive Function®/Behavior Rating Inventory 
of Executive Function-Preschool Version® [BRIEF®/BRIEF-P®]).  
Change #7 
Section 2 INTRODUCTION 
Paragraphs 1 through 3 
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). 
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 epilepsies can 
be further classified as primary/idiopathic and secondary/symptomatic epilepsies. Idiopathic 
generalized epilepsy is a category of disorders defined by strict clinical and 
electroencephalogram 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. 
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Have 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 unknown origin.  
Generalized seizures are those in which the first clinical changes indicate initial involvement 
of both brain hemispheres. Consciousness typically is 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 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 in IGE is complex because the patient population is 
heterogeneous, as PGTC seizures can occur as an isolated seizure type or in association with 
other generalized seizure types. 
Paragraph 5, first sentence 
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); 
Has been changed to: 
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 (Bartolomei et al, 1997; 
Verrotti et al, 2007); 
Paragraph 6  
The following paragraph was deleted: 
Of patients with IGE experiencing PGTC seizures, clinical experience has shown that up to 
30% of patients 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. 
Paragraph 8 
The following paragraph was added: 
Preliminary safety and PK data suggest that exposure-response in pediatric and adult subjects 
treated with LCM will be similar. Lacosamide is evaluated in pediatric subjects 1 month to 17 
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years of age in 2 completed studies and 1 ongoing study: SP847 (open-label, Phase 2, PK, 
tolerability, and safety study), SP1047 (PK study with a 1 day Evaluation Period), and SP848 
(open-label long-term safety study). 
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 patients 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 patients with IGE and 
uncontrolled PGTC seizures. 
Paragraphs 11, 12, and 13 
SP0961, the Phase 2, multicenter, open-label pilot study 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. 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, 
cannot be distinguished between the drug versus 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. 
SP0982 is a Phase 3, double-blind, randomized, placebo-controlled, parallel-group, 
multicenter study designed to evaluate the efficacy and safety of LCM for uncontrolled 
PGTC seizures in subjects ≥12 years of age with IGE. 
The current study (EP0012) will assess the long-term safety, tolerability, and efficacy of 
LCM and will enroll subjects who have completed SP0982 as well as eligible Baseline 
failures from SP0982. EP0012 will also allow subjects to receive LCM until it is approved for 
use in the subject’s country for the treatment of PGTC seizures in IGE. 
Have been changed to: 
SP0961, the Phase 2, multicenter, open-label pilot study 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. 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, cannot be 
distinguished between the drug versus 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. 
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SP0982 is a Phase 3, double-blind, randomized, placebo-controlled, parallel-group, 
multicenter study designed to evaluate the efficacy and safety of LCM for uncontrolled 
PGTC seizures in subjects ≥4 years of age with IGE. 
The current study (EP0012) will assess the long-term safety, tolerability, and efficacy of 
LCM and will enroll subjects who have completed SP0982 as well as eligible Baseline 
failures from SP0982. At the completion of the study, investigators should discuss treatment 
options with the subject and/or legal representative to best manage the subject's epilepsy. 
Change #8 
Section 4.1.2 
 Secondary safety variables 
Secondary safety variables are: 
• Changes in hematology, chemistry, and urinalysis parameters 
• Changes in 12-lead ECGs 
• Changes in vital sign measurements (ie, BP and pulse rate), including body weight and 
physical (including neurological) examination findings 
• Achenbach CBCL 
• Cognitive function assessment BRIEF 
Has been changed to: 
Secondary safety variables are: 
• Changes in hematology, chemistry, and urinalysis parameters 
• Changes in 12-lead ECGs 
• Changes in vital sign measurements (ie, BP and pulse rate), including body weight and 
physical (including neurological) examination findings 
Change #9 
The following section has been added: 
Section 4.1.3 
Other safety variables 
• Achenbach CBCL1½-5 or CBCL/6-18 
• Cognitive function assessment BRIEF/BRIEF-P 
Change #10 
Section 4.2 Efficacy variables 
Efficacy variables are: 
• Percent change in PGTC seizure frequency per 28 days from Baseline, where Baseline is 
defined as the 12-week Historical Baseline and 4-week Prospective Baseline periods 
immediately prior to randomization in the parent study (SP0982) 
• Percent change in days with myoclonic seizures per 28 days from Baseline 
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• Percent change in days with absence seizures per 28 days from Baseline 
• Percentage of subjects with at least a 50% reduction in PGTC seizure frequency 
compared to Baseline 
• Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared 
to Baseline 
• Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Baseline 
• Seizure-free status (yes/no) for PGTC seizures 
• Seizure-free status (yes/no) for myoclonic seizures 
• Seizure-free status (yes/no) for absence seizures 
• Seizure-free status (yes/no) for all generalized seizure types 
• 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 
• EuroQol 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 
Has been changed to: 
Section 4.2.1 
Primary efficacy variable 
No primary efficacy variables are defined for this study. 
Section 4.2.2 
Secondary efficacy variable 
The second efficacy variable is: 
• Percent change in PGTC seizure frequency per 28 days from Baseline, where Baseline is 
defined as the 12-week Historical Baseline and 4-week Prospective Baseline periods 
immediately prior to randomization in the parent study (SP0982) 
Section 4.2.3 
Other efficacy variables 
The other efficacy variables are: 
• Percent change in days with myoclonic seizures per 28 days from Baseline 
• Percent change in days with absence seizures per 28 days from Baseline 
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• Percentage of subjects with at least a 50% reduction in PGTC seizure frequency 
compared to Baseline 
• Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared 
to Baseline 
• Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Baseline 
• Seizure-free status (yes/no) for PGTC seizures 
• Seizure-free status (yes/no) for myoclonic seizures 
• Seizure-free status (yes/no) for absence seizures 
• Seizure-free status (yes/no) for all generalized seizure types 
• 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 in the 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 
Change #11 
The following section has been deleted 
Section 4.3 Pharmacokinetic variables 
The plasma concentrations of LCM will be assessed. 
Change #12 
Section 5.1 Study description 
Paragraph 1 
This is a multicenter, open-label extension study to assess the long-term safety and change in 
seizure frequency associated with long-term adjunctive oral LCM for uncontrolled PGTC 
seizures in subjects with IGE. This study will enroll consenting subjects who have completed 
the LCM SP0982 study as well as eligible Baseline failures from SP0982. Approximately 
200 subjects from approximately 150 study sites will be enrolled in EP0012. For the purposes 
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of this study Baseline failures and study completers from SP0982 who are eligible for 
inclusion are defined as: 
Has been changed to: 
This is a multicenter, open-label extension study to assess the long-term safety and change in 
seizure frequency associated with long-term adjunctive oral LCM for uncontrolled PGTC 
seizures in subjects ≥4 years of age with IGE. This study will enroll consenting subjects, or 
subjects whose legal representatives have given consent, who have completed the LCM 
SP0982 study as well as eligible Baseline failures from SP0982. Approximately 200 subjects 
from approximately 150 study sites are planned to be enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, and study completers from SP0982 who are eligible for inclusion in EP0012 are 
defined as: 
Paragraph 2, bulleted items  
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry 
criteria except the minimum PGTC seizure criteria required for randomization (Baseline 
failures) 
• Subjects who complete the end of the first 5 weeks of the Treatment Period (after 
randomization) of SP0982 and have experienced at least 2 PGTC seizures during that 
time or  
• Subjects who experience a second PGTC seizure after the first 5 weeks of the Treatment 
Period of SP0982 or 
• Subjects who do not have 2 PGTC seizures within the 24-week Treatment Period of 
SP0982 
Have been changed to: 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry 
criteria except the minimum PGTC seizure criteria required for randomization (Baseline 
failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) 
of SP0982 and experienced ≥2 PGTC seizures during that time or  
• Subjects who experience a second PGTC seizure after the first 6 weeks of the Treatment 
Period of SP0982  
SP0982 completers 
• Subjects who experience <2 PGTC seizures within the 24-week Treatment Period of 
SP0982 
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Paragraph 3 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 400mg/day (200mg 
bid); subjects who are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of 
LCM 100mg/day (50mg bid). During EP0012, investigators will be allowed to increase or 
decrease the dose of LCM to optimize tolerability and seizure reduction for each subject. The 
LCM dose may be adjusted after the subject receives the first dose of LCM in the study. 
Lacosamide doses may be increased up to a maximum of LCM 800mg/day or decreased to a 
minimum of LCM 100mg/day at the discretion of the investigator. A clinic visit (scheduled 
or unscheduled) is required the first time the dose is increased to LCM 500mg/day, 
LCM 600mg/day, LCM 700mg/day, and LCM 800mg/day. One week after the first time the 
dose is increased to LCM 700mg/day or LCM 800mg/day, an unscheduled telephone contact 
must be conducted to ensure that the dose is well tolerated. 
Has been changed to: 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg 
to <50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start 
at Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and 
LCM 100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects 
weighing ≥50kg.  
Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility 
based on tolerability is allowed. Investigators will assess whether a subject would tolerate a 
further LCM 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 target dose of 
4mg/kg/day (oral solution) or 200mg/day (tablets) within 14 days after Visit 1.  
At any time during the course of the study if it becomes apparent that a subject is unable to 
attain at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then 
the subject must enter the Taper Period and be withdrawn from the study. 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased 
in steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who 
have dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) 
before a subsequent dose adjustment. 
To optimize tolerability and seizure reduction, the LCM dose may be increased or decreased 
at the investigator’s discretion after the subject receives the first dose of LCM in the study 
(see Table 7‒1). Baseline failures must complete Week 1 of dosing before LCM may be 
increased or decreased. The maximum dose for pediatric subjects weighing <50kg is 
12mg/kg/day (oral solution). The maximum dose for pediatric subjects weighing ≥50kg is 
600mg/day (tablets) and for adult subjects is 800mg/day (tablets).  
A clinic visit (scheduled or unscheduled) is required if: 
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Clinical Study Protocol 
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EP0012 
 
 
 
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• The dose is increased for the first time to any dose above 10mg/kg/day for pediatric 
subjects weighing <50 kg. One week after the first time the dose is increased, an 
unscheduled telephone contact must be conducted to ensure that the dose is well tolerated. 
• The dose is increased for the first time to any dose above LCM 400mg/day for all adult 
subjects or pediatric subjects weighing ≥50kg. One week after the first time the dose is 
increased, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
Paragraph 8 
EP0012 will last up to approximately 6 years and consists of a Treatment Period and an End 
of Study Period lasting up to 5 weeks. Visit 1 of EP0012 is the same as the Final Clinic Visit 
of SP0982 for completers. Eligible Baseline failures who choose to enter EP0012 will 
undergo a complete Visit 1 in EP0012. Visit 2 will occur 2 weeks after Visit 1, and Visit 3 
will occur 4 weeks later (Week 6). Clinical visits will then occur every 8 weeks for the first 
year, every 4 months in the second year, and every 6 months thereafter until the end of the 
study. A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone 
contacts will be used to obtain information regarding concomitant medication use, and assess 
withdrawal criteria and AEs. The study duration and the total number of clinic visits will vary 
for each subject. Treatment will continue until LCM is commercially available in the 
subject’s country for the treatment of PGTC seizures in subjects with IGE, or until UCB has 
determined that the clinical development program for the indication will be formally 
discontinued, or until the sponsor decides to close the study. 
Has been changed to: 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final 
Clinic Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria. 
Eligible Baseline failures from SP0982 who choose to enter this study will undergo a 
complete Visit 1. Visit 2 will occur 2 weeks after Visit 1, and Visit 3 will occur 4 weeks later 
(Week 6). Clinic visits will then occur every 8 weeks for the first year, and every 16 weeks in 
the second year. For subjects who continue in the study after Year 2, visits will occur and 
every 24 weeks thereafter until the end of the study. From Year 3 onwards, pediatric subjects 
weighing <50kg will return to the clinic for an additional Dispensation Visit 12 weeks after 
each 24-weekly visit, for the dispensation of LCM solution; LCM usage will be reviewed and 
empty LCM bottles will be returned.  
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone 
contacts will be used to obtain information regarding concomitant medication use, and assess 
withdrawal criteria and AEs, as well as to ensure subjects are compliant with LCM 
administration and diary completion. The study duration and the total number of clinic visits 
will vary for each subject. At selected sites, subjects may also be able to participate in a 
substudy without withdrawing from EP0012. Treatment will continue until LCM is approved 
for use in the subject’s country for the treatment of PGTC seizures in subjects with IGE, or 
until UCB has determined that the clinical development program for the indication will be 
formally discontinued, or until UCB decides to close the study. 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 112 of 274 
Paragraph 9, first sentence 
Subjects will be dispensed a seizure diary to record all types of seizures, concomitant AEDs, 
and other pertinent health status information. 
Has been changed to: 
Subjects and/or their caregiver will be dispensed a seizure diary to record all types of 
seizures, concomitant AEDs, and other pertinent health status information. 
Paragraphs 10 to 12 
New concomitant AEDs may be introduced to optimize treatment, if the concomitant 
medication has been approved by the regulatory authority in the subject’s country. New 
AEDs should be added only when the subject has not optimally or adequately responded to a 
maximum tolerated dose of LCM. Concomitant AEDs may be carefully tapered and 
discontinued to achieve LCM monotherapy, if clinically appropriate. The Medical Monitor 
must be consulted prior to initiation of concomitant AED withdrawal. 
Upon study completion, subjects must either transition to commercially available LCM or 
taper off study drug. Subjects continuing treatment with commercially available LCM will 
transition at their current dose. 
Taper of LCM may not be required for some subjects who complete the study depending on 
the treatment option selected by the investigator in consultation with the subject and/or 
parent/legal guardian. Subjects tapering off LCM will do so at a recommended decrease rate 
of LCM 200mg/day per week, unless the investigator feels that safety concerns require a 
more rapid withdrawal of LCM. A slower taper (eg, LCM 100mg/day per week) is permitted, 
if medically necessary. The Medical Monitor should be contacted if a more rapid withdrawal 
is required. A Final Clinic Visit will occur 2 weeks after the final LCM dose for subjects who 
taper off LCM. 
Have been changed to: 
New concomitant AEDs may be introduced to optimize treatment, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication 
in the subject’s country. New AEDs should be added only when the subject has not optimally 
or adequately responded to a maximum tolerated dose of LCM. Concomitant AEDs may be 
carefully tapered and discontinued to achieve LCM monotherapy, if clinically appropriate. 
The Medical Monitor must be consulted prior to initiation of concomitant AED withdrawal. 
At the completion of the study, investigators should discuss treatment options with the 
subject and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. 
Taper of LCM may not be required for some subjects who complete the study depending on 
the treatment option selected by the investigator in consultation with the subject and/or their 
parent(s)/legal representative(s). 
Change #13 
Section 5.1.1 
Study duration per subject 
Paragraph 1 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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For each subject, the study will last from study entry until LCM is commercially available in 
the subject’s country for the treatment of PGTC seizures in subjects with IGE, or until UCB 
has determined that the clinical development program for the indication will be formally 
discontinued, or until the sponsor decides to close the study. It is anticipated that up to 
approximately 6 years of treatment will be performed to allow for the collection of long-term 
safety data. If LCM is not commercially available in the subject’s country at the time the 
sponsor closes the study, access to LCM will be provided according to local laws. 
Has been changed to: 
For each subject, the study will last from study entry until LCM is approved for use in the 
subject’s country for the treatment of PGTC seizures in subjects with IGE, or until UCB has 
determined that the clinical development program for the indication will be formally 
discontinued, or until the sponsor decides to close the study. It is anticipated that at least 2 
years of treatment will be performed to allow for the collection of long-term safety data. If 
LCM is not approved for use in the subject’s country at the time the sponsor closes the study, 
access to LCM will be provided according to local laws. 
Paragraph 2 
The following study periods are defined: 
• A Treatment Period lasting up to approximately 6 years. 
• An End of Study Period lasting up to 5 weeks. 
− Subjects continuing LCM treatment with commercial LCM will transition at their 
current dose (received in the Treatment Period). 
− Subjects tapering off LCM will do so over 1 to 3 weeks (see taper schedule, 
Table 7-1). 
− A Final Clinic Visit will occur 2 weeks after the final LCM dose for subjects who 
taper off LCM. 
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 following study periods are defined: 
• A Treatment Period lasting at least 2 years. 
• An up to 4-week Taper Period and a 30-day Safety Follow-Up Period.  
− Subjects continuing LCM treatment with commercially available LCM will transition 
to a dose determined by the investigator. 
− Subjects tapering off LCM will do so over a period of up to 4 weeks (see Taper 
Schedule, Table 7-2).  
− An End of Taper Visit will occur after the final LCM dose for subjects who taper off 
LCM. 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 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Taper Visit followed by a Safety Follow-Up telephone contact 30 days after the last 
dose of study drug. 
The end of the study is defined as the date of the last visit/telephone contact of the last subject 
in the study. 
Depending on the local regulations, after 2 years, subjects may continue to receive LCM in a 
named patient program. 
Change #14 
Section 5.1.2 
Planned number of subjects and site(s)  
Approximately 200 subjects across approximately 150 international sites will be eligible to 
enroll in this study. 
Has been changed to: 
Approximately 200 subjects across approximately 150 international sites are planned to be 
enrolled in this study. 
Change #15 
Section 5.1.3 
Anticipated regions and countries 
This study will be conducted in the US, Canada, Europe, Asia, and Australia with possible 
extension to other countries and regions. 
Has been changed to: 
This 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 
The schedule of study assessments for treatment Years 1 to 2 is provided in Table 5‒1. An 
additional schedule of study assessments for treatment Years 3 to 6 is provided in Table 5‒2. 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 115 of 274 
Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 
  
Treatment Perioda 
End of Study Period 
Unscheduledb 
Duration 
Open-label: up to approximately 6 years 
Up to 5 weeksc 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitd 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Telephone 
contacte 
V9 
V10 
V11 
ET 
Visitf 
Termination 
Visitg 
Final 
Clinic 
Visith 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
2 weeks 
after 
final 
LCM 
dose 
NA 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
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 update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
(complete)i 
X* 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Physical exam (brief)j 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
X 
Neurological exam 
(complete)k 
X* 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Neurological exam 
(brief)l 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
X 
12-lead ECGm 
X* 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
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28 Aug 2020 
Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 116 of 274 
Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 
  
Treatment Perioda 
End of Study Period 
Unscheduledb 
Duration 
Open-label: up to approximately 6 years 
Up to 5 weeksc 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitd 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Telephone 
contacte 
V9 
V10 
V11 
ET 
Visitf 
Termination 
Visitg 
Final 
Clinic 
Visith 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
2 weeks 
after 
final 
LCM 
dose 
NA 
Vital signs (BP and 
pulse) including 
orthostatic assessmentsn 
X* 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Body weight and heighto 
X* 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Tanner Stagep 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
 
Laboratory tests 
X* 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy testq 
X* 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
LCM plasma 
concentrationr 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X* 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Dispense subject diary 
X 
X 
X 
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 
X 
X 
X 
Dispense LCM 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Withdrawal criteria 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 117 of 274 
Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 
  
Treatment Perioda 
End of Study Period 
Unscheduledb 
Duration 
Open-label: up to approximately 6 years 
Up to 5 weeksc 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitd 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Telephone 
contacte 
V9 
V10 
V11 
ET 
Visitf 
Termination 
Visitg 
Final 
Clinic 
Visith 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
2 weeks 
after 
final 
LCM 
dose 
NA 
AE reporting 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-3L 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
QOLIE-31-P/PedsQLs 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Achenbach CBCLt 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
BRIEFu 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Healthcare resource use 
X* 
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 
X 
 
 
Days with help from a 
caregiver 
X* 
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; BRIEF=Behavior Rating Inventory of Executive Function; CBCL=Child 
Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EQ-5D-3L=EuroQol-5 Dimension Quality of Life Assessment; 
ET=early termination; exam=examination; ID=identification; IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; 
PedsQL=Pediatric Quality of Life Inventory; QOLIE-31-P=Patient Weighted Quality of Life in Epilepsy Inventory-Form 31; V=Visit; W=Week 
Note: For subjects who have completed SP0982, assessments marked (*) should have already been completed during the last visit of the previous protocol and do 
not need to be repeated at Visit 1; for eligible Baseline failures from SP0982, a full Visit 1 is required including all scheduled tasks and procedures. 
a 
The Treatment Period will continue for up to approximately 6 years or until LCM is otherwise available (eg, commercially), whichever is earlier. 
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Clinical Study Protocol 
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EP0012 
 
 
 
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b 
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments listed 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. 
c 
For subjects requiring taper, the LCM dose will be reduced by 200mg/day per week until discontinued, unless the investigator feels that safety concerns 
require a more rapid withdrawal of LCM. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically necessary. 
d 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
e 
Telephone contacts are required every 8 weeks during the study, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, telephone 
contacts in Year 2 are scheduled for Week 54, Week 70, and Week 86. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper and a Final Clinic Visit. 
g 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 19 if appropriate (see Table 5-2). For 
subjects who will not continue on LCM, this visit will be followed by LCM taper and a Final Clinic Visit. For subjects who continue on LCM, the 
Termination Visit is the last visit in the study. 
h 
A Final Clinic Visit must be completed for all subjects who taper off LCM.  
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 assessment of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function. 
m 
The brief neurological examination will include selected assessment 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 
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
p 
Height will be recorded at Visits 1 and 9, and at the ET and Termination Visit. 
q 
The Tanner Stage will be performed only for subjects who are <18 years of age. 
r 
Serum pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, Termination Visit and Final Clinic Visit. All other pregnancy tests 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 
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. For each 
developmentally appropriate version of the PedsQL subjects must have at least 1 year of data before transitioning to the next age range.  
u 
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).  
v 
The BRIEF should be used for subjects ≥12 to <18 years of age. For each developmentally appropriate version of the BRIEF subjects must have at least 
1 year of data before transitioning to the next age range. 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 119 of 274 
Table 5‒2: 
Schedule of study assessments for Years 3 through 6 for EP0012 
 
Treatment Perioda 
End of Study Period 
Unscheduledb 
Duration 
Open-label: up to approximately 6 years 
Up to 5 weeksc 
NA 
Year of study 
Year 3 
Year 4 
Year 5 
Year 6 
 
 
Visitd 
Telephone 
contacte 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19/ 
Termf 
ET 
Visitg 
Termination 
Visith 
Final Clinic 
Visiti 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
262 
286 
 
 
2 weeks after 
final LCM 
dose 
NA 
Concomitant medications and 
AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete)j 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Physical exam (brief)k 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
Neurological exam (complete)l 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Neurological exam (brief)m 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
12-lead ECGn 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Vital signs (BP and pulse) 
including orthostatic 
assessmentso 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and heightp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tanner Stageq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory tests 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy testr 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM plasma concentrations 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Call IVRS/IWRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
X 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 120 of 274 
Table 5‒2: 
Schedule of study assessments for Years 3 through 6 for EP0012 
 
Treatment Perioda 
End of Study Period 
Unscheduledb 
Duration 
Open-label: up to approximately 6 years 
Up to 5 weeksc 
NA 
Year of study 
Year 3 
Year 4 
Year 5 
Year 6 
 
 
Visitd 
Telephone 
contacte 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19/ 
Termf 
ET 
Visitg 
Termination 
Visith 
Final Clinic 
Visiti 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
262 
286 
 
 
2 weeks after 
final LCM 
dose 
NA 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LCM 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 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-3L 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
QOLIE-31-P/PedsQLt 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Achenbach CBCLu 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BRIEFv 
 
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 
 
 
 
AE=adverse event; AED=antiepileptic drug; bid=twice daily; BP=blood pressure; BRIEF=Behavior Rating Inventory of Executive Function; CBCL=Child 
Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EQ-5D-3L=EuroQol-5 Dimension Quality of Life Assessment; 
ET=early termination; exam=examination; IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; PedsQL=Pediatric 
Quality of Life Inventory; QOLIE-31-P=Patient Weighted Quality of Life in Epilepsy Inventory-Form 31; Term=Termination; V=Visit; W=Week 
a 
The Treatment Period will continue for up to approximately 6 years or until LCM is otherwise available (eg, commercially), whichever is earlier. 
b 
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments listed 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. 
c 
For subjects requiring taper, the LCM dose will be reduced by 200mg/day per week until discontinued, unless the investigator feels that safety concerns 
require a more rapid withdrawal of LCM. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically necessary. 
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Clinical Study Protocol 
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d 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
e 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned (eg, 
Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230; Year 6 - Week 246, Week 254, Week 270, Week 278. 
f 
At the completion of the study, subjects will choose to continue commercially available LCM (depending on launch and country availability) or taper off 
LCM until it has been discontinued.  
g 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper and a Final Clinic Visit. 
h 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 19 if appropriate. For subjects who will not 
continue on LCM, this visit will be followed by LCM taper and a Final Clinic Visit. For subjects who continue on LCM, the Termination Visit is the last 
visit in the study. 
i 
A Final Clinic Visit must be completed for all subjects who taper off LCM.  
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 assessment of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function. 
m 
The brief neurological examination will include selected assessment 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 
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
p 
Height will be recorded at Visits 12, 14, 16 and 18, and at the ET and Termination Visit. 
q 
The Tanner Stage will be performed only for subjects who are <18 years of age. 
r 
Serum pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, Termination Visit and Final Clinic Visit. All other pregnancy tests 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 
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. For each 
developmentally appropriate version of the PedsQL subjects must have at least 1 year of data before transitioning to the next age range.  
u 
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).  
v 
The BRIEF should be used for subjects ≥12 to <18 years of age. For each developmentally appropriate version of the BRIEF subjects must have at least 
1 year of data before transitioning to the next age range. 
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Clinical Study Protocol 
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EP0012 
 
 
 
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Has been changed to: 
The schedule of study assessments for treatment Years 1 to 2 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) is provided in Table 5‒1. An additional schedule of 
study assessments for treatment Years 3 to 5 (Treatment Period, ET Visit, Termination Visit, and 
Unscheduled Visit) is provided in Table 5‒2. The schedule of study assessments for the Taper 
and Safety Follow-Up is provided in Table 5-3. 
 
 
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Clinical Study Protocol 
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EP0012 
 
 
 
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Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET Visit, 
Termination Visit and Unscheduled Visit) 
  
Treatment Perioda 
 
Unscheduledb 
Duration 
Open-label: at least 2 years 
 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitc 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Telephone 
Contactd 
V9 
V10 
V11 
ET 
Visite 
Termination 
Visitf 
 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
NA 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
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 
update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (complete)g 
X* 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Physical exam (brief)h 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
X 
Neurological exam (complete)i 
X* 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Neurological exam (brief)j 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
12-lead ECGk 
X* 
X 
 
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 
X 
X 
X 
X 
Body weight and heightm 
X* 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Tanner Stagen 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Laboratory testso 
X* 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy testp 
X* 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
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Table 5‒1: 
Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET Visit, 
Termination Visit and Unscheduled Visit) 
  
Treatment Perioda 
 
Unscheduledb 
Duration 
Open-label: at least 2 years 
 
NA 
Year of study 
Year 1 
Year 2 
 
 
Visitc 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Telephone 
Contactd 
V9 
V10 
V11 
ET 
Visite 
Termination 
Visitf 
 
Unscheduled 
Visit 
Week 
0 
2 
6 
14 
22 
30 
38 
46 
 
62 
78 
94 
 
 
NA 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
C-SSRSq 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Dispense subject diary 
X 
X 
X 
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 
X 
X 
Dispense LCM 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Withdrawal criteria 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE reporting 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-3L 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
QOLIE-31-P/PedsQLr 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Achenbach CBCLs 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
BRIEF-P/BRIEFt 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Healthcare resource use 
X* 
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 
X 
 
Days with help from a caregiver 
X* 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; 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; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EQ-5D-3L=3-level EuroQol-5 Dimension Quality of Life Assessment; ET=early termination; exam=examination; ID=identification; 
IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; PedsQL=Pediatric Quality of Life Inventory; QOLIE-31-P=Patient 
Weighted Quality of Life in Epilepsy Inventory-Form 31; V=Visit; W=Week 
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Clinical Study Protocol 
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Note: For subjects who have completed SP0982, assessments marked (*) should have already been completed during the last visit of the previous protocol and do 
not need to be repeated at Visit 1; for eligible Baseline failures from SP0982, a full Visit 1 is required including all scheduled tasks and procedures. 
a 
The Treatment Period will continue for at least 2 years. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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, etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, telephone 
contacts in Year 2 are scheduled for Week 54, Week 70, and Week 86. 
e 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-3. 
f 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate (see Table 5‒2). For 
subjects who will not continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-3. For 
subjects who continue on LCM, the Termination Visit is the last visit in the study. 
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 assessment of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function. 
j 
The brief neurological examination will include selected assessment 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) a 12-lead ECG (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 
Height will be recorded at Visits 1 and 9, and at the ET and Termination Visit. 
n 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
o 
Urinalysis will be required for subjects ≥5 years of age only. 
p 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. 
q 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.7.3).  
r 
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 PedsQL 
form appropriate for each subject’s age should be completed, with the following exception: if a subject ages up to the next form of the PedsQL within 1 year 
after the Baseline assessment of the primary study, the form that was used at the Baseline assessment should be completed for 1 year after the Baseline 
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Clinical Study Protocol 
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EP0012 
 
 
 
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assessment, and subsequently the form consistent with his/her age at the time of assessment should be completed. For each version of the PedsQL subjects 
must have at least 1 year of data before transitioning to the next age range (see Section 9.2.1).  
s 
The Achenbach CBCL: CBCL/1½-5 for children 18 months to 5 years and 11 months of age and CBCL/6-18 for children ≥6 years to <18 years of age; to be 
completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). The version of the Achenbach CBCL appropriate to each 
subject’s age should be administered with the following exception: for subjects who completed the CBCL/1½-5 at the Baseline assessment of the previous 
study and turn 6 years of age within 1 year after the Baseline assessment of the primary study, the CBCL/1½-5 should be completed for 1 year after the 
Baseline assessment of the primary study, and subsequently the CBCL/6-18 should be completed. The Achenbach CBCL will only be administered in 
countries where a validated translated version is available. For each version of the CBCL, subjects must have at least 1 year of data before transitioning to 
the next age range. The Achenbach CBCL should be completed by the same parent/legal representative, if possible (see Section 10.7.6).  
t 
The BRIEF-P should be used for subjects who are <5 years of age at Visit 1, and the BRIEF should be used for subjects who are ≥5 years of age at Visit 1. 
For each developmentally appropriate version of the BRIEF, subjects must have at least 1 year of data before transitioning to the next age range (see 
Section 10.7.7). 
 
 
 
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Clinical Study Protocol 
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Table 5‒2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit and Unscheduled Visit) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET 
Visitf 
Term 
Visitg 
LCM Solution 
Dispensation Visith 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Concomitant medications and AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam (complete)i 
 
 
X 
 
X 
 
X 
X 
 
 
 
Physical exam (brief)j 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Neurological exam (complete)k 
 
 
X 
 
X 
 
X 
X 
 
 
 
Neurological exam (brief)l 
 
X 
 
X 
 
X 
 
 
X 
 
X 
12-lead ECGm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs (BP and pulse) including 
orthostatic assessmentsn 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body weight and heighto 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Tanner Stagep 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Laboratory tests 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy testq 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IVRS/IWRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRSr 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Clinical Study Protocol 
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EP0012 
 
 
 
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Table 5‒2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit and Unscheduled Visit) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET 
Visitf 
Term 
Visitg 
LCM Solution 
Dispensation Visith 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
EQ-5D-3L 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
QOLIE-31-P/PedsQLs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Achenbach CBCLt 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BRIEFu 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Healthcare resource use 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Work/school days lost 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Days with help from a caregiver 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE=adverse event; AED=antiepileptic drug; 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; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EQ-5D-3L=3-level EuroQol-5 Dimension Quality of Life Assessment; ET=early termination; exam=examination; 
IVRS/IWRS=interactive voice/web response system; LCM=lacosamide; NA=not applicable; PedsQL=Pediatric Quality of Life Inventory; QOLIE-31-P=Patient 
Weighted Quality of Life in Epilepsy Inventory-Form 31; Term=Termination; V=Visit; W=Week 
a 
The Treatment Period will continue for at least 2 years. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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, etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
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Clinical Study Protocol 
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d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned (eg, 
Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-3. 
g 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate. For subjects who will not 
continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-3. For subjects who continue 
on LCM, the Termination Visit is the last visit in the study.  
h 
Dispensation Visit will occur 12 weeks after each 24-weekly visit from Year 3 onwards and will be for the purpose of dispensing LCM solution for pediatric 
subjects <50kg. 
i 
The complete physical examination will include cardiac and respiratory function via auscultation and review of all body systems. 
j 
The brief physical examination will include review of the following body systems: cardiovascular, pulmonary, abdominal (hepato-gastrointestinal), and 
dermatologic.  
k 
The complete neurological examination will include selected assessment of mental status, sensory systems, motor functions, cranial nerves, reflexes, and 
coordination/cerebellar function. 
l 
The brief neurological examination will include selected assessment of general neurological status, reflexes, muscle strength, and coordination/cerebellar 
function. 
m 
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) a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
n 
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
o 
Height will be recorded at Visits 12, 14, and 16, and at the ET and Termination Visit. 
p 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
q 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. 
r 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.7.3).  
s 
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. For each version 
of the PedsQL subjects must have at least 1 year of data before transitioning to the next age range (see Section 9.2.1).  
t 
The Achenbach CBCL: CBCL/6-18 for children ≥6 years to <18 years of age; to be completed by the parent(s)/legal representative(s) (estimated completion 
time 45 minutes). For each version of the CBCL, subjects must have at least 1 year of data before transitioning to the next age range. The Achenbach CBCL 
should be completed by the same parent/legal representative, if possible (see Section 10.7.6).  
u 
The BRIEF should be used for subjects who are ≥5 years of age. For each developmentally appropriate version of the BRIEF, subjects must have at least 
1 year of data before transitioning to the next age range (see Section 10.7.7). 
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EP0012 
 
 
 
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The following table has been added: 
Table 5‒3: 
Schedule of study assessments (Taper Period and Safety Follow-
Up Period) for EP0012 
Assessment 
 
Taper Perioda 
(up to 4 weeks) 
Safety Follow-Up Periodb 
End of Taper Visitc 
 
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) 
X 
X 
 
Neurological exam (complete) 
X 
X 
 
12-lead ECGd 
X 
X 
 
Vital signs (BP and pulse) including 
orthostatic assessments 
X 
X 
 
Body weight 
X 
X 
 
Laboratory tests: 
 
 
 
 
Chemistry/hematology 
X 
Xe 
 
 
Endocrinology 
 
Xe 
 
 
Urine pregnancy testf 
X 
X 
 
Contact IVRS/IWRS 
X 
 
 
Subject diary return/reviewg 
X 
 
 
LCM review/return 
X 
 
 
Withdrawal criteria 
X 
 
 
AE reporting 
X 
X 
X 
C-SSRSh 
X 
X 
 
Healthcare resource use 
X 
X 
 
Work/school days lost 
X 
X 
 
Days with help from a caregiver 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; IVRS/IWRS= interactive voice/web response system; LCM=lacosamide; TC=telephone 
contact 
a 
All subjects who discontinue LCM must complete the End of Taper Visit.  
b 
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 Visit. 
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c 
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 7-2. 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 place at the ET or Termination Visit. 
d 
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) a 12-lead ECG (2 
interpretable recordings) approximately 20 to 30 minutes apart must be performed. 
e 
The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, or 
endocrinology) or reading (ECG) at the previous clinic visit. 
f 
Pregnancy tests will be performed for female subjects of childbearing potential only. A urine pregnancy test 
will be performed. 
g 
The last subject diary will be returned at the End of Taper Visit. 
h 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.7.3). 
Change #17 
Section 5.3 Rationale for study design and selection of dose 
Paragraph 2  
The efficacy, safety, and tolerability of LCM as an adjunctive therapy have been demonstrated in 
the partial-onset seizure population. The approach for further LCM development is to evaluate 
the use of adjunctive LCM for the treatment of uncontrolled PGTC seizures in patients with IGE. 
The maximum dose of LCM 800mg/day is the highest dose that has been used in previous 
clinical studies. Preclinical evaluations of LCM in animal models of generalized seizures 
indicate that LCM may be an effective treatment. However, 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 (eg, myoclonic seizures, absence seizures). 
Primary generalized tonic-clonic seizures may also occur in such distinct syndromes as benign 
myoclonic epilepsy in infancy, juvenile myoclonic epilepsy, epilepsy with PGTC seizures on 
awakening, childhood and juvenile absence epilepsy, and reflex-induced PGTC seizures. 
Typically, PGTC seizures present initially in childhood, adolescence, or early adulthood. 
Has been changed to: 
The efficacy, safety, and tolerability of LCM as an adjunctive therapy have been demonstrated in 
the partial onset seizure population. The approach for further LCM development is to evaluate 
the use of adjunctive LCM for the treatment of uncontrolled PGTC seizures in patients with IGE. 
Paragraph 3 
The goal of the Phase 3 LCM PGTC seizure program is to provide clinical evidence of the 
efficacy and safety of LCM as an adjunctive therapy for uncontrolled PGTC seizures in subjects 
with IGE as the basis for approval of this indication. SP0982 is a double-blind, randomized, 
placebo-controlled, parallel-group, multicenter study designed 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 goal of the Phase 3 LCM PGTC seizure program is to provide clinical evidence of the 
efficacy and safety of LCM as an adjunctive therapy for uncontrolled PGTC seizures in subjects 
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with IGE as the basis for approval of this indication. SP0982 is a double-blind, randomized, 
placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety 
of LCM for uncontrolled PGTC seizures in subjects ≥4 years of age with IGE. EP0012 will 
provide continued availability of LCM to subjects who have completed SP0982 and eligible 
Baseline failures from SP0982. 
Paragraph 4 
The following paragraph has been added: 
For adult subjects (≥18 years of age), 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. The maximum dose of LCM 800mg/day is the highest dose that has been 
used in previous clinical studies. Dose selection in EP0012 is based on the primary study 
(SP0982). During EP0012, investigators will be allowed to increase or decrease the dose of LCM 
to optimize tolerability and seizure reduction for each subject. Lacosamide doses may be 
increased up to a maximum of LCM 12mg/kg/day (oral solution) for pediatric subjects weighing 
<50kg. The maximum dose for pediatric subjects (<18 years of age) ≥50kg is 600mg/day 
(tablets) and for adult subjects is 800mg/day (tablets). 
Change #18 
Section 6.2 Exclusion criteria 
Exclusion criterion 3 
3. 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. 
Has been changed to: 
3. Subject has an active suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide Severity 
Rating Scale (C-SSRS). The subject should be referred immediately to a Mental Healthcare 
Professional. 
Change #19 
Section 6.3 Withdrawal criteria 
Paragraph 2 
Subjects must be withdrawn from the study if any of the following events occur: 
• Subject develops second or third degree atrioventricular (AV) block. 
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• 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. 
• A prolongation or worsening of overall seizure duration, frequency, type, or pattern 
considered by the investigator as serious enough to warrant discontinuation from the study. 
• In the case of liver function test (LFT) results of transaminases (alanine aminotransferase 
[ALT] and/or aspartate aminotransferase [AST]) ≥3x upper limit of normal (ULN) to 
<5xULN and total bilirubin ≥2xULN or transaminases (AST and/or ALT) ≥5xULN, LCM 
must be immediately discontinued and the subject withdrawn from the study. The LFTs will 
be repeated as soon as possible, and in no case more than 1 week later. 
• Subject has actual suicidal ideation since last visit 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. 
Has been changed to: 
Subjects must be withdrawn from the study if any of the following events occur: 
1. The subject develops second or third degree atrioventricular (AV) block. 
2. The subject becomes pregnant, as evidenced by a positive pregnancy test. 
3. The sponsor or a regulatory agency requests withdrawal of the subject. 
4. The subject is unwilling or unable to continue, or the legal representative is unwilling or 
unable to allow the subject to continue in the study. 
5. In the case of liver function test (LFT) results of transaminases (alanine aminotransferase 
[ALT] and/or aspartate aminotransferase [AST]) ≥3x upper limit of normal (ULN) to 
<5xULN and total bilirubin ≥2xULN or transaminases (AST and/or ALT) ≥5xULN, LCM 
must be immediately discontinued and the subject withdrawn from the study. The LFTs will 
be repeated as soon as possible, and in no case more than 1 week later. 
6. Subjects ≥6 years of age has actual suicidal ideation since last visit 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. 
7. Subject is unable to tolerate at least the minimum LCM target dose of 4mg/kg/day (oral 
solution) or 200mg/day (tablets). 
Paragraph 3, bulleted item 1 
• The subject requires a medication that is not permitted 
Has been changed to: 
• The subject requires a medication that is not permitted (see Section 7.8). 
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Paragraph 3, bulleted item 3 
• The following bulleted item has been added: 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. 
Change #20 
Section 7.1 Description of investigational medicinal product(s) 
Oral tablets of LCM 50mg and 100mg will be used in the study and will be supplied in 
high-density polyethylene bottles with child proof polypropylene screw caps. 
Has been changed to: 
Investigational medicinal product (IMP) will be provided as LCM oral solution (LCM 10mg/mL) 
and LCM tablets (LCM 50mg and LCM 100mg). 
The oral solution formulation contains 10mg/mL of drug substance and is colorless to pale 
yellow in appearance. 
The tablet formulation will be supplied in doses of 50mg and 100mg. The 50mg tablets are light 
pink, oval, film-coated tablets debossed with “SP” on 1 side and “50” on the other. The 100mg 
tablets are dark yellow, oval, film-coated tablets debossed with “SP” on 1 side and “100” on the 
other. 
Change #21 
Section 7.2 Treatment(s) to be administered 
Paragraphs 1 and 2 
Lacosamide will be orally administered bid (at approximately 12-hour intervals in the morning 
and in the evening) in 2 equally divided doses. During the study, investigators will be allowed to 
increase or decrease the dose of LCM to optimize tolerability and seizure reduction for each 
subject. 
At Visit 1 subjects who completed SP0982 will start on a dose of LCM 400mg/day (200mg bid); 
subjects who are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 
100mg/day (50mg bid). The LCM dose may then be adjusted at the discretion of the investigator 
within the range of 100 to 800mg/day. The investigator should increase or decrease the dose no 
faster than LCM 100mg/day per week. A clinic visit (scheduled or unscheduled) is required the 
first time the dose is increased to LCM 500mg/day, LCM 600mg/day, LCM 700mg/day, and 
LCM 800mg/day. One week after the first time the dose is increased to LCM 700mg/day or 
LCM 800mg/day, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
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Have been changed to: 
Lacosamide will be orally administered bid (at approximately 12-hour intervals in the morning 
and in the evening) in 2 equally divided doses (oral solution for pediatric subjects weighing 
<50kg or tablets for adult subjects [≥18 years of age] and pediatric subjects [<18 years of age] 
weighing ≥50kg); during the study, subjects who initially started on oral solution may transfer to 
tablets at the investigator’s discretion.  
During the study, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction for each subject, within the dose range described in 
Table 7‒1. 
Change #22 
The following section header has been added: 
Section 7.2.1 
Treatment Period 
Paragraphs 1 through 11 
Subjects withdrawing from the study will complete the Early Termination (ET) Visit and LCM 
will be tapered over 1 to 3 weeks (see taper schedule, Table 7‒1). Subjects completing the 
Treatment Period and not continuing with commercially available LCM will complete the 
Termination Visit and LCM will be tapered over 1 to 3 weeks (see taper schedule, Table 7-1). 
Lacosamide will be tapered off gradually at a recommended decrease rate of LCM 200mg/day 
per week, unless the investigator feels that safety concerns require a more rapid withdrawal of 
LCM. A slower taper (eg, LCM 100mg/day per week) is permitted, if medically necessary. The 
Medical Monitor should be contacted if a more rapid withdrawal is required. A Final Clinic Visit 
will occur 2 weeks after the final LCM dose for subjects who taper off LCM. 
Has been changed to: 
At Visit 1, subjects who completed SP0982 will start on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg to 
<50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start at 
Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and 
LCM 100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing 
≥50kg.  
Baseline failures are required to complete Week 1 of dosing before LCM dosing flexibility based 
on tolerability is allowed. Investigators will assess whether a subject would tolerate a further 
LCM 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 target dose of 4mg/kg/day (oral 
solution) or 200mg/day (tablets).  
At any time during the course of the study if it becomes apparent that a subject is unable to attain 
at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then the subject 
must enter the Taper Period and be withdrawn from the study. 
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During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who have 
dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) before a 
subsequent dose adjustment. 
Table 7-1 provides the minimum and maximum LCM dose during the Treatment Period. 
Table 7-1: 
Minimum and maximum LCM dose during the Treatment Period 
Formulation 
Minimum LCM dose 
Maximum LCM dose 
Oral solution (pediatric subjects <50kg) 
4mg/kg/day 
12mg/kg/day 
Tablets (pediatric subjects ≥50kg) 
200mg/day 
600mg/day 
Tablets (adult subjects) 
200mg/day 
800mg/day 
LCM=lacosamide 
The LCM dose may be adjusted at the investigator’s discretion after the subject receives the first 
dose of LCM in the study. Baseline failures must complete Week 1 of dosing before LCM may 
be increased or decreased. The maximum dose for pediatric subjects weighing <50kg is 
12mg/kg/day (oral solution). The maximum dose for pediatric subjects weighing ≥50kg is 
600mg/day (tablets) and for adult subjects is 800mg/day (tablets).  
A clinic visit (scheduled or unscheduled) is required if: 
• The dose is increased for the first time to any dose above 10mg/kg/day for pediatric subjects 
weighing <50kg. One week after the first time the dose is increased, an unscheduled 
telephone contact must be conducted to ensure that the dose is well tolerated.  
• The dose is increased for the first time to any dose above LCM 400mg/day for all adult 
subjects or pediatric subjects weighing ≥50kg. One week after the first time the dose is 
increased, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
Subjects withdrawing from the study must complete the Early Termination (ET) Visit and an up 
to 4-week taper followed by an End of Taper Visit (see taper schedule, Table 7‒2). 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. A slow 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. In case of an emergency, a faster taper 
is permitted after discussion with the Medical Monitor, whenever possible.  
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their legal representative(s) to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or their legal representative(s). 
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Subjects completing the Treatment Period and not continuing with commercially available LCM 
must complete the Termination Visit and also undergo taper, followed by an End of Taper Visit 
(see taper schedule, Table 7‒2), and a 30-day Safety Follow-Up Period.  
Subjects completing the Treatment Period and not continuing with commercially available LCM 
must complete the Termination Visit and also undergo taper, followed by an End of Taper Visit 
(see taper schedule, Table 7‒2), and a 30-day Safety Follow-Up Period.  
The following table summarizes the recommended LCM dose taper: 
Table 7‒1: Lacosamide dosing for subjects requiring taper 
Table 7‒1: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
Week 1 
Week 2 
Week 3 
LCM 800mg/day 
LCM 600mg/day 
LCM 400mg/day 
LCM 200mg/day 
LCM 700mg/day 
LCM 500mg/day 
LCM 300mg/day 
LCM 100mg/day 
LCM 600mg/day 
LCM 400mg/day 
LCM 200mg/day 
LCM 0mg/day 
LCM 500mg/day 
LCM 300mg/day 
LCM 100mg/day 
LCM 0mg/day 
LCM 400mg/day 
LCM 200mg/day 
LCM 0mg/day 
- 
LCM 300mg/day 
LCM 100mg/day 
LCM 0mg/day 
- 
LCM 200mg/day 
LCM 0mg/day 
- 
- 
LCM 100mg/day 
LCM 0mg/day 
- 
- 
ET=early termination; LCM=lacosamide 
a Subjects will begin taper on ET/Termination Visit. 
Has been changed to: 
Table 7‒2: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
750 to 800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
650 to 700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
550 to 600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
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Table 7‒2: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
Week 1 
Week 2 
Week 3 
Week 4 
450 to 500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
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 
ET=early termination; LCM=lacosamide 
Note: The oral solution is dosed as mg/kg/day and tablets are dosed as mg/day. 
a Subjects will begin taper on ET/Termination Visit. 
Change #23 
Section 7.3 Packaging 
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing Practice 
guidelines and applicable laws or regulations. The investigational medicinal product (IMP) is 
suitably packaged in such a way as to protect the IMP from deterioration during transport and 
storage. Lacosamide will be packaged in high-density polyethylene bottles with child proof 
polypropylene screw caps. 
Has been changed to: 
Lacosamide (tablets and oral solution) 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. 
Oral solution will be packaged in amber polyethylene terephthalate bottles. Tablets will be 
supplied in high density polyethylene bottles with child proof polypropylene screw caps. 
Change #24 
Section 7.5 Handling and storage requirements 
Paragraphs 2 through 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. 
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: 
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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 #25 
Section 7.6 Drug accountability 
Paragraph 1, second sentence 
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, first sentence 
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 #26 
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. 
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. 
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Change #27 
Section 7.8 Concomitant medication(s)/treatment(s) 
The following paragraphs have been added: 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(eg, eCRF and source document). 
Contraceptive treatment is allowed for female subjects of childbearing potential. 
The use of neuroleptics, monoamine oxidase inhibitors, barbiturates (except for treatment of 
epilepsy), and narcotic analgesics is prohibited throughout the study. However, in the case of 
narcotics or marijuana, certain limited usage may become necessary (eg, acute medical situation, 
perioperative period for subjects requiring surgery). Upon learning of such situations, the 
investigator should consult the medical monitor to determine whether the narcotic or marijuana 
use should result in discontinuation of a subject’s further participation in the study. 
The use of vigabatrin and felbamate is also prohibited throughout the study. 
Only stable use of amphetamines and sedative antihistamines is allowed during the study. Also, 
only stable, low doses of anxiolytics or hypnotics are allowed for nonepilepsy indications. 
Stable use of benzodiazepines is allowed as concomitant AEDs, but intermittent use is only 
allowed as rescue medication for epilepsy indications (maximum 1 dose per week). 
During the Treatment Period, new concomitant AEDs may be introduced, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication in 
the subject’s country. For example, a new AED may be added when the subject has not optimally 
or adequately responded (lack of efficacy or tolerance) to LCM. Concomitant AEDs may be 
carefully tapered and discontinued to achieve LCM monotherapy, if clinically appropriate. The 
Medical Monitor must be consulted prior to initiation of concomitant AED withdrawal. 
Change #28 
The following section has been deleted: 
Section 7.8.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are restricted during the study: 
• Use of benzodiazepines 
− The chronic (daily dose) use of benzodiazepines is allowed for treatment of epilepsy and 
will be counted as 1 of the AEDs. 
− The stable use of benzodiazepines for non-epilepsy indications is allowed during the 
study and will be counted as 1 of the AEDs. 
− The intermittent use of benzodiazepines is allowed only for rescue therapy for epilepsy 
indications, but limited to 4 doses per 28 days. 
During the Treatment Period, new concomitant AEDs may be introduced to optimize treatment, 
if the concomitant medication has been approved by the regulatory authority in the subject’s 
country. New AEDs should be added only when the subject has not optimally or adequately 
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responded to a maximum tolerated dose of LCM. Concomitant AEDs may be carefully tapered 
and discontinued to achieve LCM monotherapy, if clinically appropriate. The Medical Monitor 
must be consulted prior to initiation of concomitant AED withdrawal. 
Change #29 
Section 8 
STUDY PROCEDURES BY VISIT 
Paragraph 3 
A detailed schedule of study assessments for treatment Years 1 to 2 is provided in Table 5‒1 and 
for treatment Years 3 to 6 in Table 5‒2. 
Has been changed to: 
A detailed schedule of study assessments for treatment Years 1 to 2 is provided in Table 5‒1, for 
treatment Years 3 to 5 in Table 5‒2, and for the Taper Period and Safety Follow-Up Period in 
Table 5‒3. 
Change #30 
Section 8.1.1 
Visit 1 (Week 0) 
The following bulleted item has been deleted 
• Socio-professional data 
Bulleted items number 11, 12, 19, and 20 
• Tanner staging (for subjects <18 years of age) 
• C-SSRS assessment* 
• EQ-5D-3L 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) 
Have been changed to: 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
Change #31 
Section 8.1.2 
Visits 2 to 8 (Weeks 2 to 46, Year 1) 
Bulleted items number 1 through 19 
• Concomitant medications and AEDs 
• Physical examination (brief) 
• Neurological examination (brief) 
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• ECG (12-lead) assessment (Visit 2, 3, 4 and 8 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight (Visit 4, 6 and 8 only) 
• Tanner staging (for subjects <18 years of age) (Visit 5 and 8 only) 
• C-SSRS assessment 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis) [Visit 2, 3, 4, 6 and 8 only], and a urine pregnancy test [for women of 
childbearing potential]) 
• LCM plasma concentration (Visit 2 and 6 only) 
• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 5 only) 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) (Visit 5 and 8 
only) 
Have been changed to: 
• Concomitant medications and AEDs  
• Physical examination (brief, Visit 2, 3, 4, 5, 6, and 7; complete, Visit 8) 
• Neurological examination (brief, Visit 2, 3, 4, 5, 6, and 7; complete, Visit 8) 
• ECG (12-lead) assessment (Visit 2, 4, 6, and 8 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight (Visit 4, 6, and 8 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 8 only) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis) [Visit 2, 5, and 8 only], and a urine pregnancy test [for women of 
childbearing potential])  
• Contact IVRS/IWRS 
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• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 5 and 8) (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) (Visit 5 
and 8 only) 
Change #32 
Section 8.1.3 
Visits 9 to 11 (Weeks 62 to 94, Year 2) 
Bulleted items 1 through 18 
• Concomitant medications and AEDs 
• Physical examination (complete, Visit 9; brief, Visit 10 and 11) 
• Neurological examination (complete, Visit 9; brief, Visit 10 and 11) 
• ECG (12-lead) assessment (Visit 11 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 9 only) 
• Tanner staging (for subjects <18 years of age) (Visit 10 and 11 only) 
• 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]) 
• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 9 only) 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) (Visit 9 and 11 
only) 
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Have been changed to: 
• Concomitant medications and AEDs  
• Physical examination (brief, Visit 9 and 10; complete, Visit 11) 
• Neurological examination (brief, Visit 9 and 10; complete, Visit 11) 
• ECG (12-lead) assessment (Visit 9, 10, and 11) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 9 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 11 only) 
• 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]) 
• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 9 and 11) (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) (Visit 9 
and 11 only) 
Change #33 
Section 8.1.4 
Visits 12 to 19 (Weeks 118 to 286, Years 3 to 6) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (complete, Visit 12, 14, 16, 18 and 19; brief, Visit 13, 15, and 17) 
• Neurological examination (complete, Visit 12, 14, 16, 18 and 19; brief, Visit 13, 15, and 17) 
• ECG (12-lead) assessment (Visit 13, 15, 17, and 19) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 12, 14, 16 and 18) 
• Tanner staging (for subjects <18 years of age) 
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• 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]) 
• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 12, 14, 16, 18 and 19) 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Has been changed to: 
Section 8.1.4 Visits 12, 13, 14, 15, 16, and 17 (Weeks 118, 142, 166, 190, 
214, and 238, Years 3 to 5) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (brief, Visit 12, 14, and 16; complete, Visit 13, 15, and 17) 
• Neurological examination (brief, Visit 12, 14, and 16; complete, Visit 13, 15, and 17) 
• ECG (12-lead) assessment  
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 12, 14, and 16) 
• Tanner staging (for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) (Visit 13, 15, and 17) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and a urine pregnancy test [for women of childbearing potential]) 
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• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
• Achenbach CBCL for subjects ≥6 years to <18 years of age 
• BRIEF for subjects ≥5 to <18 years of age 
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Change #34 
Section 8.1.5 
Telephone Contact (Years 2 to 6) 
Has been changed to: 
Section 8.1.5 
Telephone Contact  
Paragraph 1 
Telephone contacts are required every 8 weeks during Year 2 to Year 6, except during weeks in 
which a clinic visit is planned (eg, Week 62). Therefore, telephone contacts in Year 2 are 
scheduled for Week 54, Week 70, and Week 86. Telephone contacts in Years 3 to 6 are 
scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 
158, Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230; Year 6 - Week 
246, Week 254, Week 270, Week 278. 
Has been changed to: 
Telephone contacts are required every 8 weeks during Year 2 to Year 5, except during weeks in 
which a clinic visit is planned (eg, Week 62). Therefore, telephone contacts in Year 2 are 
scheduled for Week 54, Week 70, and Week 86. Telephone contacts in Years 3 to 5 are 
scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 
158, Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. 
Paragraph 2 
The following paragraph has been deleted: 
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One week after the first time the dose is increased to LCM 700mg/day or LCM 800mg/day, an 
unscheduled telephone contact must be conducted to ensure that the dose is well tolerated. 
Paragraph 3 
The following paragraph has been added: 
The investigator will also ensure subjects are compliant with LCM administration and diary 
completion during the telephone contact. 
Change #35 
The following section has been added: 
Section 8.1.6 
LCM solution Dispensation Visit 
From Year 3 onwards, pediatric subjects weighing <50kg will return to the clinic for an 
additional Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of LCM 
solution; LCM usage will be reviewed and empty LCM bottles will be returned. 
Change #36 
The following section header has been deleted: 
Section 8.2 End of Study Period 
Change #37 
Section 8.2.1 
Early Termination Visit (Years 1 to 6) 
Has been changed to: 
Section 8.2  
Early Termination Visit  
Paragraph 1 
Subjects withdrawing from the study will complete the ET Visit and LCM will be tapered over 1 
to 3 weeks (see taper schedule, Table 7‒1). 
Has been changed to: 
Subjects withdrawing from the study will complete the ET Visit, and LCM will be tapered over a 
period of up to 4 weeks (see taper schedule, Table 7‒2). 
Paragraph 2, bulleted items number 7 through 19 
• Tanner staging (for subjects <18 years of age) 
• 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]) 
• LCM plasma concentration 
• Contact IVRS/IWRS 
• Dispense subject diary 
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• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) 
Have been changed to: 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) 
• 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]) 
• Contact IVRS/IWRS 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
Change #38 
Section 8.2.2 
Termination Visit (Years 1 to 6) 
Has been changed to: 
Section 8.3 Termination Visit 
Paragraphs 1 and 2 
Subjects completing the Treatment Period and not continuing with commercially available LCM 
will complete the Termination Visit, and LCM will be tapered over 1 to 3 weeks (see taper 
schedule, Table 7‒1). 
Once LCM becomes commercially available and the subject elects to continue treatment, they 
must also complete the Termination Visit and transition to commercially available LCM. Taper 
of LCM is not required for subjects who complete the study and continue on commercially 
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available LCM. Subjects transitioning to commercially available LCM will do so immediately 
and will continue with the dose they were taking at the Termination Visit. 
Have been changed to: 
Subjects completing the Treatment Period and not continuing with commercially available LCM 
will complete the Termination Visit, and LCM will be tapered over a period of up to 4 weeks 
(see taper schedule, Table 7‒2). 
Once LCM is approved for use and the subject elects to continue treatment, they must also 
complete the Termination Visit and transition to commercially available LCM. Taper of LCM is 
not required for subjects who complete the study and continue on commercially available LCM. 
Subjects transitioning to commercially available LCM will do so immediately and will continue 
at a dose determined by the investigator. 
Note: this visit can be combined with Visit 17 if appropriate. 
Paragraph 4, bulleted items number 7 through 24 
• Tanner staging (for subjects <18 years of age) 
• 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])  
• LCM plasma concentration 
• Contact IVRS/IWRS 
• Dispense subject diary for subjects undergoing taper 
• Subject diary return/review 
• Dispense LCM for subjects undergoing taper 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L 
• QOLIE-31-P (subjects ≥18 years of age)/PedsQL (subjects <18 years of age) 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
• Healthcare resource use (Years 1 to 2 only) 
• Work/school days lost (Years 1 to 2 only) 
• Days with help from a caregiver (Years 1 to 2 only) 
Have been changed to: 
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• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) 
• 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]) 
• Contact IVRS/IWRS 
• Dispense subject diary for subjects undergoing taper 
• Subject diary return/review 
• Dispense LCM for subjects undergoing taper 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
• Healthcare resource use  
• Work/school days lost  
• Days with help from a caregiver 
Change #39 
Section 8.2.3 
Final Clinic Visit 
A Final Clinic Visit will occur 2 weeks after the final LCM dose for subjects who taper off 
LCM. The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight 
• C-SSRS assessment 
• Blood sample for a serum pregnancy test (for women of childbearing potential) 
• Contact IVRS/IWRS 
• Subject diary return/review 
• AE reporting 
Has been changed to: 
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Section 8.4.1 
End of Taper Visit 
An End of Taper Visit will occur after the final LCM dose for subjects who taper off LCM. The 
following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Physical examination (complete) 
• Neurological examination (complete) 
• ECG (12-lead) assessment 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and a urine pregnancy test [for women of childbearing potential]) 
• Contact IVRS/IWRS 
• Subject diary return/review 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Change #40 
Section 8.3 Unscheduled Visit 
Has been changed to: 
Section 8.5 Unscheduled Visit 
Paragraph 1 
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. A clinic visit (scheduled or unscheduled) is required the first time the dose is 
increased to LCM 500mg/day, LCM 600mg/day, LCM 700mg/day, and LCM 800mg/day. One 
week after the first time the dose is increased to LCM 700mg/day or LCM 800mg/day, an 
unscheduled telephone contact must be conducted to ensure that the dose is well tolerated. 
Has been changed to: 
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. A clinic visit (scheduled or unscheduled) is required the first time the dose is 
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increased above the dose of 10mg/kg/day (oral solution) for pediatric subjects weighing <50kg 
or 400mg/day (tablets) for adult and pediatric subjects ≥50kg. One week after the first time the 
dose is increased above the dose of 10mg/kg/day or 400mg/day, an unscheduled telephone 
contact must be conducted to ensure that the dose is well tolerated. Similarly, a clinic visit 
(scheduled or unscheduled) is required for pediatric subjects weighing <50 kg the first time the 
dose is increased to 11mg/kg/day, or 12mg/kg/day, and all adult subjects or pediatric subjects 
weighing ≥50kg the first time the dose is increased to LCM 500mg/day, LCM 600mg/day, LCM 
700mg/day, and LCM 800mg/day. One week after the first time the dose is increased to 
11mg/kg/day, or 12mg/kg/day for pediatric subjects <50kg, and LCM 500mg/day, LCM 
600mg/day, LCM 700mg/day, or LCM 800mg/day for all adult subjects or pediatric subjects 
weighing ≥50kg, an unscheduled telephone contact must be conducted to ensure that the dose is 
well tolerated. 
Paragraph 3 
If unscheduled visit is due to an AE, then the C-SSRS is required. 
Has been changed to: 
If Unscheduled Visit is due to an AE, then the C-SSRS is required. 
Change #41 
The following header section was added: 
Section 8.4 Taper and Safety Follow-Up Period 
Change #42 
The following section has been added: 
Section 8.4.2 
Safety Follow-Up Visit 
Following the End of Taper Visit, the subject will return 2 weeks 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: 
• Concomitant medications and AEDs 
• Physical examination (complete) 
• Neurological examination (complete) 
• ECG (12-lead) assessment (only required for subjects with an abnormal reading at the 
previous clinic visit) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology, [only required for subjects with an abnormal value at the previous 
clinic visit], and a urine pregnancy test [for women of childbearing potential]) 
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• AE reporting 
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Change #43 
The following section has been added: 
Section 8.4.3 
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. During the Safety Follow-Up telephone contact, the following 
assessments will be performed: 
• Concomitant medications and AEDs  
• AE reporting 
Change #44 
Section 9.1 Seizure frequency 
The following paragraph was added: 
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 #45 
Section 9.2.1 
Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P) 
Paragraphs 1 and 2 
The QOLIE-31-P Version 2 (see Section 17.2) will be used to evaluate the health-related quality 
of life (HRQoL) of study subjects (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. 
Have been changed to: 
The QOLIE-31-P Version 2 (see Section 16.2) 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 
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Functioning [6 items], Medication Effects [3 items], and Daily Activities/Social Functioning [5 
items]) and 1 health status item. 
Change #46 
Section 9.2.2 
Pediatric Quality of Life Inventory 
Paragraphs 2 through 4 
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. For each developmentally appropriate version of 
the PedsQL subjects must have at least 1 year of data before transitioning to the next age range. 
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. 
Have been changed to: 
The PedsQL Measurement Model consists of 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 
HRQoL is measured for pediatric subjects ≤4 years of age. The PedsQL appropriate for each 
subject’s age should be completed, with the following exception: if a subject ages up to the next 
form of the PedsQL within 1 year after the Baseline assessment of the primary study, the form 
that was used at the Baseline assessment should be completed for 1 year after the Baseline 
assessment, and subsequently the form consistent with his/her age at the time of assessment 
should be completed. 
For each version of the PedsQL subjects, must have at least 1 year of data before transitioning to 
the next age range. 
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 #47 
Section 9.2.3 
EuroQol-5D-3L Quality of Life Assessment 
Paragraph 1, first sentence 
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The EQ-5D-3L (EuroQol Group, 2011) (see Section 17.3) is a self-administered questionnaire 
designed to measure health status. 
Has been changed to: 
The EQ-5D-3L (EuroQol Group, 2011) (see Section 16.3) is a self-administered questionnaire 
designed to measure health status in subjects ≥12 years of age. 
Paragraph 2 
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. 
Has been changed to: 
The EQ-5D-3L also captures a self-rating of health status on a 20cm vertical VAS, anchored at 
100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the bottom. 
Change #48 
Section 9.2.5 
Number of working 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. 
Change #49 
Section 9.2.6 
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 #50 
The following section has been deleted 
Section 9.2.7 
Socio-professional data 
Socio-professional data, such as highest level of education, current professional status, housing 
status, and regular assistance will be collected according to the schedule of study assessments in 
Table 5‒1. 
Change #51 
The following section has been deleted: 
Section 10 ASSESSMENT OF PHARMACOKINETIC VARIABLE(S) 
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 5-1and Table 5‒
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2. 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. 
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. 
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. 
 
Change #52 
Section 11.3 
Adverse events of special interest 
Has been changed to: 
Section 10.3 
Adverse events of special interest 
Paragraph 2, bulleted item number 3 
• Serious suspected multiorgan hypersensitivity reactions; serious suspected multiorgan 
hypersensitivity cases may be identified and reported to the sponsor by the investigator using 
the following algorithm as agreed with the US Food and Drug Administration: 
− An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) 
combined with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ Eosinophils % ≥10% 
◦ Eosinophils absolute ≥0.5G/L 
◦ Neutrophils absolute <1.5G/L 
◦ Platelets ≤100G/L 
◦ ALT ≥2xULN 
◦ AST ≥2xULN 
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Has been changed to: 
• Serious suspected multiorgan hypersensitivity reactions.  
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US Food and 
Drug Administration: 
An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, 
encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) combined 
with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ involvement 
or eosinophilia: 
◦ 
Eosinophils % ≥10% 
◦ 
Eosinophils absolute ≥0.5G/L 
◦ 
Neutrophils absolute <1.5G/L 
◦ 
Platelets ≤100G/L 
◦ 
ALT ≥2xULN 
◦ 
AST ≥2xULN 
Bulleted item number 4 has been added 
• Emergence of non-pre-existing or worsening of any existing epileptic seizure types 
Change #53 
Section 11.6 
Laboratory measurements 
Has been changed to: 
Section 10.6 
Laboratory measurements 
Paragraph 1, 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 and 
Table 5‒2. 
Has been changed to: 
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, Table 
5‒2, and Table 5-3. 
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Table 11-2: Laboratory tests 
Table 11‒2: 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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Has been changed to: 
Table 10-2: Laboratory tests 
Hematology 
Clinical chemistry 
Endocrinology 
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 
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 
 
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; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid stimulating hormone; WBC=white blood cell 
Change #54 
Section 11.6.1 Liver function tests 
Has been changed to: 
Section 10.6.1 Liver function tests 
Paragraph 4 
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C will 
be done. 
Has been changed to: 
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C will 
be performed. In all cases of transaminases (AST, ALT, or both) ≥8xULN or a potential case of 
drug-induced liver injury (ie, Hy’s law), testing for hepatitis E immunoglobulin M antibodies 
will be performed. 
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Change #55 
Section 11.6.2 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 and Table 5‒2. 
Has been changed to: 
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, Table 5‒2, and Table 5-3. 
Change #56 
Section 11.7.1 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 and Table 5‒2. Assessment of orthostatic changes will be as follows: after the 
3-minute measurement in a supine position, the subject is asked to stand 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 schedule of study assessments in Table 5‒1 and Table 
5‒2. 
Has been changed to: 
Section 10.7.1 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 schedule of study assessments in Table 5‒1, Table 5‒2, 
and Table 5-3. 
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Change #57 
Section 11.7.2 12-lead ECG 
Standard 12-lead ECGs will be performed according to the schedule of study assessments in 
Table 5‒1 and Table 5‒2. 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 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. 
Section 11.7.2.1 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 6.3). The investigator may consult with 
the cardiologist at the central ECG laboratory to confirm the presence of a clinically significant 
ECG abnormality. It remains the responsibility of the investigator to decide whether an ECG 
finding is of clinical significance on the basis of the complete clinical picture and whether this 
finding influences the subject’s participation in the study. 
Has been changed to: 
Section 10.7.2 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.  
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), a 12-lead ECG (2 interpretable recordings) approximately 
20 to 30 minutes apart must be performed. 
Section 10.7.2.1 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 6.3). 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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Change #58 
Section 11.7.3 Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed according to the 
schedule of study assessments in Table 5‒1 and Table 5‒2. 
Has been changed to: 
Section 10.7.3 Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed according to the 
schedule of study assessments in Table 5‒1, Table 5‒2, and Table 5-3. 
The C-SSRS will be completed for subjects who are ≥6 years of age. The “Since Last Visit” 
version of the C-SSRS should be used. If a subject becomes 6 years of age during the study, the 
"Already Enrolled" version of the C-SSRS should be used once, followed by the “Since Last 
Visit” version 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. 
Change #59 
Section 11.7.4 
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 and Table 5‒2. 
Clinically significant physical examination findings are to be reported as AEs. 
Has been changed to: 
Section 10.7.4 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. 
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Change #60 
Section 11.7.4.1 
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: 
Section 10.7.4.1 
Complete physical examination 
The complete physical examination will include cardiac and respiratory function via auscultation 
and review of all body systems. 
Change #61 
Section 11.7.5 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 and Table 5‒2. 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.  
Has been changed to: 
Section 10.7.5 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. 
Change #62 
Section 11.7.5.2 Brief neurological examination 
The brief neurological examination will include selected assessment of mental status, cranial 
nerves, and coordination/cerebellar function. 
Has been changed to: 
Section 10.7.5.2 Brief neurological examination 
The brief neurological examination will include selected assessments of: general neurological 
status, reflexes, muscle strength, and coordination/cerebellar function. 
Change #63 
Section 11.7.6 Achenbach CBCL 
Has been changed to: 
Section 10.7.6 Achenbach CBCL 
Paragraphs 1 and 2 
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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 completion of the Achenbach CBCL will require approximately 45 
minutes. 
Has been changed to: 
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. 
The Achenbach CBCL consists of the CBCL/1½ -5 for children <5 years and 11 months of age, 
and the CBCL/6 18 for children ≥6 years to <18 years of age. These are to be completed by the 
parent(s)/legal representative(s). The completion of the Achenbach CBCL will require 
approximately 45 minutes. The version of the Achenbach CBCL appropriate to each subject’s 
age should be administered with the following exception: for subjects who completed the 
CBCL/1½-5 at the Baseline assessment of the previous study and turn 6 years of age within 
1 year after the Baseline assessment of the primary study, the CBCL/1½-5 should be completed 
for 1 year after the Baseline assessment of the primary study, and subsequently the CBCL/6-18 
should be completed. The Achenbach CBCL will only be administered in countries where a 
validated translated version is available. For each version of the CBCL, subjects must have at 
least 1 year of data before transitioning to the next age range. 
Change #64 
Section 11.7.7 BRIEF 
The BRIEF is a validated tool that will be used for the evaluation of subjects ≥5 years of age. 
The BRIEF includes Rating forms used by parents to assess subjects’ executive functioning and 
include validity scales to measure negativity and inconsistency of responses. For each 
developmentally appropriate version of the BRIEF subjects must have at least 1 year of data 
before transitioning to the next age range. 
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. 
Has been changed to: 
Section 10.7.7 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 or BRIEF 
appropriate for each subject’s age should be completed, with the following exception: For 
subjects who completed the BRIEF-P at the Baseline assessment of the previous study and turn 5 
years of age within 1 year after the Baseline assessment of the primary study, the BRIEF-P 
should be completed for 1 year after the Baseline assessment of the primary study, and 
subsequently the BRIEF should be completed. The BRIEF-P and BRIEF will be administered 
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according to the tabular schedules of study procedures (Section 5.2). The BRIEF-P and BRIEF 
will be used only in countries where a translated scale is available. For each developmentally 
appropriate version of the BRIEF subjects must have at least 1 year of data before transitioning 
to the next age range. 
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 #65 
Section 11.7.8 Tanner stage 
The Tanner Stage will be performed for subjects who are <18 years of age, according to the 
schedule of study assessments in Table 5‒1 and Table 5‒2. The investigator or qualified 
designee will evaluate the subject’s sexual development using the 3-item scale. 
Has been changed to: 
Section 10.7.8 Tanner stage 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter 
puberty during the course of the study, according to the schedule of study assessments in Table 
5‒1 and Table 5‒2. The investigator or qualified designee will evaluate the subject’s sexual 
development using the 3-item 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 the evaluation of Tanner Stage (ie, those subjects who are pubescent at Visit 1 or 
who will enter puberty during the course of the study). 
Change #66 
Section 12.3.2 Database entry and reconciliation 
Has been changed to: 
Section 11.3.2 Database entry and reconciliation 
Paragraph 1, third sentence 
The study will be performed using remote data capture; the data are entered into the eCRFs once 
and are subsequently verified. 
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Has been changed to: 
This study will be performed using remote data capture; the data are entered into the eCRFs once 
and are subsequently verified. 
Change #67 
The following section has been deleted 
Section 13.1.3 Pharmacokinetic Set 
The Pharmacokinetic Set is a subset of the SS and consists of all subjects with at least 
1 evaluable assessment of plasma concentration data. 
Change #68 
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 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 Clinical 
Program Manager, the study biostatistician, study physician, a representative of the monitoring 
team, and other appropriate team members. 
Has been changed to: 
Section 12.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on either the primary efficacy outcome or key safety outcomes for an 
individual subject. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the project Data Cleaning 
Plan. To the extent feasible, rules for identifying protocol deviations will be defined without 
review of the data and without consideration of the frequency of occurrence of such deviations. 
Whenever possible, criteria for identifying important protocol deviations will be implemented 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock to confirm exclusion from analysis sets. 
Change #69 
Section 13.7 
Planned interim analysis and data monitoring 
No interim analysis is planned for this study. 
Has been changed to: 
Section 12.7 
Planned interim analysis and data monitoring 
No interim analysis or Data Monitoring Committee is planned. However, data may be reported 
prior to the completion of this study to support annual reports, regulatory submissions, and 
publications. 
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Change #70 
Section 13.8 
Determination of sample size 
Has been changed to: 
Section 12.8 
Determination of sample size 
Paragraph 1 
The sample size of this open-label extension study will be determined by the parent SP0982 
study, where approximately 200 subjects will be randomized. 
Has been changed to: 
The sample size of this open-label extension study will be determined by the parent SP0982 
study, where approximately 200 subjects are planned to be randomized. 
Change #71 
Section 16  
References 
Has been changed to: 
Section 15  
References 
The following reference was deleted: 
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-68. 
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16.5 
Appendix 5: Protocol Amendment 2 
Rationale for the amendment 
The protocol was amended following a request from the Taiwanese MoH, that for dose 
escalation, subjects who are eligible Baseline failures from SP0982 must remain on the dose for 
≥7 days before a subsequent dose escalation. Additionally, the purpose of the amendment was to 
remove superfluous description of a substudy, to clarify the requirement for ECG at subsequent 
visits, requirement for endocrinology and timing of endocrinology assessments, pregnancy 
testing, definition of contraceptive methods, and seizure count, and to add a definition of the 
Enrolled Set. Several assessments will not be done in Years 3-5, including brief physical 
examination (complete physical examination will be done),  complete neurological examination 
(brief neurological examination will be done), and health outcome measures. 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 EP0012 Amendment 1” to “Protocol EP0012 
Amendment 2.” 
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 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Has been changed to: 
Protocol/Amendment Number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
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Change #2 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
Clinical Project Manager  
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
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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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World (except Japan): +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 (except Japan):  
Has been updated to: 
Sponsor Study Physician 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
Clinical Project Manager  
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Phone: 
 
Email: 
 
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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 
BMI 
body mass index 
EDC 
electronic data capture 
EI-AED 
enzyme-inducing antiepileptic drug 
ES 
Enrolled Set 
ICH 
International Conference on Council for Harmonisation  
IRT 
interactive response technology 
IVRS/IWRS 
interactive voice/web response system 
MAO-A 
monoamine oxidase A 
MAP 
managed access program 
PDILI 
potential drug-induced liver injury 
PS 
patient safety 
SFU 
Safety Follow Up 
TMF 
trial master file 
These abbreviations have also been changed wherever they occur throughout the protocol. 
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Change #4 
Section 1, SUMMARY 
Paragraph 5 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who have 
dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) before a 
subsequent dose adjustment.  
Has been changed to: 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must remain 
on the dose for ≥7 days before a subsequent dose escalation.  
Change #5 
Section 1 SUMMARY 
Paragraph 7 
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. The study duration 
and the total number of clinic visits will vary for each subject. At selected sites, subjects may 
also be able to participate in a substudy without withdrawing from EP0012. Treatment will 
continue until LCM is approved for use in the subject’s country for the treatment of PGTC 
seizures in subjects with IGE, or until UCB has determined that the clinical development 
program for the indication will be formally discontinued, or until UCB decides to close the 
study. 
Has been changed to: 
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. The study duration 
and the total number of clinic visits will vary for each subject. Treatment will continue until 
LCM is approved for use in the subject’s country for the treatment of PGTC seizures in subjects 
with IGE, or until UCB has determined that the clinical development program for the indication 
will be formally discontinued, or until UCB decides to close the study. 
Change #6 
Section 1, SUMMARY 
Paragraph 10 
The primary safety variables are adverse events (AEs) and subject withdrawals due to AEs. 
Secondary safety variables are changes in hematology, chemistry, and urinalysis parameters; 
changes in 12-lead electrocardiograms (ECGs); and changes in vital sign measurements (ie, 
blood pressure [BP] and pulse rate), including body weight and physical (including neurological) 
examination findings. In addition, for pediatric subjects <18 years of age, safety will be 
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evaluated using behavioral assessments (Achenbach Child Behavior Checklist [CBCL]), and 
cognitive function assessments (Behavior Rating Inventory of Executive Function®/Behavior 
Rating Inventory of Executive Function-Preschool Version® [BRIEF®/BRIEF-P®]). Efficacy 
variables are evaluations of seizure frequency, based on information included in subject diaries, 
and health outcome variables, including the Patient Weighted Quality of Life in Epilepsy 
Inventory-Form 31 (QOLIE-31-P), the Pediatric Quality of Life Inventory™ (PedsQL™), the 
3-level EuroQol 5 Dimension Quality of Life Assessment (EQ-5D-3L) Quality of Life 
Assessment, healthcare resource use, the number of working or school days lost by subjects, and 
the number of days with help from a caregiver. 
Has been changed to: 
The primary safety variables are adverse events (AEs), subject withdrawals due to AEs, 
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. Secondary safety variables are changes in 
hematology, chemistry, and urinalysis parameters; changes in 12-lead electrocardiograms 
(ECGs); and changes in vital sign measurements (ie, blood pressure [BP] and pulse rate), 
including body weight and physical (including neurological) examination findings. In addition, 
for pediatric subjects <18 years of age, safety will be evaluated using behavioral assessments 
(Achenbach Child Behavior Checklist [CBCL]), and cognitive function assessments (Behavior 
Rating Inventory of Executive Function®/Behavior Rating Inventory of Executive Function-
Preschool Version® [BRIEF®/BRIEF-P®]). The seizure efficacy variables are evaluations of 
seizure frequency, based on information included in subject diaries. The health outcome 
variables, including the Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 
(QOLIE-31-P), the Pediatric Quality of Life Inventory™ (PedsQL™), the 3-level EuroQol 
5 Dimension Quality of Life Assessment (EQ-5D-3L), healthcare resource use, the number of 
working or school days lost by subjects due to epilepsy, and the number of days with help from a 
caregiver due to epilepsy will be assessed for the first 2 years of treatment. 
Change #7 
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 unknown origin. 
Has been changed to: 
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 unknown 
origin. 
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Change #8 
Section 2, INTRODUCTION 
Paragraph 8 
Preliminary safety and PK data suggest that exposure-response in pediatric and adult subjects 
treated with LCM will be similar. Lacosamide is evaluated in pediatric subjects 1 month to 17 
years of age in 2 completed studies and 1 ongoing study: SP847 (open-label, Phase 2, PK, 
tolerability, and safety study), SP1047 (PK study with a 1 day Evaluation Period), and SP848 
(open-label long-term safety study). 
Has been changed to: 
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 
Change #9 
Section 4.1.1, Primary safety variables 
The primary safety variables are: 
• Adverse events as reported spontaneously by the subject and/or caregiver or observed by the 
investigator 
• Subject withdrawals due to AEs 
Has been changed to: 
The primary safety variables are: 
• Adverse events as reported spontaneously by the subject and/or caregiver or observed by the 
investigator 
• Subject withdrawals due to AEs 
• Incidence of new seizure types during the Treatment Period 
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• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
absence seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline 
Change #10 
Section 4.1.2, Secondary safety variables 
Bullet point 3 
• Changes in vital sign measurements (ie, BP and pulse rate), including body weight and 
physical (including neurological) examination findings 
Has been changed to: 
• Changes in vital sign measurements (ie, BP and pulse rate), including BMI and physical 
(including neurological) examination findings 
Change #11 
Section 4.2.2, Secondary efficacy variable 
The secondary efficacy variable is: 
• Percent change in PGTC seizure frequency per 28 days from Baseline, where Baseline is 
defined as the 12-week Historical Baseline and 4-week Prospective Baseline periods 
immediately prior to randomization in the parent study (SP0982) 
Has been changed to: 
The secondary efficacy variable is: 
• Percent change in PGTC seizure frequency per 28 days from Combined Baseline, where 
Combined Baseline is defined as the combined 12-week Historical Baseline and 4-week 
Prospective Baseline periods immediately prior to randomization in the parent study 
(SP0982) 
Change #12 
Section 4.2.3, Other efficacy variables 
The other efficacy variables are: 
• Percent change in days with myoclonic seizures per 28 days from Baseline 
• Percent change in days with absence seizures per 28 days from Baseline 
• Percentage of subjects with at least a 50% reduction in PGTC seizure frequency compared to 
Baseline 
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• Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
Baseline 
• Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
Baseline 
• Seizure-free status (yes/no) for PGTC seizures 
• Seizure-free status (yes/no) for myoclonic seizures 
• Seizure-free status (yes/no) for absence seizures 
• Seizure-free status (yes/no) for all generalized seizure types 
• 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 in the 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 
Has been changed to: 
The other efficacy variables are: 
• Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
• Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline 
• Change in days with absence seizures per 28 days relative to the Prospective Baseline 
• Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
• Percentage of subjects with at least a 50% reduction in PGTC seizure frequency compared to 
the Combined Baseline 
• Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
the Prospective Baseline 
• Percentage of subjects with at least a 50% reduction in absence seizure days compared to the 
Prospective Baseline 
• Seizure-free status (yes/no) for PGTC seizures 
• Seizure-free status (yes/no) for all generalized seizure types 
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• 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 for the first two years of treatment  
• Change from Baseline in the EQ-5D-3L visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age) for the first two 
years of treatment 
• Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
for the first two years of treatment 
• Number of working or school days lost by subject due to epilepsy for the first two years of 
treatment 
• Number of days with help from a caregiver due to epilepsy for the first two years of 
treatment 
Change #13 
Section 5.1, Study description 
Paragraph 3 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg to 
<50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start at 
Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and LCM 
100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing 
≥50kg. 
Paragraph 6 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who have 
dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) before a 
subsequent dose adjustment.  
Have been changed to: 
Paragraph 3 
Randomized subjects meeting SP0982 exit criteria and subjects who completed SP0982 will start 
at Visit 1 on a dose of LCM 10mg/kg/day for pediatric subjects weighing <30kg, LCM 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 400mg/day (200mg bid) 
for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who are 
eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day for 
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pediatric subjects weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects (≥18 
years of age) or pediatric subjects weighing ≥50kg. 
Paragraph 6 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must remain 
on the dose for ≥7 days before a subsequent dose escalation.  
Change #14 
Section 5.1, Study description 
Paragraph 10 
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone contacts 
will be used to obtain information regarding concomitant medication use, and assess withdrawal 
criteria and AEs, as well as to ensure subjects are compliant with LCM administration and diary 
completion. The study duration and the total number of clinic visits will vary for each subject. At 
selected sites, subjects may also be able to participate in a substudy without withdrawing from 
EP0012. Treatment will continue until LCM is approved for use in the subject’s country for the 
treatment of PGTC seizures in subjects with IGE, or until UCB has determined that the clinical 
development program for the indication will be formally discontinued, or until UCB decides to 
close the study. 
Paragraph 11 
Subjects and/or their caregiver will be dispensed a seizure diary to record all types of seizures, 
concomitant AEDs, and other pertinent health status information. Subjects must bring their diary 
to each visit. Seizure frequency and type will be verified by a reliably documented seizure 
history collected (eg, in a seizure diary). 
Have been changed to: 
Paragraph 10 
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone contacts 
will be used to obtain information regarding concomitant medication use, and assess withdrawal 
criteria and AEs, as well as to ensure subjects are compliant with LCM administration and diary 
completion. The study duration and the total number of clinic visits will vary for each subject. 
Treatment will continue until LCM is approved for use in the subject’s country for the treatment 
of PGTC seizures in subjects with IGE, or until UCB has determined that the clinical 
development program for the indication will be formally discontinued, or until UCB decides to 
close the study. 
Paragraph 11 
Subjects and/or their caregiver will be dispensed a seizure diary to record all types of seizures, 
concomitant AEDs, and other pertinent health status information. Subjects must bring their diary 
to each visit. Baseline seizure frequency and type will be verified by a reliably documented 
seizure history collected (eg, in a seizure diary during SP0982). 
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Change #15 
Section 5.1.1, Study duration per subject 
Last paragraph 
Depending on the local regulations, after 2 years, subjects may continue to receive LCM in a 
named patient program. 
Has been changed to: 
Depending on the local regulations, after 2 years, subjects may continue to receive LCM in a 
managed access program (MAP). 
Change #16 
Section 5.1.3, Anticipated regions and countries 
This study is planned to be conducted in the US, Canada, Europe, Asia, and Australia with 
possible extension to other countries and regions. 
Has been changed to: 
This study is planned to be conducted in the US, Europe, Asia, and Australia with possible 
extension to other countries and regions. 
Change #17 
Table 5‒1: Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit) 
Rows 
A row was added to schedule laboratory tests for endocrinology at Visit 1, ET and Termination 
Visits. 
Work/school days lost and Days with help from a caregiver were changed to Work/school days 
lost due to epilepsy, and Days with help from a caregiver due to epilepsy. 
Footnotes 
o Urinalysis will be required for subjects ≥5 years of age only. 
p Pregnancy tests will be performed for female subjects of childbearing potential only. Serum 
 
pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, and 
 
Termination Visit. All other pregnancy tests will be urine dipstick. 
Have been changed to: 
o Urinalysis will be required for all subjects. 
p If the patient was treated in SP0982, endocrinology should be done if age was <18 years at 
SP0982 Visit 1. If the patient was a Baseline failure in SP0982, endocrinology should be 
done if age is <18 years at EP0012 Visit 1. 
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q Pregnancy tests will be performed for female subjects of childbearing potential only. Serum 
pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, and Termination 
Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may 
have an additional urine pregnancy test at V1 of EP0012, at the investigator’s discretion. 
Change #18 
Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 
(Treatment Period, ET Visit, Termination Visit, and Unscheduled Visit) 
Rows 
A row was added to schedule laboratory tests for endocrinology at ET and Termination Visits. 
The following assessments have been removed from the schedule for Years 3 through 5: Physical 
exam (brief), Neurological exam (complete), EQ-5D-3L, QOLIE-31-P/PedsQLs, Healthcare 
resource use, Work/school days lost, and Days with help from a caregiver. 
The following assessments will now be done at Visits 13, 15, and 17 only: 12-lead ECG, 
Achenbach CBCL, and BRIEF. 
Footnotes 
b Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone 
contacts, at the discretion of the investigator. 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, etc. The C-SSRS 
must be performed if the Unscheduled Visit is due to an AE. 
q Pregnancy tests will be performed for female subjects of childbearing potential only. Serum 
pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, and Termination 
Visit. All other pregnancy tests will be urine dipstick. 
Has been changed to: 
b Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone 
contacts, at the discretion of the investigator. 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 physical or neurological examination, ECG, vital 
signs, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to 
a psychiatric AE. 
o Laboratory tests are applicable for combined Visit 17/Termination Visit. If Visit 17 is not the 
Termination Visit, laboratory tests are not required. 
p If the patient was treated in SP0982, endocrinology should be done if age was <18 years at 
SP0982 Visit 1. If the patient was a Baseline failure in SP0982, endocrinology should be 
done if age is <18 years at EP0012 Visit 1. 
q Pregnancy tests will be performed for female subjects of childbearing potential only. Serum 
pregnancy tests will be conducted at the following visits: Visit 1 (W0), ET, and Termination 
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Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may 
have an additional urine pregnancy test at V1 of EP0012, at the investigator’s discretion. 
Change #19 
Table 5‒3: Schedule of study assessments (Taper Period and Safety Follow-Up 
Period) for EP0012 
Rows 
Neurological exam (complete), Work/school days lost, and Days with help from a caregiver were 
changed to Neurological exam (brief), Work/school days lost due to epilepsy, and Days with help 
from a caregiver due to epilepsy. 
The following footnote has been added: 
i 
Healthcare resource use, work/schools days lost due to epilepsy, and days with help from a 
caregiver due to epilepsy will be assessed only for patients completing the study after 
≤2 years. These assessments are not applicable for patients tapering down or performing the 
SFU-visits during Years 3, 4 or 5). 
Change #20 
Section 6.1, Inclusion criteria 
2. Subject must have completed or be an eligible Baseline failure from the parent study 
(SP0982), as defined in Section 5.1.  
Has been changed to: 
2. Subject must have completed or be an eligible Baseline failure from the parent study 
(SP0982), as defined in Section 5.1. Note: Other subjects screened for SP0982 may be 
considered for roll-over to EP0012 if the investigator considers that the subject could benefit 
from treatment with open-label LCM and based on prior discussion with and approval from 
the UCB Study Physician or representative. 
Change #21 
Section 6.2, Exclusion criteria 
A new criterion has been added: 
4. 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 Case Report form (CRF). 
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 
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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. 
Change #22 
Section 6.3, Withdrawal criteria 
Bullet point 5 
• 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 
will decide whether or not to stop the study drug. 
Has been changed to: 
• Discontinuation criteria for potential drug-induced liver injury (PDILI) are described in 
Section 6.3.1. 
Change #23 
A new section has been added: 
Section 6.3.1, 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%). 
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume IMP 
administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 10.3.1.2.1 are followed. 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator.  
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• 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 10.3.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. See 
Section 6.3 for when and how to discontinue subjects from the IMP. See Section 8.2 for the 
procedures to be performed at the time of discontinuation. 
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 CRF must document the primary 
reason for IMP discontinuation. 
Change #24 
Section 7.2, Treatment(s) to be administered 
New paragraph 2: 
Tablets must not be broken. In rare cases where uneven dosing (e.g., 350mg/day, 450mg/day, 
550mg/day, etc) is medically needed, although the interactive response technology (IRT) will not 
dispense the exact dose, please contact the medial monitor for additional instructions. 
Change #25 
Section 7.2.1, Treatment Period 
Paragraph 4 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects who have 
dose adjustments must remain on the dose for ≥3 days (in order to reach steady state) before a 
subsequent dose adjustment. 
Table 7‒2: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
750 to 800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
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Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
Week 1 
Week 2 
Week 3 
Week 4 
650 to 700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
550 to 600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
450 to 500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
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 
Has been changed to: 
Paragraph 4 
During EP0012, investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction. Lacosamide doses may be increased or decreased in 
steps of no more than 2mg/kg/day (oral solution) or 100mg/day (tablets). Subjects must remain 
on the dose for ≥7 days before a subsequent dose escalation.  
Table 7‒2: 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
NA 
300mg/day 
200mg/day 
100mg/day 
NA 
NA 
200mg/day 
100mg/day 
NA 
NA 
NA 
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Change #26 
Section 7.5, Handling and storage requirements 
Paragraphs 1 through 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 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 Handing Manual 
Change #27 
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. 
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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 #28 
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 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. 
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.  
Change #29 
Section 7.8, Concomitant medication(s)/treatment(s) 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(eg, eCRF and source document). 
Contraceptive treatment is allowed for female subjects of childbearing potential. 
The use of neuroleptics, monoamine oxidase inhibitors, barbiturates (except for treatment of 
epilepsy), and narcotic analgesics is prohibited throughout the study. However, in the case of 
narcotics or marijuana, certain limited usage may become necessary (eg, acute medical situation, 
perioperative period for subjects requiring surgery). Upon learning of such situations, the 
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investigator should consult the medical monitor to determine whether the narcotic or marijuana 
use should result in discontinuation of a subject’s further participation in the study. 
The use of vigabatrin and felbamate is also prohibited throughout the study. 
Only stable use of amphetamines and sedative antihistamines is allowed during the study. Also, 
only stable, low doses of anxiolytics or hypnotics are allowed for nonepilepsy indications. 
Stable use of benzodiazepines is allowed as concomitant AEDs, but intermittent use is only 
allowed as rescue medication for epilepsy indications (maximum 1 dose per week). 
During the Treatment Period, new concomitant AEDs may be introduced, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication in 
the subject’s country. For example, a new AED may be added when the subject has not optimally 
or adequately responded (lack of efficacy or tolerance) to LCM. Concomitant AEDs may be 
carefully tapered and discontinued to achieve LCM monotherapy, if clinically appropriate. The 
Medical Monitor must be consulted prior to initiation of concomitant AED withdrawal. 
Section 7.8.1, Rescue medication 
The intermittent use of benzodiazepines is allowed only for epilepsy indications (see 
Section 7.8). 
Have been changed to: 
Section 7.8, Concomitant medication(s)/treatment(s) 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(eg, eCRF and source document). 
7.8.1 Permitted concomitant treatments (medications and therapies) 
Female subjects not surgically sterile or 2 years postmenopausal should practice 1 highly 
effective method of contraception (according to 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. Recommended contraception methods for subjects on enzyme-inducing 
antiepileptic drugs (EI-AEDs) or not on EI-AEDs are detailed in Section 16.6. Subjects on 
EI-AEDs who do not use one of the highly effective contraception methods recommended for 
this group may practice 2 combined methods of contraception (ie, combined hormonal 
contraception plus barrier method with spermicidal agent). 
The initiation of felbamate treatment while participating in EP0012 is prohibited. 
The use of neuroleptics except for clozapine is allowed. The use of barbiturates and narcotic 
analgesics is also allowed. Stable use of benzodiazepines is allowed as concomitant AEDs, but 
intermittent use is only allowed as rescue medication for epilepsy indications (maximum 1 dose 
per week). 
During the Treatment Period, new concomitant AEDs may be introduced, if the concomitant 
medication has been approved by the regulatory authority for the respective patient indication in 
the subject’s country. For example, a new AED may be added when the subject has not optimally 
or adequately responded (lack of efficacy or tolerance) to LCM. Concomitant AEDs may be 
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carefully tapered and discontinued to achieve LCM monotherapy, if clinically appropriate. The 
Medical Monitor must be consulted prior to initiation of concomitant AED withdrawal. 
7.8.2 Prohibited concomitant treatments (medications and therapies) 
The following medications/therapies are prohibited during the course of this study: 
• Clozapine 
• MAO-A inhibitors 
• Vigabatrin 
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. 
Change #30 
Section 8.1.1, Visit 1 (Week 0) 
Bullet points 13, 24, and 25 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a serum pregnancy test [for women of childbearing potential])*.  
• Work/school days lost* 
• Days with help from a caregiver* 
Have been changed to: 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential])*. Baseline failures from SP0982 may 
have an additional urine pregnancy test at V1 of EP0012, at the investigator’s discretion. 
• Work/school days lost due to epilepsy* 
• Days with help from a caregiver due to epilepsy* 
Change #31 
Section 8.1.2, Visits 2 to 8 (Weeks 2 to 46, Year 1) 
Bullet points 22 and 23 
• Work/school days lost 
• Days with help from a caregiver 
Have been changed to: 
• Work/school days lost due to epilepsy 
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• Days with help from a caregiver due to epilepsy 
Change #32 
Section 8.1.3, Visits 9 to 11 (Weeks 62 to 94, Year 2) 
Bullet points 22 and 23 
• Work/school days lost 
• Days with help from a caregiver 
Have been changed to: 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
Change #33 
Section 8.1.4, Visits 12, 13, 14, 15, 16, and 17 (Weeks 118, 142, 166, 190, 214, and 
238, Years 3 to 5) 
Bullet points 2, 3, 4, 9, and 17 through 23 
• Physical examination (brief, Visit 12, 14, and 16; complete, Visit 13, 15, and 17) 
• Neurological examination (brief, Visit 12, 14, and 16; complete, Visit 13, 15, and 17) 
• ECG (12-lead) assessment 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and a urine pregnancy test [for women of childbearing potential])  
• EQ-5D-3L (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) 
• Achenbach CBCL for subjects ≥6 years to <18 years of age  
• BRIEF for subjects ≥5 to <18 years of age  
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Have been changed to: 
Bullet points 2, 3, 4, 9, 10, 18, and 19 
• Physical examination (complete, Visit 13, 15, and 17) 
• Neurological examination (brief, Visit 12, 14, and 16) 
• ECG (12-lead) assessment (Visit 13, 15, and 17) 
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• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 17/Termination 
Visit. If Visit 17 is not the Termination Visit, laboratory tests are not required) 
• Urine pregnancy test [for women of childbearing potential]) 
• Achenbach CBCL for subjects ≥6 years to <18 years of age (Visits 13, 15, and 17) 
• BRIEF for subjects ≥5 to <18 years of age (Visits 13, 15, and 17) 
EQ-5D-3L, QOLIE-31-P, Healthcare resource use, Work/school days lost, and Days with help 
from a caregiver were removed from Table 5-2 as health outcome variables will be assessed only 
during the first 2 years of treatment. 
Change #34 
Section 8.2 Early Termination Visit  
Bullet points 3 and 9, and health outcome bullets 
• Neurological examination (complete) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a serum pregnancy test [for women of childbearing potential]) 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost  
• Days with help from a caregiver  
Have been changed to: 
• Neurological examination (brief) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
The following assessments are only applicable at the ET Visit for subjects early terminating the 
study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
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Change #35 
Section 8.3 Termination Visit  
Paragraph 2  
Taper of LCM is not required for subjects who complete the study and continue on commercially 
available LCM. Subjects transitioning to commercially available LCM will do so immediately 
and will continue at a dose determined by the investigator. 
Bullet points 3 and 9, and health outcome bullets 
• Neurological examination (complete)  
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, urinalysis, and a serum pregnancy test [for women of childbearing potential]) 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost  
• Days with help from a caregiver  
Have been changed to: 
Paragraphs 2 and 3 
Patients transitioning to the MAP will complete the Treatment Period after 2 years but continue 
their treatment with MAP LCM. 
Taper of LCM is not required for subjects who complete the study and continue on MAP LCM 
or commercially available LCM. Subjects transitioning to MAP LCM or commercially available 
LCM will do so immediately and will continue at a dose determined by the investigator. 
Bullet points 3 and 9, and health outcome bullets 
• Neurological examination (complete) Note: Complete neurological exam to be performed for 
patients terminating the study during Years 1-2, brief exam for patients terminating during 
Years 3-5. 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
The following assessments are only applicable at the Termination Visit for subjects terminating 
the study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
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• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
Change #36 
Section 8.4.1, End of Taper Visit  
Bullet points 3, 14, 15, and 16 
• Neurological examination (complete)  
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Have been changed to: 
• Neurological examination (brief) 
The following assessments are only applicable at the End of Taper Visit for subjects 
terminating/early terminating the study during the first 2 years (see Section 4.2.3): 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
Change #37 
Section 8.4.2, Safety Follow-Up Visit 
Bullet points 3, 10, 11, and 12 
• Neurological examination (complete)  
• Healthcare resource use 
• Work/school days lost 
• Days with help from a caregiver 
Have been changed to: 
• Neurological examination (brief) 
The following assessments are only applicable at the Safety Follow-Up Visit for subjects 
terminating/early terminating the study during the first 2 years (see Section 4.2.3): 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
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Change #38 
Section 8.5, Unscheduled Visit 
Bullet points 2 and 3 
• Physical examination (brief)  
• Neurological examination (brief)  
Paragraph 3 
If Unscheduled Visit is due to an AE, then the C-SSRS is required. 
Have been changed to: 
• Physical examination (brief) during the first 2 years  
• Neurological examination (brief) during the first 2 years 
Paragraph 3 
If Unscheduled Visit is due to a psychiatric AE, then the C-SSRS is required. 
Change #39 
Section 9.1, Seizure frequency 
Subjects will keep a diary to record daily seizure activity from Visit 1 until the end of study 
participation. Efficacy variables will be assessed using the seizure count information recorded on 
the subject diaries. 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: 
9.1 Seizure variables 
Subjects will keep a diary to record seizure activity from Visit 1 until the end of study 
participation. Efficacy variables will be assessed using the seizure count information recorded on 
the subject diaries. The subject should be reminded to bring the diary to each clinic visit.  
9.1.1 PGTC seizures 
The following information will be recorded as applicable: 
• Seizure type 
• Number of PGTC seizures 
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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. 
9.1.2 Absence and myoclonic seizures 
In the subject diary, the following information will be recorded: 
• 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 #40 
9.2 Health outcome variables 
The following text has been added: 
Health outcome variables will be evaluated during the first two years of treatment. 
Change #41 
9.2.4 Healthcare resource use 
Healthcare resource use will include concomitant medical procedures, hospitalizations, and 
healthcare provider visits. 
9.2.5 Number of working or school days lost  
The number of working or school days lost by the subject will be recorded, as applicable. 
9.2.6 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: 
9.2.4 Healthcare resource use 
Healthcare resource use will include concomitant medical procedures, hospitalizations, and 
healthcare provider visits during the first 2 years of treatment. 
9.2.5 Number of working or school days lost due to epilepsy 
The number of working or school days lost by the subject due to epilepsy will be recorded, as 
applicable, during the first 2 years of treatment. 
9.2.6 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, 
during the first 2 years of treatment. 
Change #42 
Section 10, ASSESSMENT OF SAFETY 
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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. 
Change #43 
Section 10.1.1.3, Adverse events of special interest 
A bullet point has been 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 #44 
Section 10.1.3, 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: 
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 10.3.1.4. 
New paragraph 3 
Information on SAEs obtained after clinical database lock will be captured through the patient 
Safety (PS) database without limitation of time. 
Change #45 
Section 10.1.6, Pregnancy 
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Paragraph 1 
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 should be scheduled 2 weeks after the subject has discontinued her 
IMP. 
Paragraphs 3 through 6 
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. 
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. 
Have been changed to: 
Section 10.1.4, Pregnancy 
Paragraph 1 
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 Patient Safety (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 should be scheduled 2 weeks after the subject has discontinued her 
IMP. 
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Paragraphs 3 through 5 
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, UCB 
will ask the investigator or designee to contact the subject and his partner to request consent 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/contract research organization (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. 
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. 
Change #46 
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 CRF, 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 #47 
The following section has been added: 
Section 10.2, New seizure types  
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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 9.1). 
Change #48 
Section 10.6.1, Liver function tests 
Refer to Section 6.3 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 
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 performed. In all cases of transaminases (AST, ALT, or both) ≥8xULN or a potential case of 
drug-induced liver injury (ie, Hy’s law), testing for hepatitis E immunoglobulin M antibodies 
will be performed. 
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 10.3.1, Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 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 10.3.1.1). 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 
10.3.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
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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 CRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 10.3.1.2.1 are met, rechallenge with IMP may be appropriate.  
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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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 
≥2xULNb 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 10.3.1.3); 
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 
10.3.1.2). 
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 
10.3.1.3). 
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. 
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c Details provided in Section 10.3.1.1. 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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10.3.1.1 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 10.3.1.3) and SAE report (if 
applicable). 
10.3.1.2 Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) 
to immediate and permanent discontinuation (see Section 6.3.1 and Table 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. 
10.3.1.2.1 IMP restart/rechallenge (if applicable) 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur. 
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 10-3), but for whom an alternative diagnosis 
is confirmed, can rarely restart IMP. Rechallenge with IMP can occur only if ALL of the 
following requirements are met: 
• The results of additional testing and monitoring described in Section 10.3.1.3 and Section 
10.3.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory parameters 
and any associated symptoms (ie, a subsequent alternative diagnosis fully explains the 
hepatic findings).  
• No alternative treatment options are available to the subject. 
• The subject has shown clear therapeutic benefit from the IMP. 
• Subject’s ALT or AST elevations do not exceed ≥3xULN. 
• Subject’s total bilirubin is <1.5xULN. 
• Subject has no signs or symptoms of hypersensitivity.  
• The rechallenge is approved by the UCB responsible physician and a hepatologist. The 
hepatologist must be external to UCB. It is recommended that the hepatologist be a local 
hepatology expert or the hepatologist treating the subject. 
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• Subject agrees to the investigator-recommended monitoring plan. 
10.3.1.3 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 CRF. 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: 
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/INRa 
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; 
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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). 
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  
10.3.1.4 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. 
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Change #49 
Section 12.1, Definition of analysis sets 
The following subsection has been added:  
12.1.1 Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have a signed Informed Consent/
Assent form. 
Change #50 
Section 12.3.1, Safety analyses 
A new Paragraph 2 has been added: 
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. Laboratory 
measurements as described in Section 10.3 and other safety measurements as described in 
Section 10.4 will be presented. 
Change #51 
Section 12.4, Planned efficacy analyses 
Paragraph 2  
Days with myoclonic or absence seizures are more clinically relevant endpoints; therefore, 
days with myoclonus and absence will be summarized separately using the same method for 
PGTC seizures. Subjects who were seizure-free from all generalized seizures will also be 
tabulated (PGTC, myoclonic and absence seizures combined). 
Has been changed to: 
Days with myoclonic or absence seizures are more clinically relevant endpoints; therefore, 
change in and percent change in days with myoclonus and absence will be summarized. The 
percentage of subjects with 50% reduction in days with absence and myoclonic seizures per 
28 days compared to the Prospective Baseline will be presented. Subjects who were seizure 
free from all generalized seizures will also be tabulated. 
Change #52 
Section 15, 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. doi: 
10.1212/WNL.0b013e31822cfc90.  
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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. 
Change #53 
Appendix 6: Contraception Table was added in Section 16.6. 
 
 
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16.6 
Appendix 6: Protocol Amendment 3 
Rationale for the amendment 
The primary purpose of this amendment is to simplify the assessments and procedures for all 
subjects during the first 94 weeks of study and to simplify the assessments and procedures for 
adults after Week 94. Pediatric assessments will be kept as they are after Week 94 for 
regulatory purposes.  
In addition, the following changes have been made: 
• To allow the Safety Follow-Up for subjects tapered in SP0982 after the 125th event occurs 
in SP0982, this will be performed at Visit 1 of EP0012 and subjects will have their 
4-week Safety Follow-Up in EP0012. 
• To restructure the safety variables  
• The planned number of subject is aligned with the pivotal study SP0982 
• To update the introduction section with regulatory information on the marketing 
authorization of Vimpat and to provide an update on the lacosamide (LCM) clinical 
program. 
• To clarify the potential drug-induced liver injury (PDILI) criteria requiring immediate 
and permanent discontinuation of the investigational medicinal product (IMP). 
• To update the 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 EP0012 Amendment 2” to “Protocol EP0012 
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 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
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Has been changed to: 
Protocol/Amendment Number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
Change #2 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
Clinical Project Manager 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
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Clinical Project Manager 
 
 
 
 
 
 
Change #3 
Section 1 SUMMARY 
Paragraph 1 (last sentence) 
It is estimated that approximately 200 subjects across approximately 150 sites will be 
enrolled in EP0012. 
Paragraph 2 
Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg 
to <50kg, and LCM 400mg/day (200mg twice daily [bid]) for adult subjects (≥18 years of 
age) or pediatric subjects weighing ≥50kg. 
Paragraph 10 
The primary safety variables are adverse events (AEs), subject withdrawals due to AEs, 
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. Secondary safety variables 
are changes in hematology, chemistry, and urinalysis parameters; changes in 12-lead 
electrocardiograms (ECGs); and changes in vital sign measurements (ie, blood pressure [BP] 
and pulse rate), including body mass index (BMI) and physical (including neurological) 
examination findings. In addition, for pediatric subjects <18 years of age, safety will be 
evaluated using behavioral assessments (Achenbach Child Behavior Checklist [CBCL]), and 
cognitive function assessments (Behavior Rating Inventory of Executive Function®/Behavior 
Rating Inventory of Executive Function-Preschool Version® [BRIEF®/BRIEF-P®]). The 
seizure efficacy variables are evaluations of seizure frequency, based on information included 
in subject diaries. The health outcome variables, including the Patient Weighted Quality of 
Life in Epilepsy Inventory-Form 31 (QOLIE-31-P), the Pediatric Quality of Life Inventory™ 
(PedsQL™), the 3-level EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L), 
healthcare resource use, the number of working or school days lost by subjects due to 
epilepsy, and the number of days with help from a caregiver due to epilepsy will be assessed 
for the first 2 years of treatment. 
Name: 
 
Address: 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Phone: 
 
Email: 
 
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Has been changed to: 
Paragraph 1 (last sentence) 
It is estimated that up to 250 subjects across approximately 150 to 180 sites will be enrolled 
in EP0012. 
Paragraph 2 
Once 125 subjects have had a second PGTC seizure in SP0982, that study will have met its 
protocol-defined stopping and all subjects will transition into EP0012 or taper off study 
medication. Subjects who completed SP0982 will start at Visit 1 on a dose of LCM 
10mg/kg/day for pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects 
weighing ≥30kg to <50kg, and LCM 400mg/day (200mg twice daily [bid]) for adult subjects 
(≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who are eligible Baseline 
failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects 
weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects (≥18 years of age) or 
pediatric subjects weighing ≥50kg.   
Paragraph 10 
The primary safety variables are adverse events (AEs), subject withdrawals due to AEs, 
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. Secondary safety variables 
are percentage of treatment-emergent marked abnormalities in hematology, and chemistry 
parameters; percentage of treatment-emergent marked abnormalities in 12-lead 
electrocardiograms (ECGs); and percentage of treatment-emergent marked abnormalities in 
vital sign measurements (ie, blood pressure [BP] and pulse rate). Other safety variables 
include changes in hematology, chemistry, and urinalysis parameters, changes in 12-lead 
ECGs, and changes in in vital sign measurements (ie, BP and pulse rate), including weight 
and height and physical (including neurological) examination findings.  In addition, for 
pediatric subjects <18 years of age, safety will be evaluated using behavioral assessments 
(Achenbach Child Behavior Checklist [CBCL]), and cognitive function assessments 
(Behavior Rating Inventory of Executive Function®/Behavior Rating Inventory of Executive 
Function-Preschool Version® [BRIEF®/BRIEF-P®]). The seizure efficacy variables are 
evaluations of seizure frequency, based on information included in subject diaries. The health 
outcome variables, including the Patient Weighted Quality of Life in Epilepsy Inventory-
Form 31 (QOLIE-31-P), the Pediatric Quality of Life Inventory™ (PedsQL™), the 3-level 
EuroQol-5 Dimension Quality of Life Assessment (EQ-5D-3L), healthcare resource use, the 
number of working or school days lost by subjects due to epilepsy, and the number of days 
with help from a caregiver due to epilepsy will be assessed for the first 2 years of treatment. 
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. 
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Lacosamide has also been approved in the US (oral tablets, oral solution [syrup], and solution 
for iv infusion) as monotherapy and 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. 
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 
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 also 
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. 
Paragraph 8 
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 
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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. 
Change #5 
Section 4.1.2 Secondary safety variables 
Secondary safety variables are: 
• Changes in hematology, chemistry, and urinalysis parameters 
• Changes in 12-lead ECGs 
• Changes in vital sign measurements (ie, BP and pulse rate), including BMI and physical 
(including neurological) examination findings 
Has been changed to: 
Secondary safety variables are: 
• Percentage of treatment-emergent marked abnormalities in hematology and chemistry 
parameters 
• Percentage of treatment-emergent marked abnormalities in 12-lead ECGs 
• Percentage of treatment-emergent marked abnormalities in vital sign measurements (ie, 
BP and pulse rate) 
Change #6 
Section 4.1.3 Other safety variables 
• Achenbach CBCL1½-5 or CBCL/6-18 
• Cognitive function assessment BRIEF/BRIEF-P 
Has been changed to: 
• Changes in hematology, chemistry, and urinalysis parameters 
• Changes in 12-lead ECGs 
• Changes in vital sign measurements (ie, BP and pulse rate), including weight and height 
and physical (including neurological) examination findings 
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• Achenbach CBCL1½ 5 or CBCL/6 18 (for pediatric subjects only) 
• Cognitive function assessment BRIEF/BRIEF-P (for pediatric subjects only) 
Change #7 
Section 5 Study design 
Paragraph 1 
This study will enroll consenting subjects, or subjects whose legal representatives have given 
consent, who have completed the LCM SP0982 study as well as eligible Baseline failures 
from SP0982. Approximately 200 subjects from approximately 150 study sites are planned to 
be enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, and study completers from SP0982 who are eligible for inclusion in EP0012 are 
defined as: 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry 
criteria except the minimum PGTC seizure criteria required for randomization (Baseline 
failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) 
of SP0982 and experienced ≥2 PGTC seizures during that time or  
• Subjects who experience a second PGTC seizure after the first 6 weeks of the Treatment 
Period of SP0982  
SP0982 completers 
• Subjects who experience <2 PGTC seizures within the 24-week Treatment Period of 
SP0982  
Randomized subjects meeting SP0982 exit criteria and subjects who completed SP0982 will 
start at Visit 1 on a dose of LCM 10mg/kg/day for pediatric subjects weighing <30kg, LCM 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 400mg/day (200mg 
bid) for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who 
are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day 
for pediatric subjects weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects 
(≥18 years of age) or pediatric subjects weighing ≥50kg. 
Has been changed to: 
Paragraph 1 
This study will enroll consenting subjects, or subjects whose legal representatives have given 
consent, who have completed the LCM SP0982 (or have left the primary study at the time of 
the 125th event, whichever came first)  as well as eligible Baseline failures from SP0982. 
Then, some subjects who tapered in SP0982 after the 125th event may enter EP0012 for the 
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Safety Follow-Up only (ICF to be signed beforehand). Up to 250 subjects from 150 to 180 
study sites are planned to be enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, and study completers from SP0982 who are eligible for inclusion in EP0012 are 
defined as: 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry 
criteria except the minimum PGTC seizure criteria required for randomization (Baseline 
failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) 
of SP0982 and experienced ≥2 PGTC seizures during that time or  
• Subjects who experience a second PGTC seizure after the first 6 weeks of the Treatment 
Period of SP0982  
SP0982 completers 
• Subjects who experience <2 PGTC seizures within the 24-week Treatment Period of 
SP0982  
• Subjects who were ongoing in SP0982 when the 125th event occurred 
SP0982 Safety Follow-Up subjects 
• Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up Visit only.  
Randomized subjects meeting SP0982 exit criteria and subjects who completed SP0982 will 
start at Visit 1 on a dose of LCM 10mg/kg/day for pediatric subjects weighing <30kg, LCM 
8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg, and LCM 400mg/day (200mg 
bid) for adult subjects (≥18 years of age) or pediatric subjects weighing ≥50kg. Subjects who 
are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM 2mg/kg/day 
for pediatric subjects weighing <50kg, and LCM 100mg/day (50mg bid) for adult subjects 
(≥18 years of age) or pediatric subjects weighing ≥50kg. In addition, once 125 subjects have 
had a second PGTC seizure in SP0982 (ie, the 125th event has occurred),  that study will have 
met its protocol-defined end. All subjects ongoing in SP0982 will transition into EP0012 for 
further long term treatment for a Safety Follow-Up. 
Change #8 
Section 5.1.1 Study duration per subject 
Bullet 5 has been updated. 
− An End of Taper Visit will occur after the final LCM dose for subjects who taper off 
LCM. 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 
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Taper Visit followed by a Safety Follow-Up telephone contact 30 days after the last 
dose of study drug. 
Has been changed to: 
− An End of Taper Visit will occur after the final LCM dose for subjects who taper off 
LCM. 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 same design will apply to some of the subjects tapered in 
SP0982 at the time of the 125th event and who entered EP0012 for the Safety 
Follow-Up Visit only and to subjects who entered EP0012 for a Safety Follow-up 
Visit after discontinuing SP0982 due to the study stopping. 
Change #9 
Section 5.1.2 Planned number of subjects and site(s) 
Up to 200 subjects across approximately 150 international sites are planned to be enrolled in 
this study. 
Has been changed to: 
Up to 250 subjects across 150 to 180 international sites are planes to be enrolled in this study. 
Change #10 
Section 5.2 Schedule of study assessments 
The schedule of study assessments for treatment Years 1 to 2 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) is provided in Table 5‒1. An additional schedule 
of study assessments for treatment Years 3 to 5 (Treatment Period, ET Visit, Termination 
Visit, and Unscheduled Visit) is provided in Table 5‒2. The schedule of study assessments 
for the Taper and Safety Follow-Up is provided in Table 5‒3. 
Has been changed to: 
The schedule of study assessments for treatment Years 1 to 2 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) is provided in Table 5-1. An additional schedule 
of study assessments for treatment Years 3 to 5 (Treatment Period, ET Visit, Termination 
Visit, and Unscheduled Visit) is provided in Table 5-2 for subjects <18 years and Table 5-3 
for subjects ≥18 years. The schedule of study assessments for the Taper Period and Safety 
Follow-Up Visit (including subjects who tapered in SP0982 after the 125th event consented to 
enter EP0012 for the Safety Follow-up only) is provided in Table 5-4. 
 
Table 5-1 
A has been added to explain that Visit 6, Visit 7 and Visit 10 will not be performed according 
to Protocol Amendment 3. Footnote ‘b’ has ‘vital signs’ removed and for footnote ‘d’ Week 
30 Week 38 and Week 78 has been added to footnote for consistency. 
Note: Visit 6, Visit 7 and Visit 10 (**) assessments will not be performed according to 
Protocol Amendment 3. 
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b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the 
discretion of the investigator. 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, etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
d 
Telephone contacts are required every 8 weeks including Week 30 and Week 38 during the study, except 
during weeks in which a clinic visit is planned (eg, Week 62). Therefore, telephone contacts in Year 2 are 
scheduled for Week 54, Week 70, Week 78, and Week 86. 
Has been changed to: 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the 
discretion of the investigator. 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, laboratory tests, 
etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
d 
Telephone contacts are required every 8 weeks including Week 30 and Week 38 during the study, except 
during weeks in which a clinic visit is planned (eg, Week 62). Therefore, telephone contacts in Year 2 are 
scheduled for Week 54, Week 70, Week 78, and Week 86. 
 
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Table 5-2 
Table title has been updated for pediatrics only, a note has been added and footnote ‘b’ and ‘h’ have been updated.   
Table 5-2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ Terme 
ET Visitf 
Term Visitg 
LCM Solution Dispensation 
Visith 
Unscheduled Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
b Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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, etc. The C-SSRS must be performed if the Unscheduled Visit is due to an AE. 
h Dispensation Visit will occur 12 weeks after each 24-weekly visit Year 3 onwards and will be for the purpose of dispensing LCM solution for pediatric subjects 
<50kg. 
 
 
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Has been changed to 
Table 5-2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit for subjects <18 years) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET Visitf 
Term Visitg 
LCM Solution Dispensation 
Visith 
Unscheduled Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Note: Subjects who turn 18 years during the course of this study will be considered as pediatric, however these subjects will not need to complete the Achenbach 
CBCL and BRIEF assessments. 
h 
Dispensation Visit will occur 12 weeks after each 24-weekly visit from Year 2 (Visit 11) to Year 3 onwards and will be for the purpose of dispensing LCM 
solution for pediatric subjects <50kg. 
Change #11 
The following table has been added for adult subjects for Years 3 to 5.  
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Table 5-3: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit for subjects ≥18 years) 
 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET Visitf 
Term Visitg 
LCM Solution 
Dispensation Visith 
Unscheduled Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Concomitant medications 
and AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory testsh 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Pregnancy testi 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Call IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; IRT=interactive 
response technology; LCM=lacosamide; NA=not applicable; Term=Termination; V=Visit 
a 
The Treatment Period will continue for at least 2 years. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
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physical or neurological examination, ECG, vital signs, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric 
AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned (eg, 
Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, Week 
174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-4. 
g 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate. For subjects who will not 
continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue 
on LCM, the Termination Visit is the last visit in the study.  
h 
Laboratory tests include chemistry, hematology and urinalysis. 
i 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion 
 
Change #12 
Table 5-4 
A note and footnote ‘b’ have been amended. 
b There will be a 30-day (-1/+3 days) Safety Follow-Up Period for subjects who complete the End of Taper Visit for SP0982 and EP0012. 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 Visit. 
Has been changed to 
Note: The schedule of study assessments for the Taper Period and Safety Follow-Up Visit includes some of the subjects who tapered in SP0982 after the 125th 
event who consented to enter EP0012 for the Safety Follow-Up only. 
b 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 Visit. 
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Change #13 
Section 6.3 Withdrawal criteria 
The following new criterion has been added 
1. Tapered subjects from SP0982 who enter EP0012 after the 125th event will be withdrawn at 
the enrollment visit and enter directly into the Safety Follow-Up Period without and ET Visit 
being performed in EP0012. 
Change #14 
Section 6.3.1 Potential drug-induced liver injury IMP discontinuation 
criteria 
Subjects with PDILI must be assessed to determine if investigational medicinal product (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%). 
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%). 
Change #15 
Section 7.2 Treatment(s) to be administered 
Paragraph 2 has been updated 
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Tablets must not be broken. In rare cases where uneven dosing (e.g., 350mg/day, 450mg/day, 
550mg/day, etc) is medically needed, although the interactive response technology (IRT) will not 
dispense the exact dose, please contact the medial monitor for additional instructions. 
Has been changed to: 
Tablets must not be broken. In rare cases where uneven dosing (e.g., 350mg/day, 450mg/day, 
550mg/day, etc) is medically needed, although the interactive response technology (IRT) will not 
dispense the exact dose, please contact the Medical Monitor for additional instructions. 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]). 
Change #16 
Section 7.2.1 Treatment Period 
Paragraph 1 and 3 
At Visit 1, subjects who completed SP0982 will start on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg to 
<50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start at 
Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and LCM 
100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing 
≥50kg. 
At any time during the course of the study if it becomes apparent that a subject is unable to attain 
at least this minimum dose of 4mg/kg/day (oral solution) or 200mg/day (tablets), then the subject 
must enter the Taper Period and be withdrawn from the study. 
Has been changed to: 
At Visit 1, subjects who completed SP0982 will start on a dose of LCM 10mg/kg/day for 
pediatric subjects weighing <30kg, LCM 8mg/kg/day for pediatric subjects weighing ≥30kg to 
<50kg, and LCM 400mg/day (200mg bid) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg. Subjects who are eligible Baseline failures from SP0982 will start at 
Visit 1 on a dose of LCM 2mg/kg/day for pediatric subjects weighing <50kg, and LCM 
100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing 
≥50kg. 
Subjects who tapered in SP0982 after the 125th event will enroll at Visit 1 and proceed directly to 
the Safety Follow-up Period without receiving LCM. At any time during the course of the study 
if it becomes apparent that a subject is unable to attain at least this minimum dose of 4mg/kg/day 
(oral solution) or 200mg/day (tablets), then the subject must enter the Taper Period and be 
withdrawn from the study. 
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Change #17 
Section 8.1.1 Visit 1 (Week 0) 
The following tasks and procedures are to be performed at this visit (for subjects who have 
completed SP0982, assessments marked [*] should have already been completed during the last 
visit of the previous protocol and do not need to be repeated at Visit 1; for eligible Baseline 
failures from SP0982, a full Visit 1 is required including all scheduled tasks and procedures). 
Has been changed to: 
The following tasks and procedures are to be performed at this visit (for subjects who have 
completed SP0982, assessments marked [*] should have already been completed during the last 
visit of the previous protocol and do not need to be repeated at Visit 1; for eligible Baseline 
failures from SP0982, a full Visit 1 is required including all scheduled tasks and procedures). 
Tapered subjects from SP0982 will enter EP0012 for the Safety Follow-Up only and will be 
withdrawn at Visit 1 once Visit 1 assessments have been performed. Details of the Safety 
Follow-Up are provided in Section 8.4.2 and Section 8.4.3. 
Change #18 
Section 8.1.2 Visits 2 to 8 (Weeks 2 to 46, Year 1) 
Section 8.1.2 Visits 2 to 8 (Weeks 2 to 46, Year 1) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (brief, Visit 2, 3, 4, 5, 6, and 7; complete, Visit 8) 
• Neurological examination (brief, Visit 2, 3, 4, 5, 6, and 7; complete, Visit 8) 
• ECG (12-lead) assessment (Visit 2, 4, 6, and 8 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight (Visit 4, 6, and 8 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 8 only) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) [Visit 2, 5, and 8 only], and a urine pregnancy test [for women of 
childbearing potential])  
Has been changed to:  
8.1.2 Visits 2 to 8 (Weeks 2 to 46, Year 1, excluding Visit 6 and Visit 7) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (brief, Visit 2, 3, 4, and 5; complete, Visit 8) 
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• Neurological examination (brief, Visit 2, 3, 4, and 5; complete, Visit 8) 
• ECG (12-lead) assessment (Visit 2, 4, and 8 only) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight (Visit 4,and 8 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 8 only) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) [Visit 2, 5, and 8 only], and a urine pregnancy test [for women of 
childbearing potential])  
Change #19 
Section 8.1.3 Visits 9 to 11 (Weeks 62 and 94, Year 2) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs  
• Physical examination (brief, Visit 9 and 10; complete, Visit 11) 
• Neurological examination (brief, Visit 9 and 10; complete, Visit 11) 
• ECG (12-lead) assessment (Visit 9, 10, and 11) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 9 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 11 only) 
• 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]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 9 and 11) (for subjects ≥12 years of age) 
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• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) (Visit 9 
and 11 only) 
• Achenbach CBCL for subjects <18 years of age (Visit 9 and 11 only) 
• BRIEF for subjects <18 years of age (Visit 9 and 11 only) 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
Has been changed to: 
8.1.3 Visits 9 and 11 (Weeks 62 and 94, Year 2, excluding Visit 10) 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs  
• Physical examination (brief, Visit 9; complete, Visit 11) 
• Neurological examination (brief, Visit 9; complete, Visit 11) 
• ECG (12-lead) assessment (Visit 9, and 11) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 9 only) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 11 only) 
• 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]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• EQ-5D-3L (Visit 9 and 11) (for subjects ≥12 years of age) 
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age) (Visit 9 
and 11 only) 
• Achenbach CBCL for subjects <18 years of age (Visit 9 and 11 only) 
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• BRIEF for subjects <18 years of age (Visit 9 and 11 only) 
• Healthcare resource use 
• Work/school days lost due to epilepsy 
• Days with help from a caregiver due to epilepsy 
Change #20 
Section 8.1.4 Visits 12, 13, 14, 15, 16, and 17 (Weeks 118, 142, 166, 190, 
214, and 238, Years 3 to 5) 
This section has been split into two - 8.1.4.1 and 8.1.4.2 
8.1.4.1 Subjects <18 years 
The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Physical examination (complete, Visit 13, 15, and 17) 
• Neurological examination (brief, Visit 12, 14, and 16) 
• ECG (12-lead) assessment (Visit 13, 15, and 17) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 12, 14, and 16) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 13, 15, and 17) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 17/Termination 
Visit. If Visit 17 is not the Termination Visit, laboratory tests are not required). Laboratory 
tests are not performed at Visit 13 and Visit 15 according to Protocol Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects ≥6 years to <18 years of age (Visit 13, 15, and 17) 
• BRIEF for subjects ≥5 to <18 years of age (Visit 13, 15, and 17) 
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8.1.4.2 Subjects ≥18 years 
• The following tasks and procedures are to be performed at these visits: 
• Concomitant medications and AEDs 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 17/Termination 
Visit. If Visit 17 is not the Termination Visit, laboratory tests are not required. Laboratory 
tests are not performed at Visit 13 and Visit 15 according to Protocol Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
Change #21 
Section 8.1.5 Telephone contact 
Telephone contacts are required every 8 weeks during Year 2 to Year 5, except during weeks in 
which a clinic visit is planned (eg, Week 62). Therefore, telephone contacts in Year 2 are 
scheduled for Week 54, Week 70, and Week 86. Telephone contacts in Years 3 to 5 are 
scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 
158, Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, and Week 230. 
Has been changed to: 
Telephone contacts are required at Week 30 and Week 38 and every 8 weeks during Year 2 to 
Year 5, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, 
telephone contacts in Year 2 are scheduled for Week 54, Week 70, and Week 86. Telephone 
contacts in Years 3 to 5 are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; 
Year 4 - Week 150, Week 158, Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, 
and Week 230. 
Change #22 
Section 8.2 Early Termination Visit 
This section has been updated to indicate the tasks and procedures which exclude subjects ≥18 
years. 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
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• Physical examination (complete) 
• Neurological examination (brief)  
• ECG (12-lead) assessment  
• Vital signs (pulse rate, BP) including orthostatic assessments  
• Body weight and height 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study)  
• C-SSRS assessment (for subjects ≥6 years of age)  
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the ET Visit for subjects early terminating the 
study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
Has been changed to: 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Physical examination (complete) excluding subjects ≥18 years after the first 2 years 
• Neurological examination (brief) excluding subjects ≥18 years after the first 2 years 
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• ECG (12-lead) assessment excluding subjects ≥18 years after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments excluding subjects ≥18 years 
after the first 2 years 
• Body weight and height excluding subjects ≥18 years after the first 2 years 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) excluding subjects ≥18 years after the first 2 
years 
• C-SSRS assessment (for subjects ≥6 years of age) excluding subjects ≥18 years after the first 
2 years 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the ET Visit for subjects early terminating the 
study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy  
Change #23 
Section 8.3 Termination Visit 
This section has been updated to indicate the tasks and procedures which exclude subjects 
≥18 years. 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
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• Physical examination (complete) 
• Neurological examination (complete) Note: Complete neurological exam to be performed for 
patients terminating the study during Years 1-2, brief exam for patients terminating during 
Years 3-5. 
• ECG (12-lead) assessment 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height  
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (excluding subjects ≥18 years) 
• C-SSRS assessment (for subjects ≥6 years of age) (excluding subjects ≥18 years) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary for subjects undergoing taper 
• Subject diary return/review 
• Dispense LCM for subjects undergoing taper 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the Termination Visit for subjects terminating 
the study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
Days with help from a caregiver due to epilepsy 
Has been changed to: 
The following tasks and procedures are to be performed at this visit: 
• Concomitant medications and AEDs 
• Physical examination (complete) excluding subjects ≥18 years after the first 2 years 
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• Neurological examination (complete) Note: Complete neurological exam to be performed for 
patients terminating the study during Years 1-2 for all subjects and brief exam for subjects 
<18 years terminating during Years 3-5 (excluding subjects ≥18 years). Neurological exam is 
excluded for subjects ≥18 years after the first 2 years. 
• ECG (12-lead) assessment excluding subjects ≥18 years after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments excluding subjects ≥18 years 
after the first 2 years 
• Body weight and height excluding subjects ≥18 years after the first 2 years 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) excluding subjects ≥18 years after the first 2 
years 
• C-SSRS assessment (for subjects ≥6 years of age) excluding subjects ≥18 years after the first 
2 years 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, endocrinology for subjects <18 years of age at Visit 1, urinalysis, and a serum 
pregnancy test [for women of childbearing potential]) 
• Contact IRT 
• Dispense subject diary for subjects undergoing taper 
• Subject diary return/review 
• Dispense LCM for subjects undergoing taper 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects <18 years of age 
• BRIEF for subjects <18 years of age 
The following assessments are only applicable at the Termination Visit for subjects terminating 
the study within the first 2 years (see Section 4.2.3): 
• EQ-5D-3L (for subjects ≥12 years of age)  
• QOLIE-31-P (for subjects ≥18 years of age)/PedsQL (for subjects <18 years of age)  
• Healthcare resource use  
• Work/school days lost due to epilepsy  
• Days with help from a caregiver due to epilepsy 
Change #24 
Section 8.4.1 
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The following sentence has been added at the end of the section: 
Subjects who were already tapered in SP0982 after the 125th event occurred do not need to 
undergo the End of Taper Visit assessments in EP0012 as the assessments were performed in 
SP0982. 
Change #25 
Section 8.4.2 Safety Follow-Up Visit 
Following the End of Taper Visit, the subject will return 2 weeks 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: 
Has been changed to: 
Following the End of Taper Visit, the subject will return 2 weeks after the last dose of study drug 
for a Safety Follow-Up Visit (including subjects tapered in SP0982 after the 125th event occurs 
who enter EP0012 only for a Safety Follow-Up Visit). During the Safety Follow-Up Visit, the 
following assessments will be performed: 
Change #26 
Section 8.5 Unscheduled Visit 
This section has been updated to indicate the tasks and procedures which exclude subjects ≥18 
years. 
During an Unscheduled Visit the following assessments are required: 
• Concomitant medications and AEDs  
• Physical examination (brief) during the first 2 years  
• Neurological examination (brief) during the first 2 years  
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Contact IRT 
• Subject diary return/review 
• Assess withdrawal criteria 
• AE reporting 
Has been changed to: 
During an Unscheduled Visit the following assessments are required: 
• Concomitant medications and AEDs  
• Physical examination (brief) during the first 2 years ≥18 years after the first 2 years 
• Neurological examination (brief) during the first 2 years ≥18 years after the first 2 years 
• Vital signs (pulse rate, BP) including orthostatic assessments ≥18 years after the first 2 years 
• Contact IRT 
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• Subject diary return/review 
• Assess withdrawal criteria 
• AE reporting 
Change #27 
Section 10.3.1 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. 
16.7 
Appendix 7: Protocol Amendment 4 
Rationale for the amendment 
The primary purpose of this amendment is to extend the treatment of the subjects and have LCM 
available for the subjects till the main approvals for an extended PGTCS indication are obtained. 
UCB seeks to obtain the approvals in first instance in US, EU, and Japan. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• Globally changed PGTC seizures to PGTCS. 
Specific changes 
Change #1 
Title page: 
The title was updated from “Protocol EP0012 Amendment 3” to “Protocol EP0012 
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 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
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Has been changed to: 
Protocol/Amendment Number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
Protocol Amendment 4 
13 Dec 2019 
Substantial 
 
Change #2 
Section 1 
Summary 
Paragraph 6 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. During the Treatment Period, Visit 2 will occur 
2 weeks after Visit 1, and Visit 3 will occur 4 weeks later (Week 6). Clinical visits will then 
occur every 8 weeks for the first year, and every 16 weeks in the second year. For subjects who 
continue in the study after Year 2, visits will occur every 24 weeks thereafter until the end of the 
study. From Year 3 onwards, pediatric subjects weighing <50kg will return to the clinic for an 
additional Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of LCM 
solution; LCM usage will be reviewed and empty LCM bottles will be returned. 
Has been changed to: 
EP0012 will consist of a Treatment Period, an up to 4-week Taper Period, and a 30-day Safety 
Follow-Up Period. During the Treatment Period, Visit 2 will occur 2 weeks after Visit 1, and 
Visit 3 will occur 4 weeks later (Week 6). Clinical visits will then occur every 8 weeks for the 
first year, and every 16 weeks in the second year. For subjects who continue in the study after 
Year 2, visits will occur every 24 weeks thereafter until the end of the study. From Year 2 (Visit 
11) to 3 onwards, pediatric subjects weighing <50kg will return to the clinic for an additional 
Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of LCM solution; 
LCM usage will be reviewed, and empty LCM bottles will be returned. 
Change #3 
Section 4.1.1 Primary safety variables 
The primary safety variables are: 
• Adverse events as reported spontaneously by the subject and/or caregiver or observed by the 
investigator 
• Subject withdrawals due to AEs 
• Incidence of new seizure types during the Treatment Period 
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• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
absence seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline 
Has been changed to: 
The primary safety variables are: 
• Adverse events as reported spontaneously by the subject and/or caregiver or observed by the 
investigator 
• Subject withdrawals due to AEs 
• Incidence of new appearance of absence and/or myoclonic seizures during the Treatment 
Period 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
absence seizures per 28 days compared to the Prospective Baseline 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days compared to the Prospective Baseline 
• Percentage of subjects with at least 50% worsening in days with absence seizures 
• Percentage of subjects with at least 50% worsening in days with myoclonic seizures 
Change #4 
Section 5.1 Study description 
Paragraph 2 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, and study completers from SP0982 who are eligible for inclusion in EP0012 are defined 
as: 
 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry criteria 
except the minimum PGTC seizure criteria required for randomization (Baseline failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) of 
SP0982 and experienced ≥2 PGTC seizures during that time or  
Subjects who experience a second PGTC seizure after the first 6 weeks of the Treatment Period 
of SP0982 
SP0982 completers 
• Subjects who experience <2 PGTC seizures within the 24-week Treatment Period of SP0982  
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• Subjects who were ongoing in SP0982 when the 125th event occurred 
SP0982 Safety Follow-Up subjects 
• Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up Visit only.  
Has been changed to: 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, study completers from SP0982 who are eligible for inclusion in EP0012, SP0982 Safety 
Follow-Up subjects, and Other are defined as: 
SP0982 Baseline failures 
• Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry criteria 
except the minimum PGTCS criteria required for randomization (Baseline failures)  
Randomized subjects meeting SP0982 exit criteria 
• Subjects who completed the first 6 weeks of the Treatment Period (after randomization) of 
SP0982 and experienced ≥2 PGTCS during that time or  
Subjects who experience a second PGTCS after the first 6 weeks of the Treatment Period of 
SP0982 
SP0982 completers 
• Subjects who experience <2 PGTCS within the 24-week Treatment Period of SP0982  
• Subjects who were ongoing in SP0982 when the 125th event occurred 
SP0982 Safety Follow-Up subjects 
• Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up Visit only 
Other 
• Subjects that enrolled in EP0012 that did not fall into the above categories 
Change #5 
Section 5.1 Study description 
Paragraphs 9 and 10 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final Clinic 
Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria. Eligible Baseline 
failures from SP0982 who choose to enter this study will undergo a complete Visit 1. Visit 2 will 
occur 2 weeks after Visit 1, and Visit 3 will occur 4 weeks later (Week 6). Clinic visits will then 
occur every 8 weeks for the first year, and every 16 weeks in the second year. For subjects who 
continue in the study after Year 2, visits will occur every 24 weeks thereafter until the end of the 
study. From Year 3 onwards, pediatric subjects weighing <50kg will return to the clinic for an 
additional Dispensation Visit 12 weeks after each 24-weekly visit, for the dispensation of LCM 
solution; LCM usage will be reviewed and empty LCM bottles will be returned.  
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A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone contacts 
will be used to obtain information regarding concomitant medication use, and assess withdrawal 
criteria and AEs, as well as to ensure subjects are compliant with LCM administration and diary 
completion. The study duration and the total number of clinic visits will vary for each subject. 
Treatment will continue until LCM is approved for use in the subject’s country for the treatment 
of PGTC seizures in subjects with IGE, or until UCB has determined that the clinical 
development program for the indication will be formally discontinued, or until UCB decides to 
close the study. 
Have been changed to: 
EP0012 will last at least 2 years and consist of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final Clinic 
Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria. Eligible Baseline 
failures from SP0982 who choose to enter this study will undergo a complete Visit 1. Visit 2 will 
occur 2 weeks after Visit 1 and Visit 3 will occur 4 weeks later (Week 6). Clinic visits will then 
occur every 8 weeks for the first year, and every 16 weeks in the second year. For subjects who 
continue in the study after Year 2, visits will occur every 24 weeks thereafter until the end of the 
study. From Year 2 (Visit 11) to 3 onwards, pediatric subjects weighing <50kg will return to the 
clinic for an additional Dispensation Visit 12 weeks after each 24-weekly visit, for the 
dispensation of LCM solution; LCM usage will be reviewed, and empty LCM bottles will be 
returned.  
A telephone contact will occur every 8 weeks if no clinic visit is scheduled. Telephone contacts 
will be used to obtain information regarding concomitant medication use, and assess withdrawal 
criteria and AEs, as well as to ensure subjects are compliant with LCM administration and diary 
completion.  
Change #6 
Section 5.1 Study description 
Paragraph 13 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. Taper of 
LCM may not be required for some subjects who complete the study depending on the treatment 
option selected by the investigator in consultation with the subject and/or their parent(s)/legal 
representative(s).  
Has been changed to: 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. Taper of 
LCM (Taper Visit and SFU) may not be required for some subjects who leave the study 
depending on the treatment option selected by the investigator in consultation with the subject 
and/or their parent(s)/legal representative(s).  
Change #7 
Section 5.1.1 Study duration per subject 
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For each subject, the study will last from study entry until LCM is approved for use in the 
subject’s country for the treatment of PGTC seizures in subjects with IGE, or until UCB has 
determined that the clinical development program for the indication will be formally 
discontinued, or until the sponsor decides to close the study. It is anticipated that at least 2 years 
of treatment will be performed to allow for the collection of long-term safety data. If LCM is not 
approved for use in the subject’s country at the time the sponsor closes the study, access to LCM 
will be provided according to local laws. 
The following study periods are defined: 
• A Treatment Period lasting at least 2 years. 
• An up to 4-week Taper Period and a 30-day Safety Follow-Up Period.  
− Subjects continuing LCM treatment with commercially available LCM will transition to a 
dose determined by the investigator. 
− Subjects tapering off LCM will do so over a period of up to 4 weeks (see taper schedule, 
Table 7‒2). 
− An End of Taper Visit will occur after the final LCM dose for subjects who taper off 
LCM. 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 same design will apply to some of the subjects tapered in SP0982 at the 
time of the 125th event and who entered EP0012 for the Safety Follow-Up Visit only and 
to subjects who entered EP0012 for a Safety Follow-up Visit after discontinuing SP0982 
due to the study stopping. 
The end of the study is defined as the date of the last visit/telephone contact of the last subject in 
the study. 
Depending on the local regulations, after 2 years, subjects may continue to receive LCM in a 
managed access program (MAP). 
Has been changed to: 
For adult subjects, treatment will continue for at least 2 years.  Once 2 years of participation are 
reached, adult subjects will continue to participate until 1 of the 2 following conditions are met.  
• LCM is approved for use for the treatment of PGTCS in subjects with IGE in the subject’s 
country for or until the latest approval is granted either by EMA, FDA, or PMDA.  
• For pediatric subjects, treatment will continue until the latest of 1 of the following 
2 conditions are met: 
− up to 5 years of participation or  
− until the latest approval is granted either by EMA, FDA, or PMDA  
Adult and pediatric subjects are completers if they continue in the study for the maximum 
duration in their respective region. 
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The following study periods are defined: 
• A Treatment Period lasting for at least 5 years (238 weeks) for the population less than 
18 years old at enrollment and will be shorter for adults leaving the study when the PGTCS 
indication approvals are being obtained during the course of the study.  
• An up to 4-week Taper Period and a 30-day Safety Follow-Up Period.  
− Subjects continuing LCM treatment with commercially available LCM will transition to a 
dose determined by the investigator and do not have to perform the tapering (Taper Visit 
and SFU). 
− Subjects tapering off LCM will do so over a period of up to 4 weeks (see taper schedule, 
Table 7‒2). 
− An End of Taper Visit (latest 3 days after the final dose) will occur after the final LCM 
dose for subjects who taper off LCM. 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 same design will apply to some of the subjects 
tapered in SP0982 at the time of the 125th event and who entered EP0012 for the Safety 
Follow-Up Visit only and to subjects who entered EP0012 for a Safety Follow-up Visit 
after discontinuing SP0982 due to the study stopping. 
The end of the study is defined as the date of the last visit/telephone contact of the last subject in 
the study. 
Subjects who entered EP0012 as <18 years and become adults (≥18 years) during the study, will 
remain in the study for at least 5 years (238 weeks).  
Change #8 
Section 5.2 
Schedule of study assessments 
Table 5-1 Schedule of study assessments for Years 1 and 2 for EP0012 (Treatment Period, ET 
Visit, Termination Visit, and Unscheduled Visit) 
Footnote ‘a’ 
The Treatment Period will continue for at least 2 years. 
Footnote ‘e’ 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. 
This will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see 
Table 5-4. 
Has been changed to: 
Footnote ‘a’ 
The duration of the Treatment Period will continue for at least 2 years and vary by subject age 
group and is defined in Section 5.1.1. 
Footnote ‘e’ 
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An ET Visit must be completed for all subjects who prematurely discontinue from the study. 
This will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see 
Table 5-4. For subjects who continue on commercial LCM, the early Termination Visit is the last 
visit in the study.  
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 241 of 274 
Change #9 
Section 5.2 
Schedule of study assessments 
Table 5‒2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, Termination 
Visit, and Unscheduled Visit for subjects <18 years) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET Visitf 
Term Visitg 
LCM Solution 
Dispensation Visith 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Concomitant medications and 
AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam (complete)i 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Neurological exam (brief)j 
 
X 
 
X 
 
X 
 
 
X 
 
 
12-lead ECGk 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Vital signs (BP and pulse) including 
orthostatic assessmentsl 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body weight and heightm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Tanner Stagen 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Laboratory tests 
 
X 
 
X 
 
X 
Xo 
X 
X 
 
 
Endocrinologyp 
 
 
 
 
 
 
 
X 
X 
 
 
Pregnancy testq 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRSr 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 242 of 274 
Table 5‒2: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, Termination 
Visit, and Unscheduled Visit for subjects <18 years) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET Visitf 
Term Visitg 
LCM Solution 
Dispensation Visith 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Achenbach CBCLs 
 
 
X 
 
X 
 
X 
X 
X 
 
 
BRIEFt 
 
 
X 
 
X 
 
X 
X 
X 
 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; 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; ET=early termination; exam=examination; IRT=interactive response technology; LCM=lacosamide; NA=not applicable; 
Term=Termination; V=Visit 
Note: Subjects who turn 18 years during the course of this study will be considered as pediatrics, however these subjects will not need to complete the 
Achenbach CBCL and BRIEF assessments.  
a 
The Treatment Period will continue for at least 2 years. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
physical or neurological examination, ECG, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned 
(eg, Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-4. 
g 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate. For subjects who will not 
continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue 
on LCM, the Termination Visit is the last visit in the study.  
h 
Dispensation Visit will occur 12 weeks after each 24-weekly visit from Year 2 (Visit 11) to Year 3 onwards and will be for the purpose of dispensing LCM 
solution for pediatric subjects <50kg. 
i 
The complete physical examination will include cardiac and respiratory function via auscultation and review of all body systems. 
j 
The brief neurological examination will include selected assessment 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) a 12-lead ECG (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 
Height will be recorded at Visits 12, 14, and 16, and at the ET and Termination Visit. 
n 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
o 
Laboratory tests are applicable for combined Visit 17/Termination Visit. If Visit 17 is not the Termination Visit, laboratory tests are not required. 
p 
If the patient was treated in SP0982, endocrinology should be done if age was <18 years at SP0982 Visit 1. If the patient was a Baseline failure in SP0982, 
endocrinology should be done if age is <18 years at EP0012 Visit 1. 
q 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion. 
r 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3).  
s 
The Achenbach CBCL: CBCL/6-18 for children ≥6 years to <18 years of age; to be completed by the parent(s)/legal representative(s) (estimated completion 
time 45 minutes). For each version of the CBCL, subjects must have at least 1 year of data before transitioning to the next age range. The Achenbach CBCL 
should be completed by the same parent/legal representative, if possible (see Section 10.4.6).  
t 
The BRIEF should be used for subjects who are ≥5 years of age. For each developmentally appropriate version of the BRIEF, subjects must have at least 
1 year of data before transitioning to the next age range (see Section 10.4.7). 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 244 of 274 
Has been changed to: 
Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit for subjects <18 years at enrollment) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 + Extended 
Period 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17 
Vxf 
ET Visitg 
Term Visith 
LCM Solution 
Dispensation Visiti 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
X 
 
 
 
NA 
Concomitant medications and 
AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam (complete)j 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Neurological exam (brief)k 
 
X 
 
X 
 
X 
X 
X (even 
visit only) 
 
X 
 
 
12-lead ECGl 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Vital signs (BP and pulse) 
including orthostatic 
assessmentsm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body weight and heightn 
 
X 
X 
X 
X 
X 
X 
X (even 
visits only) 
X 
X 
 
 
Tanner Stageo 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
Laboratory tests 
 
X 
 
X 
 
X 
Xp 
Xp 
X 
X 
 
 
Endocrinologyq 
 
 
 
 
 
 
 
 
X 
X 
 
 
Pregnancy testr 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-SSRSs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Clinical Study Protocol 
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EP0012 
 
 
 
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Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM 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 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Achenbach CBCLt 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
BRIEFu 
 
 
X 
 
X 
 
X 
X (odd 
visits only) 
X 
X 
 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; 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; ET=early termination; exam=examination; IRT=interactive response technology; LCM=lacosamide; NA=not applicable; 
Term=Termination; V=Visit; Vx=Visit X 
Note: Subjects who turn 18 years during the course of this study will be considered as pediatrics, however these subjects will not need to complete the 
Achenbach CBCL and BRIEF assessments.  
a 
The duration of the Treatment Period will vary by subject age group and is defined in Section 5.1.1. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
physical or neurological examination, ECG, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no 
clinic visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned 
(eg, Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. If the subject remains in the study beyond Week 238, telephone contacts will 
continue at 8-week intervals. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
f 
Subjects may require additional routine visits (Visit X) if the study is still ongoing at Week 238 for the respective subject. Vx visits are to be performed 
every 24 weeks. Additional routine visits should be scheduled and performed in accordance with footnote ‘b’ to avoid visit window deviations. 
Assessments must be performed in accordance with Table 5‒3. 
g 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, 
and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on commercial LCM, the early Termination Visit is the last visit in the study.  
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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h 
A Termination Visit must be completed for all subjects who complete the study. This can be performed in alignment of the date of the last scheduled visit 
if appropriate. For subjects who will not continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up 
Period; see Table 5-4. For subjects who continue on LCM, the Termination Visit is the last visit in the study.  
i 
Dispensation Visit will occur 12 weeks after each 24-weekly visit from Year 2 (Visit 11) to Year 3 onwards and will be for the purpose of dispensing 
LCM solution for pediatric subjects <50kg. 
j 
The complete physical examination will include cardiac and respiratory function via auscultation and review of all body systems. 
k 
The brief neurological examination will include selected assessment of general neurological status, reflexes, muscle strength, and coordination/cerebellar 
function. 
l 
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) a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
m 
Blood pressure measurements should be taken with the proper placement and proper sized cuff to obtain accurate measurements. 
n 
Height will be recorded at Visits 12, 14, 16, Visit X (even visits), and at the ET and Termination Visit. 
o 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who enter puberty during the course of the study. 
p 
Laboratory tests are applicable for combined the last scheduled visit/Termination Visit. If the last scheduled visit is not the Termination Visit, laboratory 
tests are not required. 
q 
If the patient was treated in SP0982, endocrinology should be done if age was <18 years at SP0982 Visit 1. If the patient was a Baseline failure in SP0982, 
endocrinology should be done if age is <18 years at EP0012 Visit 1. 
r 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: 
Visit 1 (W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine 
pregnancy test at V1 of EP0012, at the investigator’s discretion. 
s 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3).  
t 
The Achenbach CBCL: CBCL/6-18 for children ≥6 years to <18 years of age; to be completed by the parent(s)/legal representative(s) (estimated 
completion time 45 minutes). For each version of the CBCL, subjects must have at least 1 year of data before transitioning to the next age range. The 
Achenbach CBCL should be completed by the same parent/legal representative, if possible (see Section 10.4.6).  
u 
The BRIEF should be used for subjects who are ≥5 years of age. For each developmentally appropriate version of the BRIEF, subjects must have at least 
1 year of data before transitioning to the next age range (see Section 10.4.7). 
 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
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Page 247 of 274 
 
Table 5-3: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, Termination Visit, 
and Unscheduled Visit for subjects ≥18 years) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of study 
Year 3 
Year 4 
Year 5 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17/ 
Terme 
ET Visitf 
Term Visitg 
LCM Solution Dispensation 
Visit 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
 
 
 
NA 
Concomitant medications and 
AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory testsh 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Pregnancy testi 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Call IRT 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM review/return 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; IRT=interactive 
response technology; LCM=lacosamide; NA=not applicable; Term=Termination; V=Visit 
a 
The Treatment Period will continue for at least 2 years. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 
physical or neurological examination, ECG, vital signs, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to a psychiatric 
AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no clinic 
visit is scheduled. 
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Clinical Study Protocol 
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EP0012 
 
 
 
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d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned (eg, 
Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, Week 
174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230. 
e 
At the completion of the study, investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's 
epilepsy. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. This will be followed by LCM taper, an End of Taper Visit, and 
a Safety Follow-Up Period; see Table 5-4. 
g 
A Termination Visit must be completed for all subjects who complete the study. This can be combined with Visit 17 if appropriate. For subjects who will not 
continue on LCM, this visit will be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue 
on LCM, the Termination Visit is the last visit in the study.  
h 
Laboratory tests include chemistry, hematology and, urinalysis. 
i 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: Visit 1 
(W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine pregnancy 
test at V1 of EP0012, at the investigator’s discretion. 
 
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Clinical Study Protocol 
Lacosamide 
EP0012 
 
 
 
Confidential 
Page 249 of 274 
 Has been changed to: 
Table 5-3: 
Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment Period, ET Visit, 
Termination Visit, and Unscheduled Visit for subjects ≥18 years) 
 
Treatment perioda 
End of Study period 
 
Unscheduledb 
Duration 
Open-label: up to approximately 5 years 
Up to 5 weeks 
 
 
Year of 
study 
Year 3 
Year 4 
Year 5 +Extended Period 
 
 
 
Visitc 
TCd 
V12 
V13 
V14 
V15 
V16 
V17e 
Vxe 
ET Visitf 
Term Visitg 
LCM 
Solution 
Dispensati
on Visit 
Unscheduled 
Visit 
Week 
 
118 
142 
166 
190 
214 
238 
X 
 
 
 
NA 
Concomitant 
medications 
and AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory 
testsh 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy 
testi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense 
subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject diary 
return/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Call IRT 
 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
 
X 
Dispense 
LCM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LCM 
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 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Clinical Study Protocol 
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EP0012 
 
 
 
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AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ET=early termination; 
IRT=interactive response technology; LCM=lacosamide; NA=not applicable; Term=Termination; V=Visit; Vx=Visit X 
a 
The duration of the Treatment Period will vary by patient age group and is defined in Section 5.1.1. 
b 
Unscheduled Visits may be performed at any time after Visit 1 as clinic visits or telephone contacts, at the discretion of the investigator. 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 physical or neurological examination, ECG, vital signs, laboratory tests, etc. The C-SSRS must be performed if the Unscheduled Visit is due to 
a psychiatric AE. 
c 
A window of ±7 days relative to Visit 1 is applicable for all visits and telephone contacts. Subjects will have a Telephone Contact every 8 weeks if no 
clinic visit is scheduled. 
d 
Telephone contacts are required every 8 weeks during the study. Telephone contacts are not required during weeks in which a clinic visit is planned 
(eg, Week 118). Therefore, telephone contacts are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 134; Year 4 - Week 150, Week 158, 
Week 174, Week 182; Year 5 - Week 198, Week 206, Week 222, Week 230.  If the subject remains in the study beyond Week 238, telephone contacts 
will continue at 8-week intervals. 
e 
Vx visits are to be performed every 24 weeks. When subjects leave the study, investigators should discuss treatment options with the subject and/or 
legal representative to best manage the subject's epilepsy. 
f 
An ET Visit must be completed for all subjects who prematurely discontinue from the study. For subjects who will not continue on LCM, this visit will 
be followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on commercial LCM, the 
early Termination Visit is the last visit in the study. Investigators should discuss treatment options with the subject and/or legal representative to best 
manage the subject's epilepsy.  
g 
A Termination Visit must be completed for all subjects who complete the Treatment Period (Week 238 or extended treatment period). This can be 
performed in alignment of the date of the last scheduled visit if applicable. For subjects who will not continue on commercial LCM, this visit will be 
followed by LCM taper, an End of Taper Visit, and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on LCM, the Termination 
Visit is the last visit in the study. A Termination Visit is to be done if the subject is leaving the study prior to Week 238 following the approval of the 
PGTCS indication in their respective region/country as follows: for US subjects, when the US approval is obtained; for EU subjects, if the EU approval 
is obtained; and for all other adults at the approval of the PGTCS indication in Japan (last targeted approval). When subjects leave the study, 
investigators should discuss treatment options with the subject and/or legal representative to best manage the subject's epilepsy.  
h 
Laboratory tests include chemistry, hematology and, urinalysis. 
i 
Pregnancy tests will be performed for female subjects of childbearing potential only. Serum pregnancy tests will be conducted at the following visits: 
Visit 1 (W0), ET, and Termination Visit. All other pregnancy tests will be urine dipstick. Baseline failures from SP0982 may have an additional urine 
pregnancy test at V1 of EP0012, at the investigator’s discretion. 
 
 
 
 
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Table 5-4: Schedule of study assessments (Taper Period and Safety Follow-Up Period) 
Assessment 
 
Taper Perioda 
(up to 4 weeks) 
Safety Follow-Up Periodb 
End of Taper Visitc 
 
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) 
X 
X 
 
Neurological exam (brief) 
X 
X 
 
12-lead ECGd 
X 
X e 
 
Vital signs (BP and pulse) including orthostatic 
assessments 
X 
X 
 
Body weight  
X 
X 
 
Laboratory tests: 
 
 
 
 
Chemistry/hematology 
X 
Xe 
 
 
Endocrinology 
 
Xe 
 
 
Urine pregnancy testf 
X 
X 
 
Contact IRT 
X 
 
 
Subject diary return/reviewg 
X 
 
 
LCM review/return 
X 
 
 
Withdrawal criteria 
X 
 
 
AE reporting 
X 
X 
X 
C-SSRSh 
X 
X 
 
Healthcare resource usei 
X 
X 
 
Work/school days lost due to epilepsyi 
X 
X 
 
Days with help from a caregiver due to epilepsyi 
X 
X 
 
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AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; IRT=interactive 
response technology; LCM=lacosamide; TC=telephone contact 
Note: The schedule of study assessments for the Taper Period and Safety Follow-Up Visit includes some of the subjects who tapered in SP0982 after the 125th 
event who consented to enter EP0012 for the Safety Follow-Up only. 
a 
All subjects who discontinue LCM must complete the End of Taper Visit.  
b 
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 Visit. 
c 
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 7‒2. 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 place at the ET or Termination 
Visit. 
d 
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) a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
e 
The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, or endocrinology) or reading (ECG) at the 
previous clinic visit. 
f 
Pregnancy tests will be performed for female subjects of childbearing potential only. A urine pregnancy test will be performed. 
g 
The last subject diary will be returned at the End of Taper Visit. 
h 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3). 
i 
Healthcare resource use, work/schools days lost due to epilepsy, and days with help from a caregiver due to epilepsy will be assessed only for patients 
completing the study after ≤2 years. These assessments are not applicable for patients tapering down or performing the SFU-visits during Years 3, 4 or 5). 
 
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Has been changed to: 
Assessment 
 
Taper Perioda 
(up to 4 weeks) 
Safety Follow-Up Periodb 
End of Taper Visit (maximum 
3 days after visit)c 
 
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) 
X 
X 
 
Neurological exam (brief) 
X 
X 
 
12-lead ECGd 
X 
X e 
 
Vital signs (BP and pulse) including orthostatic 
assessments 
X 
X 
 
Body weight  
X 
X 
 
Laboratory tests: 
 
 
 
 
Chemistry/hematology 
X 
Xe 
 
 
Endocrinology 
 
Xe 
 
 
Urine pregnancy testf 
X 
X 
 
Contact IRT 
X 
 
 
Subject diary return/reviewg 
X 
 
 
LCM review/return 
X 
 
 
Withdrawal criteria 
X 
 
 
AE reporting 
X 
X 
X 
C-SSRSh 
X 
X 
 
Healthcare resource usei 
X 
X 
 
Work/school days lost due to epilepsyi 
X 
X 
 
Days with help from a caregiver due to epilepsyi 
X 
X 
 
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AE=adverse event; AED=antiepileptic drug; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; IRT=interactive 
response technology; LCM=lacosamide; TC=telephone contact 
Note: The schedule of study assessments for the Taper Period and Safety Follow-Up Visit includes some of the subjects who tapered in SP0982 after the 125th 
event who consented to enter EP0012 for the Safety Follow-Up only. 
j 
Subjects who will not continue on LCM must complete an End of Taper Visit and a Safety Follow-Up Period; see Table 5-4. For subjects who continue on 
commercial LCM, the (Early) Termination Visit is the last visit in the study. 
k 
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 Visit. 
l 
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 7‒2. 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 place at the ET or Termination 
Visit. 
m 
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) a 12-lead ECG (2 interpretable recordings) 
approximately 20 to 30 minutes apart must be performed. 
n 
The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, or endocrinology) or reading (ECG) at the 
previous clinic visit. 
o 
Pregnancy tests will be performed for female subjects of childbearing potential only. A urine pregnancy test will be performed. 
p 
The last subject diary will be returned at the End of Taper Visit. 
q 
The C-SSRS will be completed for all subjects ≥6 years of age (see Section 10.4.3). 
r 
Healthcare resource use, work/schools days lost due to epilepsy, and days with help from a caregiver due to epilepsy will be assessed only for patients 
completing the study after ≤2 years. These assessments are not applicable for patients tapering down or performing the SFU-visits during Years 3, 4 or 5). 
 
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Change #10 
Section 6.2 Exclusion criterion #4 
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. 
Has been changed to: 
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 all subjects who entered EP0012 directly 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. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. 
Change #11 
Section 7.2.1 Treatment Period 
Paragraphs 7 and 8 
Subjects withdrawing from the study must complete the ET Visit and an up to 4-week taper 
followed by an End of Taper Visit (see taper schedule, Table 7‒2). 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. A slow 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. In case of an emergency, a faster 
taper is permitted after discussion with the Medical Monitor, whenever possible.  
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At the completion of the study, investigators should discuss treatment options with the 
subject and/or their parent(s)/legal representative(s) to best manage the subject’s epilepsy. 
Taper of LCM may not be required for some subjects who complete the study depending on 
the treatment option selected by the investigator in consultation with the subject and/or 
parent(s)/legal representative(s). 
Have been changed to: 
Subjects withdrawing from the study must complete the ET Visit and (if they do not proceed 
with commercially available LCM)  an up to 4-week taper followed by an End of Taper Visit 
(see taper schedule, Table 7‒2). 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. A slow 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. In case of an emergency, a faster taper is permitted after discussion 
with the Medical Monitor, whenever possible.  
At the completion of the Treatment Period, investigators should discuss treatment options 
with the subject and/or their parent(s)/legal representative(s) to best manage the subject’s 
epilepsy. Taper of LCM may not be required for some subjects who complete the study 
depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent(s)/legal representative(s). 
Change #12 
Section 7.2.1 Treatment period 
Table 7-2 
Lacosamide dosing for subjects requiring taper 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
NA 
300mg/day 
200mg/day 
100mg/day 
NA 
NA 
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Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
Week 1 
Week 2 
Week 3 
Week 4 
200mg/day 
100mg/day 
NA 
NA 
NA 
ET=early termination; LCM=lacosamide 
Note: The oral solution is dosed as mg/kg/day and tablets are dosed as mg/day. 
aSubjects will begin taper on ET/Termination Visit. 
Has been changed to: 
Dose of LCM at 
ET/Termination Visita 
LCM taper schedule 
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 
4mg/kg/day 
2mg/kg/day 
NA 
NA 
NA 
800mg/day 
600mg/day 
400mg/day 
200mg/day 
100mg/day 
700mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
NA 
300mg/day 
200mg/day 
100mg/day 
NA 
NA 
200mg/day 
100mg/day 
NA 
NA 
NA 
ET=early termination; LCM=lacosamide 
Note: The oral solution is dosed as mg/kg/day and tablets are dosed as mg/day. 
aSubjects will begin taper on ET/Termination Visit. 
Change #13 
Section 8.1.4 Visits 12, 13, 14, 15, 16, and 17 (Weeks 118, 142, 166, 
190, 214, and 238, Years 3 to 5) 
8.1.4.1 Subjects <18years 
The following tasks and procedures are to be performed at these visits : 
• Concomitant medications and AEDs 
• Physical examination (complete, Visit 13, 15, and 17) 
• Neurological examination (brief, Visit 12, 14, and 16) 
• ECG (12-lead) assessment (Visit 13, 15, and 17) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
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• Body weight and height (height at Visit 12, 14, and 16) 
• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 13, 15, and 17) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 
17/Termination Visit. If Visit 17 is not the Termination Visit, laboratory tests are not 
required. Laboratory tests are not performed at Visit 13 and 15 according to Protocol 
Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects ≥6 years to <18 years of age (Visit 13, 15, and 17) 
• BRIEF for subjects ≥5 to <18 years of age (Visit 13, 15, and 17) 
 
Has been changed to: 
8.1.4 Visits 12, 13, 14, 15, 16, 17 and 17X (Weeks 118, 142, 166, 190, 214, and 
238, and X, Years 3 to 5 + Extended Period) 
8.1.4.1 Subjects <18years 
The following tasks and procedures are to be performed at these visits (Visit X [Vx] visits are 
to be performed every 24 weeks): 
• Concomitant medications and AEDs 
• Physical examination (complete, Visit 13, 15, 17, and odd numbered visits thereafter) 
• Neurological examination (brief, Visit 12, 14, 16, and even numbered visits thereafter) 
• ECG (12-lead) assessment (Visit 13, 15, 17, and odd numbered visits thereafter) 
• Vital signs (pulse rate, BP) including orthostatic assessments 
• Body weight and height (height at Visit 12, 14, 16, and even numbered visits thereafter) 
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• Tanner staging (will be performed only for subjects who are pubescent at Visit 1 or who 
enter puberty during the course of the study) (Visit 13, 15, 17, and odd numbered visits 
thereafter) 
• C-SSRS assessment (for subjects ≥6 years of age) 
• Blood and urine samples for clinical laboratory assessments (includes hematology, 
chemistry, and urinalysis) (laboratory tests are applicable for combined Visit 
17/Termination Visit. If Visit 17 is not the Termination Visit, laboratory tests are not 
required. Laboratory tests are not performed at Visit 13 and 15 according to Protocol 
Amendment 3. 
• Urine pregnancy test (for women of childbearing potential) 
• Contact IRT 
• Dispense subject diary 
• Subject diary return/review 
• Dispense LCM 
• LCM review/return 
• Assess withdrawal criteria 
• AE reporting 
• Achenbach CBCL for subjects ≥6 years to <18 years of age (Visit 13, 15, 17, and odd 
numbered visits thereafter) 
• BRIEF for subjects ≥5 to <18 years of age (Visit 13, 15, 17, and odd numbered visits 
thereafter) 
Change #14 
Section 8.1.4.2 Subjects ≥18 years 
First paragraph 
The following tasks and procedures are to be performed at these visits. 
Has been changed to: 
The following tasks and procedures are to be performed at these visits, additional routine 
visits (Visit X) can be done after Visit 17 (Vx visits are to be performed every 24 weeks) with 
assessments described in Table 5‒3. 
Change #15 
Section 8.1.5 Telephone contact 
First paragraph 
Telephone contacts are required at Week 30 and Week 38 and every 8 weeks during Year 2 
to Year 5, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, 
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telephone contacts in Year 2 are scheduled for Week 54, Week 70 and Week 86. Telephone 
contacts in Years 3 to 5 are scheduled for: Year 3 - Week 102, Week 110, Week 126, Week 
134; Year 4 - Week 150, Week 158, Week 174, Week 182; Year 5 - Week 198, Week 206, 
Week 222, and Week 230. 
Has been changed to: 
Telephone contacts are required at Week 30 and Week 38 and every 8 weeks during Year 2 
to Year 5, except during weeks in which a clinic visit is planned (eg, Week 62). Therefore, 
telephone contacts in Year 2 are scheduled for Week 54, Week 70, Week 78 and Week 86. 
Telephone contacts in Years 3 to 5 are scheduled for: Year 3 - Week 102, Week 110, Week 
126, Week 134; Year 4 - Week 150, Week 158, Week 174, Week 182; Year 5 - Week 198, 
Week 206, Week 214, Week 222, Week 230, Week 238, and every 8 weeks during the 
Extended Period. 
Change #16 
Section 8.2 
Early termination visit 
First paragraph 
Subjects withdrawing from the study will complete the ET Visit, and LCM will be tapered 
over a period of up to 4 weeks (see taper schedule, Table 7‒2). 
Has been changed to: 
Subjects withdrawing from the study will complete the ET Visit, and LCM will be tapered 
over a period of up to 4 weeks if not continuing with commercially available LCM (see taper 
schedule, Table 7‒2). 
Change #17 
Section 8.3 
Termination visit 
Paragraphs 1, 2, and 3 
Subjects completing the Treatment Period and not continuing with commercially available 
LCM will complete the Termination Visit, and LCM will be tapered over a period of up to 
4 weeks (see taper schedule, Table 7‒2). Once LCM becomes commercially available and the 
subject elects to continue treatment, they must also complete the Termination Visit and 
transition to commercially available LCM. 
Patients transitioning to the MAP will complete the Treatment Period after 2 years but 
continue their treatment with MAP LCM. 
Taper of LCM is not required for subjects who complete the study and continue on MAP 
LCM or commercially available LCM. Subjects transitioning to MAP LCM or commercially 
available LCM will do so immediately and will continue at a dose determined by the 
investigator. Note: this visit can be combined with Visit 17 if appropriate. 
Have been changed to: 
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A Termination Visit will be completed by subjects who complete the Treatment Period and 
meet 1 of the following conditions:   
8. The subject chooses to transition to commercial LCM. 
9. The subject chooses not to continue treatment with LCM.   
Subjects not continuing treatment with LCM will complete the Termination Visit, and LCM 
will be tapered over a period of up to 4 weeks (see taper schedule, Table 7‒2). Subjects who 
continue treatment with commercial LCM must also complete the Termination Visit. 
Taper of LCM is not required for subjects who leave the Termination Visit and transition to 
commercial LCM. Subjects transitioning to commercial LCM will do so immediately and 
will continue at a dose determined by the investigator.  In this instance, the Termination Visit 
will serve as the subject's last visit in the study.   
Change #18 
Section 9.1 
Seizure variables 
Subjects will keep a diary to record seizure activity from Visit 1 until the end of study 
participation. Efficacy variables will be assessed using the seizure count information recorded 
on the subject diaries. The subject should be reminded to bring the diary to each clinic visit.  
Has been changed to: 
Subjects will keep a diary to record all seizure activity from Visit 1 until the end of study 
participation. Efficacy variables will be assessed using the seizure count information recorded 
on the subject diaries. The subject should be reminded to bring the diary to each clinic visit. 
Should an adverse event involving a seizure be reported, it must be consistent with the 
seizure information (including specific type of seizure) reported in the seizure diary. 
Change #19 
Section 10.1.1.1 Adverse events 
Added fourth paragraph: 
Should an AE involving a seizure be reported, it must be consistent with the seizure 
information (including specific type of seizure) reported in the seizure diary. 
Change #20 
Section 10.1.1.2 Serious adverse events 
Added second paragraph: 
If commercial LCM is given during hospitalization, this needs to be recorded on the CRF. 
Change #21 
Section 10.2 New seizure types 
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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 9.1). 
Has been changed to: 
Section 10.2 New seizure types, increase in days with and worsening of days with 
absence or myoclonic seizures 
Incidence of new seizure types, increase in absence seizure days or myoclonic seizure days 
per 28 days during the Treatment Period, and 50% worsening in days with absence seizures 
or myoclonic seizures per 28 days during the Treatment Period will be assessed using the 
seizure count information recorded on the subject diaries (see Section 9.1). 
 
Change #22 
Section 10.3.1.3 Testing: identification/exclusion of alternative 
etiology 
Table 10-4 (laboratory measurements):  
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) 
Immunolog
y 
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 
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Table 10-4: PDILI laboratory measurements 
Serum CPK and LDH to evaluate possible muscle injury causing 
transaminase elevation 
Additional 
Prothrombin time/INRa 
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). 
Has been changed to: 
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) 
Immunolog
y 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology Differential count, hematocrit, hemoglobin, platelet count, RBC and WBC 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Albumin, AST, ALT, ALP, GGT, serum CPK, and LDH to evaluate possible 
muscle injury causing transaminase elevation 
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Table 10-4: PDILI laboratory measurements 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma glutamyl transferase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RBC=red blood 
cell count; RNA=ribonucleic acid; ULN=upper limit of normal; WBC=white blood cell count 
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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Change #23 
Section 12.3.1 Safety analysis 
Second 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. Laboratory 
measurements as described in Section 10.3 and other safety measurements as described in 
Section 10.4 will be presented. 
Has been changed to: 
Incidence of new seizure types, increase in days with absence seizure or myoclonic seizures 
per 28 days during the Treatment Period, and 50% worsening in days with absence seizures 
or myoclonic seizures per 28 days during the Treatment Period will be summarized. 
Laboratory measurements as described in Section 10.3 and other safety measurements as 
described in Section 10.4 will be presented. 
Change #24 
Section 12.4 
Planned efficacy analysis 
Second paragraph 
Days with myoclonic or absence seizures are more clinically relevant endpoints; therefore, 
change in and percent change in days with myoclonus and absence will be summarized. The 
percentage of subjects with 50% reduction in days with absence and myoclonic seizures per 
28 days compared to the Prospective Baseline will be presented. Subjects who were seizure-
free from all generalized seizures will also be tabulated. 
Has been changed to: 
Days with myoclonic or absence seizures are more clinically relevant endpoints; therefore, 
change in and percent change in days with myoclonic and/or absence seizures will be 
summarized. The percentage of subjects with 50% reduction in days with absence and/or 
myoclonic seizures per 28 days compared to the Prospective Baseline will be presented. 
Subjects who were seizure-free from all generalized seizures will also be tabulated. 
Change #25 
Section 12.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on either the primary efficacy outcome or key safety outcomes for an 
individual subject. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the project Data 
Cleaning Plan. To the extent feasible, 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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Important protocol deviations will be reviewed as part of the ongoing data cleaning process 
prior to database lock to confirm exclusion from analysis sets. 
Has been changed to: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for 
identifying important protocol deviations and the classification of important protocol 
deviations will be defined within the project Data Cleaning Plan. To the extent feasible, rules 
for identifying protocol deviations will be defined without review of the data and without 
consideration of the frequency of occurrence of such deviations. Whenever possible, criteria 
for identifying important protocol deviations will be implemented algorithmically to ensure 
consistency in the classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process 
prior to database lock. 
Change #26 
Added Section 13.4.1 Processing of subject health data 
The processing of the subject personal health data in this study is allowed for the purpose of 
scientific research to evaluate the efficacy and the safety of the tested drug, in accordance 
with legal requirements from: 
• the laws governing the conduct of clinical studies (ie, the provisions of the French Public 
Health Code and the EU clinical trial regulation 536/2014 which requires sponsors to 
collect and analyze such data before they are submitted to health authorities) 
• the EU regulation 1235/2010 on pharmacovigilance which requires follow-up and 
reporting of adverse events of medicinal products to the health authorities, and any other 
applicable law 
This means that after the end of the study the subject coded personal data will be retained for 
at least 25 years to ensure the validity of the research. 
The subjects will be informed that the Sponsor is legally entitled and obliged to keep, retain, 
and use your medical data to ensure the quality of scientific results and to comply with legal 
or judicial retention periods. 
 
 
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16.8 
Appendix 8: Protocol Amendment 5 
Rationale for the amendment 
The primary purpose of this amendment was to update the protocol based on comments 
received on the pediatric investigational plan as well as to clarify/solve inconsistencies 
between different sections of the protocol and to correct some minor errors. 
Modifications and changes 
Specific changes 
Change #1 
Title page: 
The title was updated from “Protocol EP0012 Amendment 4” to “Protocol EP0012 
Amendment 5.” 
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 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
Protocol Amendment 4 
13 Dec 2019 
Substantial 
 
Has been changed to: 
Protocol/Amendment Number 
Date 
Type of amendment 
Final Protocol 
15 Oct 2012 
Not applicable 
Protocol Amendment 1 
27 Jan 2015 
Substantial 
Protocol Amendment 2 
09 Jun 2016 
Substantial 
Protocol Amendment 3 
29 Nov 2017 
Substantial 
Protocol Amendment 4 
13 Dec 2019 
Substantial 
Protocol Amendment 5 
27 Aug 2020 
Non-substantial 
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Change #2 
4.1.1 Primary safety variables 
The primary safety variables are: 
• Adverse events as reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawals due to AEs 
• Incidence of new appearance of absence and/or myoclonic seizures during the Treatment 
Period 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days 
with absence seizures per 28 days compared to the Prospective Baseline 
• Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days 
with myoclonic seizures per 28 days compared to the Prospective Baseline 
• Percentage of subjects with at least 50% worsening in days with absence seizures 
• Percentage of subjects with at least 50% worsening in days with myoclonic seizures 
 
Has been changed to: 
The primary safety variables are: 
• The incidence of TEAEs over the duration of the Treatment Period. 
• Subject withdrawals due to TEAEs 
• Incidence of new appearance of absence and/or myoclonic seizures during the Treatment 
Period 
• An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with absence 
seizures per 28 days compared to the Prospective Baseline 
• An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days compared to the Prospective Baseline 
• At least 50% worsening in days with absence seizures 
• At least 50% worsening in days with myoclonic seizures 
 
Change #3 
4.2.3 
Other efficacy variables 
Bullets 5, 6 and 7 
• Percentage of subjects with at least a 50% reduction in PGTCS frequency compared to 
the Combined Baseline 
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• Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared 
to the Prospective Baseline 
• Percentage of subjects with at least a 50% reduction in absence seizure days compared to 
the Prospective Baseline 
 
Has been changed to: 
• At least a 50% reduction in PGTCS frequency compared to the Combined Baseline 
• At least a 50% reduction in myoclonic seizure days compared to the Prospective Baseline 
• At least a 50% reduction in absence seizure days compared to the Prospective Baseline 
 
Change #4 
Section 5.1.1 Study duration per subject 
Paragraph 1, bullet #2 
• For pediatric subjects, treatment will continue until the latest of 1 of the following 
2 conditions are met: 
− up to 5 years of participation or  
− until the latest approval is granted either by EMA, FDA, or PMDA 
Has been changed to: 
• For pediatric subjects, treatment will continue until 1 of the following 2 conditions are 
met: 
− up to 5 years of participation or  
− until the approval of the extension of indication to cover the target age group is 
granted 
Change #5 
5.2 
Schedule of study assessments 
Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit for subjects <18 years at 
enrollment) 
Neurological exam (brief): added ‘X’ to study ET Visit 
Footnote ‘p’ 
Laboratory tests are applicable for combined the last scheduled visit/Termination Visit. If the 
last scheduled visit is not the Termination Visit, laboratory tests are not required. 
 
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Table 5-3 Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit for subjects ≥18 years at 
enrollment) 
Deleted footnote ‘e’ from V17. 
Added footnote ‘i’: 
i 
Laboratory tests are applicable for the combined last scheduled visit/Termination Visit. If 
the last scheduled visit is not the Termination Visit, laboratory tests are not required. 
 
Table 16-6:Schedule of study assessments (Taper Period and Safety Follow-Up Period) 
Table header column 2 
End of Taper Visit (maximum 3 days after visit) 
Has been changed to: 
Table 5‒2: Schedule of study assessments for Years 3 through 5 for EP0012 (Treatment 
Period, ET Visit, Termination Visit, and Unscheduled Visit for subjects <18 years at 
enrollment) 
Footnote ‘p’ 
Laboratory tests are applicable for combined the last scheduled visit/Termination Visit. If the 
last scheduled visit is not the Termination Visit, laboratory tests are not required. 
 
Table 16-7:Schedule of study assessments (Taper Period and Safety Follow-Up Period) 
Table header column 2 
End of Taper Visit (maximum 3 days after the last dose) 
 
Change #6 
Section 8.1.4.1 
Subjects <18 years 
Bullet #3 
• Neurological examination (brief, Visit 12, 14, 16, and even numbered visits thereafter) 
Has been changed to: 
• Neurological examination (brief, Visit 12, 14, 16, 17, and even numbered visits 
thereafter) 
 
Change #7 
12.3.1 
Safety analyses  
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Paragraph 1 
The incidence and frequency of TEAEs will be summarized. The incidence of SAEs and 
TEAEs leading to premature discontinuation from study drug will also be summarized. 
Additional summaries will be provided by maximum intensity and relationship to study drug. 
All tables of AEs will include Medical Dictionary for Regulatory Activities primary System 
Organ Class and Preferred Term. Further details on the analysis of each variable will be given 
in the SAP. Frequency tables for subject withdrawal due to AE will be presented giving 
absolute and relative frequencies for the course of the study. Additionally, per year 
frequencies will be provided, where the denominator will be adjusted for the number of 
subjects still at risk, ie, the number of subjects entering the respective year of the study. 
Relative years will be used for this type of analysis, not calendar years.  
Has been changed to: 
The incidence of all TEAEs, treatment emergent SAEs and TEAEs leading to premature 
discontinuation from study drug will also be summarized descriptively. Additional 
summaries will be provided by maximum intensity and relationship to study drug. All tables 
of TEAEs will include Medical Dictionary for Regulatory Activities primary System Organ 
Class and Preferred Term. Further details on the analysis of each variable will be given in the 
SAP.  
 
 
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16.9 
Appendix 9: Contraception Table 
Method 
Abbreviatio
n 
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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17 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and 
local laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects 
of this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be 
treated confidentially, and will not be made available to third parties without prior 
authorization by UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made 
in a separate contract. 
Investigator: 
 
 
__________________________________ 
Printed name 
 
 
 
__________________________________ 
Date/Signature 
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EP0012 
 
 
 
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18 
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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Approval Signatures
Name:
ep0012-protocol-amend-5
Version:
1. 0
Document Number:
CLIN-000158392
Title:
EP0012 Protocol Amendment 5 - Open multicenter extension, evaluate long-term
safety,efficacy of adjunctive LCM for uncontrolled PGTC seizures (IGE)
Approved Date:
31 Aug 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-Aug-2020 15:55:58 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 31-Aug-2020 08:01:31 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 31-Aug-2020 13:51:25 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
Lacosamide 
EP0012 
 
 
 
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Page 1 of 175 
STATISTICAL ANALYSIS PLAN  
Study: EP0012 
Product: Lacosamide 
AN OPEN-LABEL, MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND EFFICACY OF LACOSAMIDE AS ADJUNCTIVE THERAPY 
FOR UNCONTROLLED PRIMARY GENERALIZED TONIC-CLONIC SEIZURES IN 
SUBJECTS WITH IDIOPATHIC GENERALIZED EPILEPSY 
 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
SAP Amendment #3 
15 Nov 2021 
SAP Amendment #4 
09 Sep 2022 
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. 
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EP0012 
 
 
 
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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 objectives ........................................................................................... 10 
2.2 
Study variables ............................................................................................................. 10 
2.2.1 
Safety variables .................................................................................................... 10 
2.2.1.1 
Primary safety variables ............................................................................ 10 
2.2.1.2 
Secondary safety variables ........................................................................ 10 
2.2.1.3 
Other safety variables ................................................................................ 11 
2.2.2 
Efficacy variables ................................................................................................ 11 
2.2.2.1 
Primary efficacy variables ......................................................................... 11 
2.2.2.2 
Secondary efficacy variable ...................................................................... 11 
2.2.2.3 
Other efficacy variables ............................................................................. 11 
2.2.2.4 
Additional other efficacy variables ........................................................... 12 
2.3 
Study design and conduct ............................................................................................ 13 
2.3.1 
EP0012 entry status ............................................................................................. 15 
2.3.1.1 
Rollover subjects ....................................................................................... 15 
2.3.1.2 
Direct enrollers .......................................................................................... 15 
2.3.2 
Protocol visit windows ........................................................................................ 15 
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 
3.2.1.1 
Analysis periods ........................................................................................ 16 
3.2.1.2 
Relative day ............................................................................................... 17 
3.2.1.3 
Last Visit ................................................................................................... 17 
3.2.1.4 
Month ........................................................................................................ 17 
3.2.1.5 
Completer cohorts ..................................................................................... 17 
3.2.1.6 
Time Period ............................................................................................... 18 
3.2.1.7 
Visit Algorithm .......................................................................................... 19 
3.2.2 
Protocol defined study periods ............................................................................ 19 
3.2.3 
Seizure cluster ...................................................................................................... 19 
3.2.4 
AEDs and benzodiazepines ................................................................................. 19 
3.2.4.1 
Phenytoin use ............................................................................................ 20 
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3.2.4.2 
Valproate use ............................................................................................. 20 
3.2.4.3 
Phenobarbital use ...................................................................................... 20 
3.3 
Definition of Baseline values ....................................................................................... 20 
3.4 
Protocol deviations....................................................................................................... 22 
3.5 
Analysis sets................................................................................................................. 22 
3.5.1 
Enrolled Set ......................................................................................................... 22 
3.5.2 
Safety Set ............................................................................................................. 22 
3.5.3 
Full Analysis Set .................................................................................................. 22 
3.6 
Treatment assignment and treatment groups ............................................................... 22 
3.7 
Center pooling strategy ................................................................................................ 23 
3.8 
Coding dictionaries ...................................................................................................... 23 
3.9 
Changes to protocol-defined analyses ......................................................................... 23 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 23 
4.1 
Adjustments for covariates .......................................................................................... 23 
4.2 
Handling of dropouts or missing data .......................................................................... 23 
4.2.1 
Missing seizure diary days ................................................................................... 24 
4.2.1.1 
Week 94 visit – seizure data ...................................................................... 24 
4.2.2 
Incomplete dates for first epilepsy diagnosis ....................................................... 24 
4.2.3 
Incomplete dates for adverse events and concomitant medications .................... 24 
4.2.4 
Incomplete date for the last administration of study medication ......................... 25 
4.2.5 
Missing adverse event intensity ........................................................................... 26 
4.2.6 
Missing adverse event relationship to study medication ..................................... 26 
4.3 
Interim analyses and data monitoring .......................................................................... 26 
4.4 
Multicenter studies ....................................................................................................... 26 
4.5 
Multiple comparisons/multiplicity ............................................................................... 26 
4.6 
Use of an efficacy subset of subjects ........................................................................... 26 
4.7 
Active-control studies intended to show equivalence .................................................. 27 
4.8 
Examination of subgroups ........................................................................................... 27 
4.9 
Data handling method of textual results in laboratory data ......................................... 27 
4.10 
Use of a safety subset of subjects ................................................................................ 27 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 28 
5.1 
Subject disposition ....................................................................................................... 28 
5.2 
Protocol deviations....................................................................................................... 29 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 29 
6.1 
Demographics .............................................................................................................. 29 
6.1.1 
Derivation of demographics variables ................................................................. 29 
6.1.1.1 
Body mass index ....................................................................................... 29 
6.1.2 
Analysis of demographics variables .................................................................... 29 
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6.2 
Other Baseline characteristics ...................................................................................... 29 
6.2.1 
Derivation of other Baseline characteristics ........................................................ 29 
6.2.1.1 
Time since first diagnosis .......................................................................... 29 
6.2.1.2 
Age at diagnosis ........................................................................................ 29 
6.2.2 
Analysis of other Baseline characteristics ........................................................... 30 
6.3 
Subgroups .................................................................................................................... 31 
6.4 
Medical history and concomitant diseases ................................................................... 31 
6.5 
Prior and concomitant medications .............................................................................. 31 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 32 
8 
EFFICACY ANALYSES ................................................................................................ 32 
8.1 
Statistical analysis of the primary efficacy variable .................................................... 33 
8.2 
Statistical analysis of the secondary efficacy variable ................................................. 33 
8.2.1 
Derivation of secondary efficacy variable ........................................................... 33 
8.2.2 
Analysis of secondary efficacy variable .............................................................. 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: Days with seizures per 28 days ................................................. 34 
8.3.1.2 
Variables: Responder status – reduction in PGTCS frequency ................. 34 
8.3.1.3 
Variables: Responder status – reduction in days with absence seizures ... 35 
8.3.1.4 
Variables: Responder status – reduction in days with myoclonic seizures35 
8.3.1.5 
Variables: Responder status – reduction in days with generalized seizures35 
8.3.1.6 
Variables: Responder status – reduction in days with all seizures ............ 35 
8.3.1.7 
Variables: Seizure-free status .................................................................... 36 
8.3.1.8 
Variables: All Seizure-free status .............................................................. 36 
8.3.1.9 
Variable: Worsening of PGTCS ................................................................ 36 
8.3.1.10 
Variable: Worsening of days with absence seizures ................................. 36 
8.3.1.11 
Variable: Worsening of days with myoclonic seizures ............................. 37 
8.3.1.12 
Variable: Worsening of days with generalized seizures............................ 37 
8.3.1.13 
Variable: Worsening of days with all seizures .......................................... 37 
8.3.1.14 
Variable: PGTCS free intervals ................................................................. 37 
8.3.1.15 
Variable: Generalized seizure free intervals.............................................. 38 
8.3.1.16 
Variable: All seizure-free intervals ........................................................... 38 
8.3.2 
Analysis of seizure-related other efficacy variables ............................................ 38 
8.3.2.1 
Analysis: Days with seizures per 28 days ................................................. 38 
8.3.2.2 
Analysis: Responder status – reduction in PGTCS frequency .................. 39 
8.3.2.3 
Analysis: Responder status – reduction in days with absence seizures..... 39 
8.3.2.4 
Analysis: Responder status – reduction in days with myoclonic seizures 39 
8.3.2.5 
Analysis: Responder status – reduction in days with generalized seizures40 
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8.3.2.6 
Analysis: Responder status – reduction in days with all seizures ............. 40 
8.3.2.7 
Analysis: Seizure free status ...................................................................... 40 
8.3.2.8 
Analysis: PGTCS worsening ..................................................................... 40 
8.3.2.9 
Analysis: Worsening in days with absence seizures ................................. 41 
8.3.2.10 
Analysis: Worsening in days with myoclonic seizures ............................. 41 
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 ............................................................................................ 43 
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 ....................................................................................... 44 
8.4.2.3 
EQ-5D-3L quality of life variables ........................................................... 44 
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 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 44 
10 SAFETY ANALYSES ..................................................................................................... 44 
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 ............................................................................................................. 46 
10.3 
Clinical laboratory evaluations .................................................................................... 47 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 49 
10.4.1 
Vital signs ............................................................................................................ 49 
10.4.2 
Electrocardiograms .............................................................................................. 50 
10.4.2.1 
Derivation of corrected QT values ............................................................ 50 
10.4.2.2 
Analysis of ECG parameters ..................................................................... 50 
10.4.3 
Physical examination ........................................................................................... 51 
10.4.4 
Tanner stage assessment ...................................................................................... 51 
10.4.5 
Neurological examination .................................................................................... 51 
10.4.6 
Assessment of suicidality .................................................................................... 51 
10.4.7 
Achenbach Child Behavior Checklist .................................................................. 51 
10.4.7.1 
Derivation of Achenbach variables ........................................................... 52 
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10.4.7.2 
Analysis of Achenbach variables .............................................................. 53 
10.4.8 
BRIEF-P and BRIEF assessment ......................................................................... 53 
10.4.8.1 
BRIEF-P scores ......................................................................................... 54 
10.4.8.2 
BRIEF scores ............................................................................................. 55 
10.4.9 
Safety Seizure Information .................................................................................. 55 
10.4.9.1 
New Seizure Type or Worsening Over Time ............................................ 56 
10.4.9.2 
Increase in days with absence seizures ...................................................... 56 
10.4.9.3 
Increase in days with myoclonic seizures ................................................. 56 
11 APPENDICES ................................................................................................................. 56 
11.1 
Appendix 1: QOLIE-31-P total and subscale score calculations ................................. 56 
11.2 
Appendix 2: Adverse Events ....................................................................................... 61 
11.2.1 
List of other significant AEs ................................................................................ 61 
11.2.2 
List of AEs for Potentially Drug Induced Liver Injury (PDILI).......................... 63 
11.3 
Appendix 3: Markedly abnormal values ...................................................................... 66 
11.3.1 
Hematology .......................................................................................................... 66 
11.3.2 
Chemistry ............................................................................................................. 67 
11.3.3 
Vital signs ............................................................................................................ 69 
11.3.4 
ECG ..................................................................................................................... 71 
11.4 
Appendix 4: NCI CTC ................................................................................................. 72 
11.5 
Appendix 5: Tables required for Article 41 (EudraCT) ............................................... 76 
11.6 
Additional Subgroups to be programmed in ADSL .................................................... 76 
12 AMENDMENT TO THE STATISTICAL ANALYSIS PLAN ...................................... 77 
12.1 
Amendment 1 ............................................................................................................... 77 
12.1.1 
Rationale for the amendment ............................................................................... 77 
12.1.2 
Modification and changes .................................................................................... 77 
12.1.2.1 
Specific changes ........................................................................................ 77 
12.2 
Amendment 2 ............................................................................................................... 95 
12.2.1 
Rationale for the amendment ............................................................................... 95 
12.2.2 
Modification and changes .................................................................................... 95 
12.2.2.1 
Specific changes ........................................................................................ 96 
12.3 
Amendment 3 ............................................................................................................. 116 
12.3.1 
Rationale for the amendment ............................................................................. 116 
12.3.2 
Modification and changes .................................................................................. 117 
12.3.2.1 
Specific changes ...................................................................................... 117 
12.4 
Amendment 4 ............................................................................................................. 159 
12.4.1 
Rationale for the amendment ............................................................................. 159 
12.4.2 
Modification and changes .................................................................................. 159 
12.4.2.1 
Specific changes ...................................................................................... 159 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 175 
 
LIST OF TABLES 
Table 1 
CBCL/1½-5 ...................................................................................................... 52 
Table 2 
CBCL/6-18 ....................................................................................................... 52 
Table 3 
BRIEF-P questionnaire scoring ....................................................................... 54 
Table 4 
BRIEF questionnaire scoring ........................................................................... 55 
Table 5  
Other Significant AEs ...................................................................................... 61 
Table 6  
AEs for PDILI .................................................................................................. 63 
Table 7  
Hematology Markedly Abnormal Values ........................................................ 66 
Table 8  
Chemistry - Markedly Abnormal Values ......................................................... 67 
Table 9  
Vital Signs Abnormality Criteria ..................................................................... 69 
Table 10  
ECGs Abnormality Criteria ............................................................................. 71 
Table 11  
NCI CTC .......................................................................................................... 72 
Table 12  
Hematology Markedly Abnormal Values ...................................................... 105 
Table 13  
Chemistry - Markedly Abnormal Values ....................................................... 107 
Table 14  
Vital Signs Abnormality Criteria ................................................................... 111 
Table 15  
Vital Signs Abnormality Criteria ................................................................... 112 
Table 16  
ECGs Abnormality Criteria ........................................................................... 113 
Table 17  
ECGs Abnormality Criteria ........................................................................... 114 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
bid 
twice a day 
BMI 
body mass index 
BRI 
Behavioral Regulation index 
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive 
Function®-Preschool version 
B 
Baseline 
CB 
Combined Baseline Period 
CBCL 
Child Behavior Checklist 
COVID-19 
Coronavirus disease 2019 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
ECG 
Electrocardiogram 
ES 
Enrolled Set 
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 
HRQoL 
health-related quality of life 
IGE 
idiopathic generalized epilepsy 
II 
Generalized seizures 
IIA 
Absence seizure 
IIB 
Myoclonic seizure 
IIE 
Primary generalized tonic-clonic seizure 
ILAE 
International League Against Epilepsy 
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IPD 
Important protocol deviations 
LCM 
Lacosamide 
LLN 
lower limit of normal 
MA 
Markedly abnormal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Metacognition Index 
NCI CTC 
National Cancer Institute common toxicity criteria 
PB 
Prospective Baseline Period 
PCH 
percent change 
PedsQL 
Pediatric Quality of Life Inventory  
PGTCS 
primary generalized tonic-clonic seizures 
PT 
preferred term 
QOLIE-31-P 
Patient-Weighted Quality of Life in Epilepsy 
Inventory-Form 31 
QTcB 
Bazett corrected QT 
QTcF 
Fridericia corrected QT 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS® 
statistical analysis software 
SBP 
systolic blood pressure 
SD 
standard deviation 
SF 
seizure frequency 
SOC 
system organ class 
SPD 
Specification of protocol deviations 
SS 
Safety Set 
TEAE 
treatment emergent adverse event 
TEMA 
treatment emergent markedly abnormal 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WHO-DD 
World Health Organization Drug Dictionary 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for protocol 
number EP0012, through protocol amendment #5; the data summarized will be from EP0012 
unless otherwise stated.  Since EP0012 is an open-label extension of SP0982, the SP0982 SAP 
Amendment #4 should be consulted for how variables were calculated for the randomized 
subjects rolling into EP0012.  
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to assess the safety and tolerability of lacosamide (LCM) as an 
adjunctive therapy for uncontrolled primary generalized tonic-clonic seizures (PGTCS) in 
subjects with idiopathic generalized epilepsy (IGE) during long-term exposure. 
2.1.2 
Secondary objectives 
The secondary objectives are: 
 To assess the efficacy of adjunctive LCM therapy during long-term exposure for the 
treatment of subjects with IGE experiencing uncontrolled PGTCS 
 To allow subjects who have completed SP0982 and eligible Baseline failures from SP0982 to 
receive LCM 
2.2 
Study variables 
2.2.1 
Safety variables 
2.2.1.1 
Primary safety variables 
The primary safety variables are: 
 The incidence of TEAEs over the duration of the Treatment Period 
 Subject withdrawals due to TEAEs 
 Incidence of new appearance of absence and/or myoclonic seizures during the Treatment 
Period 
 An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with absence 
seizures per 28 days during the Treatment Period as compared to the Prospective Baseline 
Period 
 An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with myoclonic 
seizures per 28 days during the Treatment Period as compared to the Prospective Baseline 
Period 
 At least 50% worsening in days with absence seizures 
 At least 50% worsening in days with myoclonic seizures 
2.2.1.2 
Secondary safety variables 
Secondary safety variables are: 
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 Percentage of treatment-emergent marked abnormalities in hematology and chemistry 
parameters 
 Percent of treatment-emergent marked abnormalities in 12-lead electrocardiogram (ECG) 
 Percentage of treatment-emergent marked abnormalities in vital sign measurements (ie, 
blood pressure (BP) and pulse rate) 
2.2.1.3 
Other safety variables 
Other safety variables are: 
 Changes in hematology, chemistry, and urinalysis parameters 
 Changes in 12-Lead ECGs 
 Changes in vital sign measurements (ie. BP and pulse rate), including weight and height and 
physical (including neurological) examination findings 
 Achenbach Child Behavior Checklist (CBCL)1½-5 or CBCL/6-18 (for pediatric subjects 
only) 
 Cognitive function assessment Behavior Rating Inventory of Executive Function 
(BRIEF)/BRIEF-P (for pediatric subjects only) 
2.2.2 
Efficacy variables 
2.2.2.1 
Primary efficacy variables 
No primary efficacy variables are defined for this study. 
2.2.2.2 
Secondary efficacy variable 
The secondary efficacy variable is: 
 Percent change in PGTCS frequency per 28 days from Combined Baseline Period, where 
Combined Baseline Period is defined as the combined 12-week Historical Baseline and 4-
week Prospective Baseline periods immediately prior to randomization in the parent study 
(SP0982) 
2.2.2.3 
Other efficacy variables 
The other efficacy variables are: 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period 
 At least a 50% reduction in PGTCS frequency compared to the Combined Baseline Period 
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 At least a 50% reduction in myoclonic seizure days compared to the Prospective Baseline 
Period 
 At least a 50% reduction in absence seizure days compared to the Prospective Baseline 
Period 
 Seizure-free status (yes/no) for PGTCS 
 Seizure-free status (yes/no) for all generalized seizure types 
 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 for the first two years of treatment 
 Change from Baseline in the EQ-5D-3L visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age) for the first two 
years of treatment 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
for the first two years of treatment 
 Number of working or school days lost by subject due to epilepsy for the first two years of 
treatment 
 Number of days with help from a caregiver due to epilepsy for the first two years of 
treatment 
2.2.2.4 
Additional other efficacy variables 
Additional other efficacy variables that will be analyzed in this SAP are: 
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period 
 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period 
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period 
 At least a 50% reduction in generalized seizure days compared to the Prospective Baseline 
Period 
 At least a 50% reduction in all seizure days compared to the Prospective Baseline Period 
 Seizure-free status (yes/no) for all seizure types 
 Duration of PGTCS free intervals 
 Duration of all generalized seizure-free intervals 
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 Duration of all seizure-free intervals 
2.3 
Study design and conduct 
This is a multicenter, open-label extension study to assess the long-term safety, tolerability and 
change in seizure frequency associated with long-term adjunctive oral LCM for uncontrolled 
PGTCS (seizure type=IIE) in subjects ≥4 years of age with IGE. This study will enroll 
consenting subjects, or subjects whose legal representatives have given consent, who have 
completed the LCM SP0982 study (or have left the primary study at the time of the 125th event, 
whichever came first) as well as eligible Baseline failures from SP0982. Then, some subjects 
who tapered in SP0982 after the 125th event may enter EP0012 for the Safety Follow-up only 
(ICF to be signed beforehand). Up to 250 subjects from 150 to 180 study sites are planned to be 
enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, study completers from SP0982 who are eligible for inclusion in EP0012, SP0982 Safety 
Follow-up subjects, and Others are defined as:  
SP0982 Baseline failures 
 Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry criteria 
except the minimum PGTCS criteria required for randomization (Baseline failures) 
Randomized subjects meeting SP0982 exit criteria 
 Subjects who completed the first 6 weeks of the Treatment Period (after randomization) of 
SP0982 and experienced ≥2 PGTCS during that time or 
 Subjects who experience a second PGTCS after the first 6 weeks of the Treatment Period of 
SP0982 
SP0982 completers 
 Subjects who experience <2 PGTCS within the 24-week Treatment Period of SP0982 
 Subjects who were ongoing in SP0982 when the 125th event occurred 
SP0982 Safety Follow-Up subjects 
 Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up only; these subjects take no study medication in EP0012 and their EP0012 reason 
for discontinuation is that they are completing SP0982 Follow-up in EP0012. 
Other 
 Subjects that enrolled in EP0012 that did not fall into the above categories, like those who 
were incomplete screeners 
For SP0982 subjects consented under SP0982 Protocol Amendment 5, after the 125th event is 
confirmed, two classes of SP0982 subjects will be allowed to enroll in EP0012.  Subjects who 
are being screened in SP0982, at the time of the 125th event, will be allowed to directly enroll 
into EP0012, thus their screening and baseline data will be captured in SP0982 but some of their 
baseline data may be captured in EP0012; their treatment information will be captured in 
EP0012.  For subjects who are concluding their SP0982 LCM treatment and tapering, these 
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SP0982 participants will be consented to enroll in EP0012 and complete their Safety Follow-Up 
(thus not receiving any LCM) in EP0012; the data captured in EP0012 will not be transferred to 
SP0982. 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final Clinic 
Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria.  Eligible 
Baseline failures and incomplete screeners from SP0982 who choose to enter this study will 
undergo a complete Visit 1.   
For adult subjects, treatment will continue for at least 2 years.  Once 2 years of participation are 
reached, adult subjects will continue to participate until 1 of the 2 following conditions are met: 
 LCM is approved for use for the treatment of PGTCS in subjects with IGE in the subject’s 
country or  
 until the latest approval is granted either by EMA, FDA or PMDA. 
For pediatric subjects, treatment will continue until 1 of the following 2 conditions are met: 
 up to 5 years of participation or 
 until the approval of the extension of indication to cover the target age group is granted. 
Adult and pediatric subjects are completers if they continue in the study for the maximum 
duration in their respective region. 
The following study periods for the EP0012 protocol (not for the analysis) are defined: 
 A Treatment Period lasting at least 2 years for adults enrolled into EP0012 (may be shorter 
for adults leaving the study when the PGTCS indication approvals are obtained during the 
course of the study). 
 A Treatment Period lasting at least 5 years (238 weeks) for the population less than 18 years 
old at enrollment in EP0012 (may be shorter as some participants leave the study when the 
PGTCS indication approvals are obtained during the course of the study). 
 An up to 4-week Taper Period and a 30-day Safety Follow-Up Period. 
 Subjects continuing LCM treatment with commercially available LCM will transition to a 
dose determined by the investigator and do not have to perform the tapering (Taper Visit 
and SFU). 
 Subjects tapering off LCM will do so over a period of up to 4 weeks. 
 An End of Taper Visit (latest 3 days after the final dose) will occur after the final LCM 
dose for subjects who taper off LCM. 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 same design will apply to some of the subjects 
tapered in SP0982 at the time of the 125th event and who entered EP0012 for the Safety 
Follow-Up Visit only and to subjects who entered EP0012 for a Safety Follow-Up Visit 
after discontinuing SP0982 due to the study stopping. 
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The end of the study is defined as the date of the last visit/telephone contact of the last subject in 
the study. 
Subjects who entered EP0012 as <18 years and become adults (18 years and older) during the 
study will remain in the study for at least 5 years (238 weeks). 
2.3.1 
EP0012 entry status 
Subjects who enter EP0012 are either rollovers from SP0982 or direct enrollers in EP0012. 
2.3.1.1 
Rollover subjects 
The subjects enrolled in EP0012 who were randomized in SP0982 and entered EP0012 after 
discontinuation or completion of SP0982. All study data captured in EP0012 prior to the Safety 
Follow-up period will be summarized as on-treatment (or during the treatment period) for these 
subjects, even if the procedure was done before the 1st dose of EP0012 study medication. 
2.3.1.2 
Direct enrollers 
The subjects enrolled in EP0012 who were baseline failures or incomplete screeners in SP0982 
who were never randomized to take SP0982 study medication. 
2.3.2 
Protocol visit windows 
Protocol visit windows are ±7 days. 
2.4 
Determination of sample size 
The sample size of this open-label extension study will be determined by the parent SP0982 
study.  SP0982 is an event-driven study. Up to 250 subjects may be enrolled to meet the required 
number of events.   Baseline failures from SP0982, subjects in screening at the end of SP0982 
and SP0982 subjects completing their Safety follow-up in EP0012 will also be eligible for 
EP0012, which may increase the sample size. 
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. 
All appropriate tables, figures and listings will present the study results by All Subjects, 
Pediatrics (>=4 to <18 years old in EP0012), and Adults (>=18 years old in EP0012).  Study 
results for assessments given only to pediatric subjects will present information by All Subjects. 
A pediatric subject is less than 18 years old at EP0012 Visit 1. 
Descriptive statistics will be displayed to provide an overview of the study 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. 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 with available measurements (n), mean, standard deviation (SD), median, 
minimum, and maximum; for some parameters, Q1 and Q3 may also be displayed. 
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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, Q1, Q3 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 all visits will be included in subject data listings.  A complete set of data 
listings containing all reported and documented study data and all calculated data (eg, change 
from Baseline) will be generated, in most cases, for the analysis population of interest. 
Efficacy analyses will be performed on data reported during the analysis Treatment Period (see 
Section 3.2.1.1 ) on the Full Analysis Set (FAS). PGTCS analyses will be done on PGTCS data 
captured while the subject is taking LCM (gaps 3 days or less are permitted); if a subject 
experiences an LCM gap > 3 consecutive days, any PGTCS reported during the gap will not be 
included in PGTCS summaries.  
Safety analyses (which include analyses on absence (seizure type=IIA) and/or myoclonic 
seizures (seizure type=IIB)) will be performed on data reported during the analysis Treatment 
Period for the Safety Set (SS).  
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
Analysis periods 
The following analysis periods are defined: 
 Treatment Period (this analysis Treatment Period differs from the protocol-defined treatment 
period): The Treatment Period, which will apply to all non-efficacy analyses, starts at the 
time of first dose of study medication during the EP0012 study for the direct enrollers (date 
of first visit for rollover subjects) and ends on the date of last dose of study medication or the 
date of last protocol-defined visit before SFU visit or death date, whichever is later. The 
Treatment Period includes the protocol-defined Taper Period (see Section 3.2.2) if the subject 
completes it.  
 An efficacy analysis Treatment Period must be calculated for the PGTCS-related 
analyses. This time period starts at the time of first dose of study medication during the 
EP0012 study (date of first visit for rollover subjects) and ends on the date of last dose of 
study medication or death date, whichever is later. 
 Post-Treatment Period: The Post-Treatment Period is defined as the treatment free (ie, no 
study medication) observational phase after the Treatment Period (in SP0982 or EP0012) 
where study is taken. It starts on the day after the end date of the Treatment Period and ends 
on the date of the final visit or date of last contact with the subject, whichever is later. For the 
subjects from SP0982 who are completing their Safety Follow-up in EP0012, their entire 
time in EP0012 will be deemed to be in the Post-Treatment Period due to the subjects not 
taking study medication in EP0012. 
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If the date of last dose of study medication is missing, see imputation rules in Section 4.2.4.  
3.2.1.2 
Relative day 
Relative day will be calculated as the current date minus the date of first dose of study 
medication in EP0012 for direct enrollers (first visit date for rollover subjects) plus 1 for days on 
or after the day of first dose of study medication and prior to or on the day of last study 
medication dose (eg, the day of first dose or first visit will be Day 1). Relative day will be 
calculated as date of first dose of study medication for direct enrollers or first visit for rollovers 
in EP0012 minus the current date for days prior to the first dose of study medication (the day 
prior to first dose or first visit will be Day -1). For days after the last dose of study medication, 
relative day will be calculated as the current date minus the date of last dose of study medication 
including a “+” to denote post treatment days (eg, the day after the last dose will be Day +1). 
Relative day will not be calculated for partial dates. 
3.2.1.3 
Last Visit 
Last Visit is defined as the last non-missing visit (including unscheduled visits) during the 
Treatment Period.  
3.2.1.4 
Month 
A month is defined as 28 days. 
3.2.1.5 
Completer cohorts 
A completer cohort will be defined as the subset of subjects in the FAS that were enrolled, 
treated with LCM for the specified duration of time (allowing gaps of 3 days or less), and have 
efficacy data available for the duration of the treatment exposure stated in the name of the cohort 
minus the visit window (7 days). For example, a 22-week completer cohort consists of subjects 
from the FAS, treated with LCM for at least 22 weeks minus 7 days and have efficacy data 
through at least 22 weeks minus 7 days of exposure (Visit 5 or ET visit). 
Subjects will be classified as belonging to one or more of the following completer cohorts for the 
purpose of subgroup analyses: 
 22 weeks 
 46 weeks 
 94 weeks. 
 142 Weeks 
 190 Weeks 
 238 Weeks 
3.2.1.5.1 
Use of ET or Termination Visit when Scheduled Visits are missing 
A subject is considered a completer of EP0012 if Visit 11 (Week 94 = 658 days minus 7 days) or 
ET or Termination visit is completed instead of Visit 11 . Visit 11 or Week 94 was chosen as the 
visit where subjects could complete the study because it was the closest visit occurring to 2 years 
given the 6 month visit schedule. Subjects also may be deemed completers of EP0012 when they 
leave the study due to LCM being approved in their region.  
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If the visit that corresponds to the completer cohort is missing, then ET or Termination visit will 
be checked to see if this data can be used for the missing visit and to complete the data needed 
for the completer cohort. 
For assessing the 22 and 46 Week completer cohorts, respectively, assess whether the ET visit 
was completed instead of Visit 5 (minus 7 days) or Visit 8 (minus 7 days), respectively; the 
Termination visit may not be an option for some subjects for the 22 Week or 46 Week Completer 
cohorts since subjects can only complete the study after 2 years or approval in their region. 
Since subjects can complete EP0012 at Week 94 (minus 7 days) for the 94 Week completer 
cohort (and for later completer cohorts), if the Week 94 (Visit 11) is missing, then assess whether 
the Termination or ET visit was completed instead of Visit 11.     
The assessment of using Termination or ET visit to determine whether a subject completes a 
cohort occurs when the subject is missing visit for XX Week Completer Cohort (Week 22 – Visit 
5(minus 7 days), Week 46 – Visit 8 (minus 7 days), Week 94 – Visit 11 (minus 7 days), Week 
142 – Visit 13 (minus 7 days), Week 190 - Visit 15 (minus 7 days), and Week 238 – Visit 17 
(minus 7 days)) and there are no other later protocol-scheduled visits indicating the subject was 
exposed longer in the study.  Review the Protocol’s Schedule of Study Assessments to determine 
the number of weeks (and calculate the expected date) from the prior visit that the Termination 
or ET visit is expected.  The Termination or ET visit must not be any more than 7 days earlier 
than expected date for XX Week Completer Cohort, as protocol visit windows are ±7 days; if the 
ET or Termination visit date is too early, the subject did not complete enough exposure to be 
included in XX Week Completer Cohort. 
Subjects in the completer cohort may have their data further presented by smaller time periods 
within the duration of the completer cohort as presented in Section 3.2.1.6.  When a subject 
qualifies for a particular completer cohort, the subject has data for the entire completer cohort; 
this means that the subject has data for the smaller time periods within the completer cohort. 
3.2.1.6 
Time Period 
Some time period labels are used for completer cohort tables as well as non-completer cohort 
tables.  When the tables present time periods within a completer cohort, the subject, by 
definition, has data for the entire time period whereas for the non-completer cohort tables, the 
subject may not have data for the entire time period. 
The time periods for the Treatment Period seizure analysis are “0 to 22 Weeks”, “>22 to 46 
Weeks”, “>46 to 94 Weeks”, “>94 to 142 Weeks”, “>142 to 190 Weeks”, “>190 to 238 Weeks”, 
“0 to 46 Weeks”, “0 to 46 Weeks (> 22 Weeks)”, “0 to 94 Weeks”, “0 to 94 Weeks (> 46 
Weeks)”, “0 to 142 Weeks”, “0 to 142 Weeks (>94 Weeks)”,  “0 to 190 Weeks”,  “0 to 238 
Weeks” and entire “Treatment Period”. Additional time periods will be added based on the visit 
schedule as subjects progress through the study.  All tables displaying Time Period should show 
all time periods. 
The time periods for the Treatment Period include all data in the time window of the time period 
of interest including termination, early termination and end of taper visit data, taking into 
account the 7 day visit window. A calculation will be needed using dates to determine what time 
period the termination, early termination and end of taper visit data fit into for each subject, 
adjusting for the 7 day visit window. While completer cohorts and their time periods involve 
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subjects having data for the entire cohort or time period, when it comes to non-completer cohort 
tables, subjects may not have data for the whole Treatment period or time period within the 
Treatment period. 
For example, for non-completer cohort tables, “0 to 46 Weeks” contains all data from all subjects 
in 0-46 weeks, where Week 46 is Visit 8, if present; if a subject discontinues the study at Visit 4, 
the subject is still summarized in “0 to 46 Weeks”. “0 to 46 Weeks (>22 Weeks)” contains all 
data for all subjects who have data through at least Visit 5 (Week 22).  If a subject only has data 
up to Week 14 (Visit 4), the subject will appear in “0 to 46 Weeks” but not in “0 to 46 Weeks 
(>22 Weeks)”. 
3.2.1.7 
Visit Algorithm 
In determining the date of visits, which is specifically helpful in determining whether patients are 
members of completer cohorts, the in-clinic date of the visit will be used instead of visit dates 
from SDTM.SV (the Study Visits SDTM dataset which contain in-clinic and non-clinic visit 
dates).  In-clinic visit dates, firstly from SDTM.VS (Vital Signs), will be used as the date of 
protocol-specified visits.  If a visit is missing in SDTM.VS, then the in-clinic visit date from 
SDTM.DA (Drug Accountability) will be used as the date of the protocol-specified visit. If a 
visit is missing in SDTM.VS and SDTM.DA, then the in-clinic visit date from SDTM.LB 
(Laboratory Results) will be used as the data of the protocol-specified visit. 
3.2.2 
Protocol defined study periods 
The following study periods are defined in the protocol: 
 Treatment Period: at least a 2-year period following enrollment. The Treatment Period starts 
on the date of Visit 1 and continues until the date of the ET Visit or Termination Visit. 
 Taper Period: up to 4-week period following the Treatment Period for subjects who 
discontinue from the study at any time.  The Taper Period starts the day after the Treatment 
Period ends and continues until the date of last dose of study medication or the End of Taper 
Visit.  
 Safety Follow-up Period: 30-day period following the Taper Period. The Safety Follow-up 
Period starts the day after the last dose of study medication or End of Taper Visit and 
continues until the Safety Follow-up telephone contact date. 
3.2.3 
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. 
3.2.4 
AEDs and benzodiazepines 
Antiepileptic drugs (AEDs) and benzodiazepines will be collected on the concomitant and prior 
medication case report form (CRF) for AEDs. New concomitant AEDs can be added at any time. 
Benzodiazepines are AEDs. The UCB study physician will review a listing of all medications 
and flag which ones are to be summarized as AEDs and benzodiazepines since AEDs may be 
entered on the wrong medication case report form.  
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Concomitant AEDs at SP0982 entry, concomitant benzodiazepine use at SP0982 entry, and 
Lifetime AEDs and Benzodiazepines for the rollover subjects are already calculated and carried 
forward into EP0012.  
For EP0012 direct enrollers, concomitant AEDs at study entry are defined as AEDs where the 
start date is on or before 28 days prior to EP0012 Visit 1 and the medication was still ongoing on 
the date of Visit 1. The concomitant AEDs for the rollover and direct enroller subjects will be 
presented as Concomitant AEDs at the start of study medication dosing. 
Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days 
prior to EP0012 (direct enrollers) Visit 1; ongoing AEDs are not counted as a lifetime AED. The 
lifetime AEDs for direct enrollers and rollover subjects will be presented as Lifetime AEDs and 
Benzodiazepines prior to start of study medication dosing  
Concomitant benzodiazepine use at EP0012 entry is the use of any benzodiazepine at EP0012 
Visit 1. The concomitant benzodiazepine use for direct enrollers and rollover subjects will be 
presented as Concomitant benzodiazepine use at the start of study medication dosing. 
Stable use of benzodiazepines is allowed as concomitant AEDs. Intermittent use of 
benzodiazepines is allowed as rescue medication for epilepsy indications with a maximum of 1 
dose per week. Benzodiazepines used as rescue medication will be flagged with “RESCUE” in 
the indication field on the CRF. Rescue AEDs will also be identified programmatically as any 
AED with an epilepsy or seizure related indication taken for 1 or 2 days, at any frequency.  
If a subject is unable to take study medication, commercial lacosamide can be taken instead in 
order to fill the gaps in exposure.  In this instance, the commercial lacosamide usage is 
considered a substitute for study medication in determining whether a subject has > 3 day LCM 
gap and counting PGTCS occurring in such a gap; no exposure records will be created to add 
commercial lacosamide to study medication exposure. The start and end date of commercial 
LCM usage will be calculated and stored in ADSL for use in PGTCS analyses.  
The preferred term reported on the concomitant medication CRF is lacosamide. 
3.2.4.1 
Phenytoin use 
The following preferred terms will be grouped as “Phenytoin”: phenytoin, phenytoin sodium, 
ethotoin, fosphenytoin, fosphenytoin sodium, and zentronal. 
3.2.4.2 
Valproate use 
The following preferred terms will be grouped as “Valproate”: valproic acid, valproate 
semisodium, valproate sodium, valproate magnesium, ergenyl chrono, and valproate. 
3.2.4.3 
Phenobarbital use 
The following preferred terms will be grouped as “Phenobarbital”: phenobarbital, phenobarbital 
sodium, methylphenobarbital, and primidone. 
3.3 
Definition of Baseline values 
The baseline data for rollover subjects in EP0012 will not be recalculated. For subjects who are 
direct enrollers, some baseline variables may be calculated in SP0982 but these calculations need 
to be reassessed as detailed below. 
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For PGTCS data, the Combined Baseline Period is defined as the combined 12-week Historical 
and 4-week Prospective Baseline Periods from the SP0982 study. The Combined Baseline Period 
starts 84 days prior to Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 
study. This means that for subjects who directly enrolled into EP0012 (were not randomized in 
SP0982), the baseline PGTCS (before first dose in EP0012) data from SP0982 is combined with 
any reported baseline seizure information from EP0012 to recalculate the subject’s baseline 
variables such as PGTCS frequency. 
Data from Combined Baseline is used for analyses involving PGTCS since the CRF was specific 
in asking for PGTCS counts.  Other seizure type data recorded in Historical Baseline are deemed 
less reliable.  For seizure calculations involving Absence, Myoclonic, Generalized (seizure 
type=II) and All seizure types (seizure types = I, II and III), Prospective Baseline data is used; 
that means for generalized and all seizure type calculations specifically, PGTCS data in 
Prospective Baseline will only be used (not the Combined Baseline data) along with the other 
seizure types. 
For absence, myoclonic, generalized and all seizure data, the Prospective Baseline Period is 
defined as the 4-week Prospective Baseline Period from the SP0982 study. This Period starts the 
date of Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 study. This 
means that for the subjects who directly enrolled into EP0012 (were not randomized in SP0982), 
the baseline absence, myoclonic, generalized or all (respectively) seizure data from SP0982’s 
Prospective Baseline period is combined with any reported baseline absence, myoclonic, 
generalized or all (respectively) seizure information in the daily seizure diary from EP0012 
(reported before first dose in EP0012) to recalculate the subject’s baseline variables such as days 
with absence, myoclonic, generalized or all seizures per 28 days. 
In order to determine emergence of new seizure type, the Combined Baseline Period as well as 
any seizures reported prior to first dose for direct enrollers in EP0012 will be used. 
For all other data, Baseline values are defined as follows; 
 For direct enrollers from SP0982, data collected at Visit 1 prior to the first dose of study 
medication 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 data not collected at Visit 1 but 
still prior to the first dose of study medication, the last data collected in SP0982 will be used 
as Baseline values, if available.  
 For rollover subjects from SP0982, the last non-missing value prior to the first dose of study 
medication in the SP0982 study will be used as the Baseline value.  
For quantitative ECG assessments, if repeat measurements pre-first dose, then the average value 
is used as the Baseline value. 
For direct enrollers, data that is used as the Baseline will be labelled as such.  In general, change 
from baseline for these subjects will be calculated from Visit 2 onward, if the subject has a 
calculated baseline. 
For rollover subjects, change from baseline for these subjects will be calculated from Visit 1 
onward, if the subject has a baseline calculation from SP0982. 
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3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for identifying 
important protocol deviations and the classification of important protocol deviations will be 
defined in the Specification of Protocol Deviation (SPD) document. 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. 
In general, protocol deviations will be considered according to the following general categories: 
 Inclusion criteria 
 Exclusion criteria 
 Withdrawal criteria 
 LCM dosing regimen 
 Prohibited concomitant medications 
 Procedural non-compliance 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. A list of subjects with important protocol deviations will be agreed upon during 
the quarterly IPD meetings and will be documented in the IPD meeting minutes. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (covid-19) will be documented. Important protocol deviations related to COVID-19 
will be included in the important protocol deviations.  
3.5 
Analysis sets 
Efficacy variables will be summarized using the FAS and safety variables will be summarized 
using the Safety Set (SS). 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have a signed Informed Consent/Assent 
form.  Subjects completing SP0982 Safety Follow-up in EP0012 are contained in this analysis 
population because no study medication is administered to them.  
3.5.2 
Safety Set 
The Safety Set (SS) is a subset of the ES and consists of all subjects who received at least 1 dose 
of LCM during EP0012. All safety analyses will be performed on the SS. 
3.5.3 
Full Analysis Set 
The FAS is a subset of the SS and consists of all subjects with seizure diary data for at least 1 
day during EP0012. PGTCS-related analyses will be performed on the FAS. 
3.6 
Treatment assignment and treatment groups 
All subjects, except those enrolled to complete Safety-Follow-up in EP0012, will receive LCM.   
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At Visit 1, rollover subjects will start on a dose of LCM as follows; 
 10mg/kg/day for pediatric subjects weighing <30kg,  
 8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg,  
 400mg/day (200mg twice a day (bid)) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg.   
Subjects who are direct enrollers into EP0012 will start at Visit 1 on a dose of LCM as follows; 
 2mg/kg/day for pediatric subjects weighing <50kg,  
 100mg/day (50mg bid) for adult subjects (≥18 years of age) or pediatric subjects weighing 
≥50kg.  
Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability 
and seizure reduction as detailed in the protocol. 
All summaries will be presented with an overall all subjects treatment group. 
3.7 
Center pooling strategy 
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. 
3.8 
Coding dictionaries 
Medical history and AEs 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).  Medical procedures will not be coded.  All coding will be 
completed prior to database lock. 
3.9 
Changes to protocol-defined analyses 
There are no changes to analyses specified in the protocol however there are additional variables 
defined in the SAP which are detailed in Section 2.2.2.4 that will be analyzed. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
The analyses will not include any covariates.  
4.2 
Handling of dropouts or missing data 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who are rollovers from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data expected and not reported for V1 in EP0012. 
• 
for subjects who are direct enrollers in EP0012, baseline data will be used from EP0012 V1 
or any unscheduled visit (if prior to first EP0012 dose) or the latest data from the screening and 
baseline visits in SP0982 can be used (also if prior to first EP0012 dose). 
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4.2.1 
Missing seizure diary days 
For evaluations based on seizure diary data, imputation for missing data will not be performed.  
This means, for example, for an analysis for an interim data cut or for the final analysis, only 
seizure data for completed visits can be used in the analyses (i.e. study participants should not be 
assumed to have zero seizures between the time of the last-known visit and the interim cutoff; 
the subject will appear as having missing seizure information). The calculation of average 28-day 
seizure frequency or days with seizure per 28 days accounts for missing data by only evaluating 
days for which the data are available. Additionally for PGTC seizure calculations, PGTCS are 
not counted during gaps when LCM is not taken > 3 consecutive days. 
4.2.1.1 
Week 94 visit – seizure data 
At Week 94, subjects switch from using daily seizure diaries (where every date is entered) to 
using a seizure log (where only non-zero seizures are logged by date).  For subjects who 
continue past Week 94 in the study, if the date of the Week 94 visit is not logged on the daily 
seizure diary with a non-zero seizure count and it does not appear on the seizure log with a non-
zero count, then it can be assumed that 0 seizures occurred on that date. 
4.2.2 
Incomplete dates for first epilepsy diagnosis 
Month and year of the first epilepsy diagnosis are collected on the SP0982 CRF. To calculate the 
time since first epilepsy diagnosis at Screening, a complete date will be imputed as following: 
 If the month and year are available, the diagnosis date is imputed as the later of the following 
dates: the first day of the month or the subject’s birthdate (imputing 1st for the day if only 
month and year are collected). 
 If only a year is available, the later of the following dates will be imputed: January 1st of the 
year or the subject’s birthdate (imputing 1st for the day if only month and year are collected). 
 If both the month and year are missing then 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.   
Imputation of Partial Start Dates 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollovers is not the same as the month and year of the start date, 
then use the 1st of the month. 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollovers is the same as the month and year of the start, then use the 
date of first dose for direct enrollers or first visit for rollover subjects. 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is not the same as the year of the start date, then use January 1 of the year of 
the start date. 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is the same as the year of the start date, then use the date of first dose for 
direct enrollers or first visit for rollover subjects. 
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 If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose for direct enrollers or first visit for rollover subjects, then use the date of first 
dose for direct enrollers or first visit for rollover subjects. 
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 use December 31 of that year. 
 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. 
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 for direct 
enrollers or first visit for rollover subjects is not the same as the month and year of onset, 
then use the 1st of the month 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollover subjects is the same as the month and year of onset, then 
use the date of first dose for direct enrollers or first visit for rollover subjects 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is not the same as the year of onset, then use January 1 of the year of onset 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is the same as the year of onset, then use the date of first dose direct 
enrollers or first visit for rollover subjects 
 If the AE onset date is completely unknown, then use the date of first dose for direct enrollers 
or first visit for rollover subjects 
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 use December 31 of that year 
 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: 
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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 to 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 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 
No formal interim analysis is planned for this study. Interim data from EP0012 may be 
summarized to support a regulatory submission, regular safety signal detection monitoring, 
publications, and annual reports to regulatory agencies. For any interim data summaries, all 
available data as of the time of the clinical cut-off date will be included. Subjects ongoing at the 
time of an interim data summary will be assumed to be treated up to and including the date of the 
clinical data cut-off. No Data Monitoring Committee is planned.  
4.4 
Multicenter studies 
Refer to Section 3.7. 
4.5 
Multiple comparisons/multiplicity 
No adjustments for multiplicity are required as all analyses are descriptive only. 
4.6 
Use of an efficacy subset of subjects 
No efficacy subsets are defined for statistical analyses. 
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4.7 
Active-control studies intended to show equivalence 
Not applicable for this study. 
4.8 
Examination of subgroups 
Disposition will be presented by age at baseline in SP0982 subgroup for the SS and FAS. 
Exposure will be presented by age at baseline in SP0982 and region subgroups for the SS. 
Overall treatment emergent adverse events (TEAE) incidence will be presented by age at 
baseline in SP0982 subgroup for the SS.  
The subgroups to be examined include: 
 Age at Baseline in SP0982 (≥ 4 to <12 years of age, ≥12 to <18 years of age, 18 to <65, ≥65) 
 Development (in EP0012) (≥ 4 to <18 years of age, ≥18) 
 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. 
The following scales are assessed by specific age subgroupings. The following age subgroupings 
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). 
Selected disposition and safety analyses will be presented by the age at enrollment into EP0012 
for the purpose of addressing requirements set in Article 46 of the European Pediatric Regulation 
(see Section 11.5  for further details). 
4.9 
Data handling method of textual results in laboratory data 
For laboratory data analysis, any textual data above the upper LOQ (eg. “>n.nnn”) will be set to 
the upper LOQ and used when determining the maximum. 
The original value will be displayed in subject data listings. 
4.10 
Use of a safety subset of subjects 
For absence seizure analyses, the population analyzed will be further restricted to the subset of 
subjects  
 who reported a seizure classification history of absence seizures in either SP0982 or 
EP0012, or 
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 who reported absence seizures during Combined Baseline Period, the Treatment Period 
or Transition Period of SP0982 or  
 who reported absence seizures at any time prior to Safety Follow-up in EP0012.   
These subjects are hereby referred to as the “Absence subpopulation” because this subgroup only 
contain subjects who have had or who are having absence seizures. 
For myoclonic seizure analyses, the population analyzed will be further restricted to the subset of 
subjects  
 who reported a seizure classification history of myoclonic seizures in either SP0982 or 
EP0012, or 
 who reported myoclonic seizures during Combined Baseline period, the Treatment Period 
or Transition Period of SP0982 or  
 who reported myoclonic seizures at any time prior to Safety Follow-up in EP0012.   
These subjects are hereby referred to as the “Myoclonic subpopulation” because this subgroup 
only contain subjects who have had or who are having myoclonic seizures. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The study eligibility criteria and those subjects who did not meet it will be listed for the ES. All 
disposition data for the ES will be presented in subject data listings.  
The number of subjects in the SS and FAS 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 number and percentage of subjects in the ES, SS and FAS will be presented by age at 
Baseline in SP0982 as well as for all subjects. 
The overall number and percentage of subjects who completed and discontinued from the study 
will be presented for the SS and FAS by age at baseline in SP0982 as well as all subjects 
including number and percentages for each reason for discontinuation. The completion of the 
study is defined as the completion of the Termination Visit. Discontinuation is defined as the 
completion of the ET Visit. The number and percentage of subjects who switch to commercial 
Vimpat use will be presented. The study termination information will be presented in the subject 
data listings.To assess what happens with subjects during the first 94 weeks of the study, the 
number and percentage of subjects who completed this time period, completed the study before 
94 weeks and discontinued during this time period will be presented for the SS and FAS by age 
at baseline in SP0982 as well as all subjects including number and percentages for each reason 
for discontinuation during this time period. 
The number and percentages of subjects impacted by COVID-19 will be presented for each visit, 
overall and by impact category, for all subjects in the SS.  These data will be presented in subject 
data listings. 
A by-subject listing will be presented to show all visit dates and the associated relative day. 
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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 prior to database lock will 
be summarized overall for the SS. 
All important protocol deviations for subjects in the SS will be listed by site, subject number, and 
protocol deviation category. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
6.1.1 
Derivation of demographics variables 
6.1.1.1 
Body mass index 
BMI will be calculated using the following formula: 


2
2
(cm)
height 
(kg)
weight 
*
10000
)
(kg/m
 
BMI

 
 
6.1.2 
Analysis of demographics variables 
Baseline demographics will be summarized for the SS and include gender, race, ethnicity, age, 
age category, height (cm), weight (kg) and BMI (kg/m2); age is calculated in the SDTM as age at 
enrollment into EP0012 and that variable should be used for defining age category. Race and 
ethnicity will be from the SP0982 study but all other demographic variables will be from 
EP0012. 
Demographics will be listed for all subjects enrolled. 
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 is calculated as follows: 
the date of informed consent from SP0982 – the date of first epilepsy diagnosis from SP0982 / 
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 from 
SP0982 and the date of birth from EP0012. Imputation for partial dates of first epilepsy diagnosis 
and date of birth are described in Section 4.2.2 .  
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6.2.2 
Analysis of other Baseline characteristics 
For direct enrollers in EP0012, the baseline characteristic variables can represent a combination 
of baseline data stored in SP0982 as well as EP0012; the subjects continuing from SP0982 are 
included but their baseline data is from SP0982 only.   
Subjects randomized in SP0982 will appear in summaries below denoted as being from “SP0982 
entry”. All subjects enrolled in EP0012 will appear in rows that have no reference to SP0982 and 
the rows denoted as being from “EP0012 entry” or “EP0012”. 
The following Baseline characteristics will be presented: 
 Time since first diagnosis at date of consent  – Time since first diagnosis calculated for all 
EP0012 subjects; this data is stored in SP0982 
 Age at diagnosis of the disease – age at diagnosis calculated for all EP0012 subjects; this data 
is stored in SP0982ILAE Seizure classification history  – see below 
 Classification of epileptic syndrome  – see below 
 Lifetime AEDs and Benzodiazepines (EP0012) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of all EP0012 subjects 
 Combined Baseline PGTCS frequency per 28 days (as continuous data) – baseline PGTCS 
seizure frequency from CRF of all EP0012 subjects; SP0982 IRT data is not used in EP0012. 
 Combined Baseline PGTCS frequency categories (≤2, >2 per 28 days)  – baseline PGTCS 
seizure frequency categorized from CRF of all EP0012 subjects 
 Concomitant AEDs at EP0012 entry (0, 1, 2, 3, 4) – categorical representation of 
concomitant AEDs of all EP0012 subjects 
 Concomitant benzodiazepine use at EP0012 entry (yes, no) – Yes/No to concomitant Benzo 
use of all EP0012 subjects 
 LCM study drug status  - continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982 or other) 
 SP0982 exit status  - Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation 
 EP0012 entry status – Direct enroller, rollover. 
ILAE Seizure Classification History (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information. 
Classification of Epileptic Syndromes (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized. SP0982 information will be summarized if EP0012 
contains no updated information.  
All Baseline characteristics will be presented in data listings. All reproductive potential and birth 
control information will be presented in data listings. 
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6.3 
Subgroups 
All subgroups detailed in Section 4.8 will be summarized in a table for the SS and FAS.  Other 
subgroups that will be summarized using SP0982 baseline information are: 
 Baseline age in SP0982 (4 to <12 years, 12 to < 18 years, 18 to < 65 years, ≥65 years) 
 Age for PedsQL (4 years, 5 to 7 years, 8 to 12 years, 13 to <18 years) 
 Age for Achenbach CBCL (4 to 5 years, 6 to 18 years) 
 Age for BRIEF-P/BRIEF (4 years, 5 to 18 years). 
Subgroup information will also be listed. 
6.4 
Medical history and concomitant diseases 
Previous and ongoing medical history conditions, initially reported in SP0982 and potentially 
updated for EP0012, will be summarized by system organ class (SOC) and preferred term (PT) 
for the subjects in the SS. For medical history events, meaning they are not ongoing, if the same 
coded condition is reported in both SP0982 and EP0012, only the EP0012 condition will be 
summarized; if the coded conditions are differently reported in SP0982 and EP0012, then both 
sets of conditions will be summarized. If no new conditions are reported in EP0012, then only 
SP0982 conditions will be summarized. A similar summary will be provided for concomitant 
diseases for the SS. Concomitant diseases are medical history events which are ongoing at the 
SP0982 Screening Visit or reported as ongoing in EP0012 on the medical history CRF page. 
The SP0982 and EP0012 data for the subjects in EP0012, 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 
Prior and concomitant medications 
Medications with a start date before the first dose of study medication for direct enrollers 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 taken by rollover subjects 
which are ongoing and concomitant in SP0982 will be considered concomitant in EP0012. 
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. Prior AEDs, benzodiazepines and other medications are not summarized 
for the EP0012 subjects. 
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. 
Concomitant AEDs and benzodiazepines taken during the Treatment Period will be summarized 
by ATC level 4 and PT for the SS. 
Concomitant medications (excluding AEDs and benzodiazepines) will be summarized by ATC 
level 1 (anatomical main group) and ATC level 2 (therapeutic subgroup) for the SS. 
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All medications will be listed. 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 subject 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. 
The number of subjects entering EP0012 on or withdrawing to Monotherapy during the 
Treatment Period will be identified.  Entering EP0012 on Monotherapy means the subject has no 
documented AEDs that are ongoing at first visit. Withdrawing to monotherapy means the subject 
has documentation that all background AEDs [except LCM] were discontinued during Treatment 
Period. A record for the discontinued background AEDs must be present in the concomitant 
AED data and study medication must be taken continuously (>3 day gaps are not allowed). For 
the subjects who withdrew to monotherapy, the following results will be listed: 
 Exposure 
 Monotherapy Start Date 
 Monotherapy End Date 
 Duration (days) of monotherapy 
 Concomitant AEDs that were discontinued 
 Period when monotherapy starts (0 to Week 46 (V8), >Week 46 to Week 94 (V11), 
>Week 94 to Week 142 (V13), >Week 142 to Week 190 (V15), >Week 190 (V15)). 
The Monotherapy period and the cutoffs are determined for any visit falling within the Treatment 
Period, after using the definition of Treatment Period from Section 3.2.1.1 and the visit algorithm 
from Section 3.2.1.7.  The start of the Monotherapy period is mapped to the period based on the 
subject’s visit schedule as denoted in the period cutoffs (V8, V11, V13, and V15). 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Compliance cannot be derived. Compliance data for oral solution as collected on the eCRF will 
be included in subject data listings. Compliance for tablet form of study medication is not 
collected. 
8 
EFFICACY ANALYSES 
Analyses of the efficacy variables (i.e. PGTCS-related variables) will be performed using the 
FAS (unless otherwise stated) and will be descriptive in manner only. Efficacy analyses will be 
performed on data reported during the efficacy analysis Treatment Period. PGTCS analyses will 
be performed on PGTCS data captured while the subject is taking LCM (gaps 3 days or less are 
permitted); if a subject experiences an LCM gap > 3 days, any PGTCS reported during the gap 
will not be included in PGTCS summaries. 
Subject seizure information will be imputed with all dates between the start and end of the 
efficacy Treatment Period; for years 3-5, all days are assumed zero seizure days except those 
with Not Dones or non-zero counts. Seizure frequency and seizure days will be calculated over 
non-missing (or evaluable) seizure diary days. Diary days captured as Not Done will not be 
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considered in the calculation of seizure frequency or days with seizure (i.e. unevaluable).  
Because the evaluation of efficacy is not the primary objective of this study, and because in an 
uncontrolled study in a variable setting, which allows individualized optimization of study 
medication and concomitant AEDs, no summaries assessing the impact of missing seizure diary 
days are planned. 
Other seizure variables are considered safety variables and the analysis will be performed using 
the SS spanning the Treatment Period. 
All seizure diary data will be listed. A listing of subjects excluded from the FAS will also be 
produced. 
8.1 
Statistical analysis of the primary efficacy variable 
No primary efficacy variables are defined for this study. 
8.2 
Statistical analysis of the secondary efficacy variable 
8.2.1 
Derivation of secondary efficacy variable 
The secondary efficacy variable, calculated on the FAS, is percent change in PGTCS frequency 
per 28 days from Combined Baseline Period for PGTCS data where there is no >3 day LCM gap. 
In order to account for potential differences in the durations of the study periods for individuals, 
seizure data will be normalized to 28 days. For years 1-2, (up to and including Visit 11 date), 
seizure information is collected every day, but for years 3-5 only days with a seizure are 
recorded. Therefore, from the day after Visit 11 date (inclusive) to the date of the end of the 
efficacy Treatment Period (inclusive) will be assumed to be seizure free days  unless non-zero 
seizure counts are recorded or the seizure diaries are recorded as being Not Done for those days. 
For years 1-2, only days with a seizure record other than Not Done are considered evaluable.  
Also see Section 4.2.1. 
The 28-day PGTCS frequency (SF) will be calculated for the Combined Baseline Period and 
Treatment Periods as: 
SF =  
(# PGTCS in the relative period on days with evaluable seizure data/# days in relative period 
with evaluable seizure data)*28 
The percent change (PCH) in PGTCS frequency per 28 days from Combined Baseline Period 
(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. 
8.2.2 
Analysis of secondary efficacy variable 
The percent change in PGTCS frequency during the efficacy Treatment Period by Completer 
Cohort and Time Period will be summarized with descriptive statistics. All calculated completer 
cohorts and time periods will be summarized. 
The percent change in PGTCS frequency over the efficacy Treatment Period by Time Period will 
be summarized with descriptive statistics. All calculated time period results will be summarized. 
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All PGTCS frequency per 28 days data will be listed. 
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 the other efficacy variables (i.e. absence, 
myoclonic, generalized and/or all seizure related variables) will be performed using the SS and 
will be descriptive in manner only. These analyses will be performed on data reported during the 
Treatment Period. 
8.3.1 
Derivations of seizure related other efficacy variables 
8.3.1.1 
Variable: Days with seizures per 28 days 
All calculations involving days with seizures per 28 days will be on the SS. 
The number of days with absence seizures per 28 days (D) will be calculated separately for the 
Prospective Baseline Period and Treatment Periods as: 
D = ([# days with absence seizures in the relative period on days with evaluable seizure data] / [# 
days in relative period with evaluable seizure data])*28. 
For years 1-2 (up to and including Visit 11 date), only days with a seizure record other than Not 
Done are considered evaluable. However, for years 3-5, from the day after Visit 11 date 
(inclusive) to the date of the end of the efficacy Treatment period (inclusive) will be assumed to 
be seizure free days if no seizures are recorded or the seizure diaries are not recorded as being 
Not Done for those days.. 
Similarly, the number of days with myoclonic, generalized and all seizures per 28 days will be 
calculated. 
The percent change (PCH) in days with absence seizures per 28 days from Prospective Baseline 
Period (PB) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DPB) / DPB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DPB corresponds to the number of days with absence seizures per 28 days 
during the Prospective Baseline Period. If DPB is zero, then PCH will be missing and any such 
subjects will be excluded from the percent change summary. 
Similarly, the percent change in the number of days with myoclonic, generalized and all seizures 
per 28 days from the Prospective Baseline Period will be calculated. 
8.3.1.2 
Variables: Responder status – reduction in PGTCS frequency   
These variables are calculated on the FAS. A 50% responder is defined as a subject experiencing 
≥50% reduction in PGTCS frequency per 28 days from Combined Baseline Period to the period 
of interest. Response to treatment will be based on the percent change in PGTCS frequency, 
calculated as described in Section 8.2.1. A 75% responder is defined as a subject experiencing 
≥75% reduction in PGTCS frequency per 28 days from Combined Baseline Period to the period 
of interest. 
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8.3.1.3 
Variables: Responder status – reduction in days with absence 
seizures   
These variables are calculated on the Absence subpopulation of the SS. A 50% responder is 
defined as a subject experiencing ≥50% reduction in the number of days with absence seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
absence seizures during the Prospective Baseline Period. Response to treatment will be based on 
the percent change in the number of days with absence seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
reduction in the number of days with absence seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting absence seizures during the Prospective 
Baseline Period. 
8.3.1.4 
Variables: Responder status – reduction in days with myoclonic 
seizures   
These variables are calculated on the Myoclonic subpopulation of the SS. A 50% responder is 
defined as a subject experiencing ≥50% reduction in the number of days with myoclonic seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
myoclonic seizures during the Prospective Baseline Period. Response to treatment will be based 
on the percent change in the number of days with myoclonic seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
reduction in the number of days with myoclonic seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting myoclonic seizures during the 
Prospective Baseline Period. 
8.3.1.5 
Variables: Responder status – reduction in days with generalized 
seizures 
These variables are calculated on the SS. A 50% responder is defined as a subject experiencing 
≥50% reduction in the number of days with generalized (all type II) seizures per 28 days from 
Prospective Baseline Period to the period of interest, for the subjects reporting generalized 
seizures during the Prospective Baseline Period. Response to treatment will be based on the 
percent change in the number of days with generalized seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
reduction in the number of days with generalized seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting generalized seizures during the 
Prospective Baseline Period. 
8.3.1.6 
Variables: Responder status – reduction in days with all seizures 
These variables are calculated on the SS. A 50% responder is defined as a subject experiencing 
≥50% reduction in the number of days with all types of seizures per 28 days from Prospective 
Baseline Period to the period of interest, for the subjects reporting any seizures during the 
Prospective Baseline Period. Response to treatment will be based on the percent change in the 
number of days with all seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% 
responder is defined as a subject experiencing ≥75% reduction in the number of days with all 
seizures per 28 days from Prospective Baseline Period to the period of interest, for the subjects 
reporting any seizures during the Prospective Baseline Period. 
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8.3.1.7 
 Variables: Seizure-free status 
For all seizure types and all subjects, any missing or Not Done day in the seizure diary renders a 
subject to be not seizure-free on that day due to the lack of information. 
8.3.1.7.1 
Variable: PGTCS free status 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary and seizures were assessed (ie, “no seizures” is marked or number is entered as 
zero). Days in the seizure diary which are marked as “not done” on the CRF will not be counted 
as a seizure-free day from PGTCS.  A subject with a >3 day LCM gap within the period of 
interest will not be PGTCS-free for that period. 
PGTCS free status will be summarized by completer cohort on the FAS. A subject will have 
seizure-free status from PGTCS for a completer cohort if the subject are in the completer cohort 
and reported only “no PGTC seizures” for all days during the completer cohort period. If 1 or 
more PGTCS are reported in the completer cohort or if the seizure data is Not Done, then the 
subject has PGTCS free status=No for the completer cohort. 
8.3.1.7.2 
Variable: Generalized seizure-free status 
If missing data is reported, then the subject is not seizure-free from generalized seizures for those 
missing days.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
A subject will have seizure-free status from all generalized seizure types for the applicable time 
period if the subject completed the time period and reported zero seizure type=II seizures and no 
“Not Done” days during the time period for the SS. If 1 or more seizure type=II seizures are 
reported or if there are “Not Done” seizure diary days in the time period, then the subject has 
generalized seizure-free status=No for the time period. 
8.3.1.8 
Variables: All Seizure-free status 
A seizure-free day from all seizures will be defined as a day where no seizures (seizure type=I, II 
or III) were reported in the seizure diary. 
A subject will have seizure-free status from all seizure types for the applicable time period if the 
subject completed the time period and reported zero seizures, with no “Not Done” days, during 
the time period for the SS. If 1 or more seizures are reported or if there are “Not Done” seizure 
diary days in the time period, then the subject has all seizure-free status=No for the time period. 
8.3.1.9 
Variable: Worsening of PGTCS 
Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.2.1 on the FAS. PGTCS worsening is defined as a subject experiencing 
≥50% increase in PGTCS frequency per 28 days from Combined Baseline Period to the period of 
interest. 
8.3.1.10 
Variable: Worsening of days with absence seizures 
Response to treatment will be based on the percent change in days with absence seizures per 28 
days on the Absence subpopulation, as calculated in Section 8.3.1.1 on the SS. Worsening is 
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defined as a subject experiencing ≥50% increase in days with absence seizures per 28 days from 
Prospective Baseline Period to the period of interest, for the subjects reporting absence seizures 
during the Prospective Baseline Period. 
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% to the period of interest, for the 
subjects reporting absence seizures during the Prospective Baseline Period. 
8.3.1.11 
Variable: Worsening of days with myoclonic seizures 
Response to treatment will be based on the percent change in days with myoclonic seizures per 
28 days on the Myoclonic subpopulation, as calculated in Section 8.3.1.1 on the SS. Worsening 
is defined as a subject experiencing ≥50% increase in days with myoclonic seizures per 28 days 
from Prospective Baseline Period to the period of interest, for the subjects reporting myoclonic 
seizures during the Prospective Baseline 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% to the period of interest, for the 
subjects reporting myoclonic seizures during the Prospective Baseline Period. 
8.3.1.12 
Variable: Worsening of days with generalized seizures 
Response to treatment will be based on the percent change in days with generalized seizures per 
28 days, as calculated in Section 8.3.1.1 on the SS. Worsening is defined as a subject 
experiencing ≥50% increase in days with generalized seizures per 28 days from Prospective 
Baseline Period to the period of interest, for the subjects reporting generalized seizures during 
the Prospective Baseline Period. 
8.3.1.13 
Variable: Worsening of days with all seizures 
Response to treatment will be based on the percent change in days with all seizures per 28 days, 
as calculated in Section 8.3.1.1 on the SS. Worsening is defined as a subject experiencing ≥50% 
increase in days with all seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting all seizures during the Prospective Baseline Period. 
8.3.1.14 
Variable: PGTCS free intervals 
PGTCS-free intervals will only be assessed for periods not containing >3 day LCM gap. If the 
>3 day LCM gap appears in the period of interest, the subject is not PGTCS-free for the interval. 
For the FAS, subjects who are PGTCS-free from the date of Visit 1 will be identified as having a 
PGTCS-free interval from Visit 1.  The duration of the PGTCS-free interval will be calculated as 
date of last day of consecutive PGTCS freedom – date of Visit 1 +1. 
To determine the longest interval of PGTCS-freedom, all PGTCS-free intervals will be identified 
with a calculation of date of last day of PGTCS freedom for Nth interval – date of the first day of 
PGTCS freedom for the Nth interval + 1. The largest duration of all N intervals will be identified 
as the longest interval of PGTCS freedom. 
To determine the total duration of PGTCS-freedom, all N PGTCS-free intervals will be summed. 
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8.3.1.15 
Variable: Generalized seizure free intervals 
For the SS, subjects who are generalized seizure-free from the date of Visit 1 will be identified as 
having a generalized seizure-free interval from Visit 1.  The duration of the generalized seizure-
free interval will be calculated as date of last day of consecutive generalized seizure freedom – 
date of Visit 1 +1. 
To determine the longest interval of generalized seizure free, all generalized seizure-free 
intervals will be identified with a calculation of date of last day of consecutive generalized 
seizure freedom for Nth interval – date of the first day of generalized seizure freedom for the Nth 
interval + 1. The largest duration of all N intervals will be identified as the longest interval of 
generalized seizure freedom. 
To determine the total duration of generalized seizure freedom, all N generalized seizure-free 
intervals will be summed. 
8.3.1.16 
Variable: All seizure-free intervals 
For the SS, subjects who are all seizure-free from the date of Visit 1 will be identified as having 
an all seizure-free interval from Visit 1.  The duration of the all seizure-free interval will be 
calculated as date of last day of consecutive all seizure freedom – date of Visit 1 +1. 
To determine the longest interval of all seizure free, all seizure-free intervals will be identified 
with a calculation of date of last day of consecutive all seizure freedom for Nth interval – date of 
the first day of all seizure freedom for the Nth interval + 1. The largest duration of all N intervals 
will be identified as the longest interval of all seizure freedom. 
To determine the total duration of all seizure freedom, all N all seizure-free intervals will be 
summed. 
8.3.2 
Analysis of seizure-related other efficacy variables 
8.3.2.1 
Analysis: Days with seizures per 28 days 
The following data will be summarized on the SS by all periods calculated for the Time Period 
or Completer Cohort with descriptive statistics only: 
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Age at Baseline in SP0982 and Time Period  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
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 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Completer Cohort. 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Time Period 
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Completer Cohort. 
 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Time Period 
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period by 
Age at Baseline in SP0982 and Completer Cohort  
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period by 
Age at Baseline in SP0982 and Time Period 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort. 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
All seizure days data for absence, myoclonic, generalized and all seizures will be listed. 
Analyses of the absence seizure related variables will summarize the Absence subpopulation.  
Analyses of the myoclonic seizure related variables will summarize the Myoclonic 
subpopulation. 
8.3.2.2 
Analysis: Responder status – reduction in PGTCS frequency   
The number and percentage of ≥50% and ≥75% responders in PGTCS will be summarized on 
the FAS by Time Period and Treatment Period. 
8.3.2.3 
Analysis: Responder status – reduction in days with absence 
seizures   
The number and percentage of ≥50% and ≥75% responders will be summarized on the Absence 
subpopulation in the SS by Time Period and Treatment Period. 
8.3.2.4 
Analysis: Responder status – reduction in days with myoclonic 
seizures   
The number and percentage of ≥50% and ≥75% responders will be summarized on the 
Myoclonic subpopulation in the SS by Time Period and Treatment Period. 
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8.3.2.5 
Analysis: Responder status – reduction in days with generalized 
seizures   
The number and percentage of ≥50% and ≥75% responders will be summarized on the SS by 
Time Period and Treatment Period. 
8.3.2.6 
Analysis: Responder status – reduction in days with all seizures   
The number and percentage of ≥50% and ≥75% responders will be summarized on the SS by 
Time Period and Treatment Period. 
8.3.2.7 
Analysis: Seizure free status 
The number and percentage of subjects with seizure-free status (yes/no) will be summarized by 
Completer Cohort for the following types of seizures: 
 Seizure-free status (yes, no) for PGTCS on the FAS 
 Seizure-free status (yes, no) for all generalized seizure types on the SS 
 Seizure-free status (yes, no) for all seizure types on the SS. 
8.3.2.7.1 
Analysis: PGTCS free intervals 
The duration of the following PGTCS-free intervals during the Treatment Period on the FAS will 
be summarized with descriptive statistics: 
 1st PGTCS free interval from Visit 1 
 Longest PGTCS-free interval 
 All PGTCS-free intervals 
8.3.2.7.2 
Analysis: Generalized seizure free intervals 
The duration of the following generalized seizure-free intervals during the Treatment period on 
the SS will be summarized with descriptive statistics:  
 1st generalized seizure-free interval from Visit 1 
 Longest generalized seizure-free interval 
 All generalized seizure-free intervals  
8.3.2.7.3 
Analysis: All seizure free intervals 
The duration of the following all seizure-free intervals during the Treatment period on the SS 
will be summarized with descriptive statistics:  
 1st all seizure-free interval from Visit 1 
 Longest all seizure-free interval 
 All seizure-free intervals 
8.3.2.8 
Analysis: PGTCS worsening 
The number and percentage of subjects with seizure worsening, ≥50% increase in PGTCS 
frequency per 28 days, will be summarized on the FAS  by Time Period and Treatment Period.  
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8.3.2.9 
Analysis: Worsening in days with absence seizures 
The number and percentage of subjects with ≥50% increase in days with absence seizures per 28 
days will be summarized on the Absence subpopulation in the SS by Time Period and Treatment 
Period. 
8.3.2.10 
Analysis: Worsening in days with myoclonic seizures 
The number and percentage of subjects with ≥50% increase in days with myoclonic seizures per 
28 days will be summarized on the Myoclonic subpopulation in the SS by Time Period and 
Treatment Period. 
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 11.1 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 11.1. 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 11.1. 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. 
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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. 
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.  Only 
whole year ages are used. 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 PedsQL Measurement Model includes 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. For each subject, the same version that is used at 
Baseline should be used for 12 months and thereafter the appropriate age versions should be 
used. 
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. For 
versions intended for subjects >8 years of age, Physical Functioning refers to questions 
 
 Emotional Functioning refers to questions 
 Social 
Functioning refers to questions 
 School Functioning refers to 
questions 
 
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. 
Item transformed score = 100 – (item raw score x 25) 
Each PedsQL scale or dimension score is then calculated as the mean of the transformed item 
scores from items of the considered dimension. In the case of item-level missing data, these will 
be replaced by the average of non-missing item scores from the considered dimension, if at least 
50% of the items from that dimension are non-missing. 
The above algorithm will also be used to calculate the PedsQL total score (all items), the 
psychosocial health summary score (a combination of the emotional, social and school 
functioning items), and the physical health summary score (the physical functioning items) for 
each subject. These summary scores will be missing if any of the scale scores contributing to 
their calculation is missing. 
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 
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 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. 
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 
for the entire Treatment Period. 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 subjects with hospital stays but no calculable hospital 
duration, the duration of hospitalization 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 the changes 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 also be summarized for each visit and 
Last Visit. 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 
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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.  If a subject has a baseline calculated for 
the 2-4 year old PedsQL, due to the difference in questionnaires, this baseline should not be used 
for calculating change from baseline for the older aged questionnaires. For the 5-7 year old, 8-12 
year old and 13-18 year old questionnaires, if the baseline was calculated from an younger aged 
questionnaire (except the 2-4 year old questionnaire) as the subject ages from 8 through 18 years 
old, change from baseline can use the younger aged baseline. 
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.   
Observed values and the change from Baseline for the VAS score for general health state will 
also be summarized. 
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.  
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. 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
Not applicable. 
10 
SAFETY ANALYSES 
Any data that appears in the database (in UCB Findings, Clinical Events, or Findings About) and 
is not covered by the sections below, will be listed. 
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10.1 
Extent of exposure 
10.1.1 
Derivation of exposure variables 
Study medication treatment duration (days) will be calculated as follows for direct enrollers: 
(last study medication dose – first study medication dose) + 1 day.  
Study medication treatment duration (days) will be calculated as follows for rollover subjects: 
(last study medication dose – visit 1 date) + 1 day. Gaps in treatment or days with unknown 
dosing will not be subtracted from the duration of exposure. 
Subject-years of exposure is the total study medication treatment duration in days divided by 
365.25. 
The maximum daily LCM dose (mg/day and mg/kg/day) is defined as the highest total daily dose 
a subject received during the exposure period in the study. 
Lacosamide modal dose will be defined as the daily LCM dose the subject received for the 
longest duration during the Treatment Period. The modal dose calculation is based on the 
number of days a subject was on a given daily dose. Gaps in LCM dosing will be excluded from 
the determination of modal dose (ie, no imputation for days with missing dosing log information 
will be performed). If a subject was on two different LCM doses for the same duration of time 
(ie, a tie when calculating modal dose), the modal dose will be set to the lower of the doses. 
Duration at modal dose (days) will be defined as the date of the last dose of the modal dose 
minus the date of the first dose of the modal dose plus 1 day. 
Because some pediatric subjects take both LCM formulations, dosing will be presented for all 
subjects within the formulation taken; this will be presented as raw dosing and some pediatric 
subjects will be summarized in both formulations. For pediatric subjects who take both LCM 
formulations, their tablet dosing in mg/day will be converted to mg/kg/day by dividing the total 
daily dose in mg/day by the most recently available (relative to the dosing date) body weight in 
kg; this will be presented as converted dosing and the summaries of subject data by formulation 
will be mutually exclusive. Should a subject receive both oral solution and an oral tablet on the 
same day, then the individual tablet dose in mg is converted to mg/kg by dividing by the most 
recently available (relative to the dosing date) body weight, and then the individual dose of oral 
solution in mg/kg is added to the tablet dose in mg/kg to obtain a total daily dose in mg/kg/day. 
10.1.2 
Analysis of exposure variables 
The following LCM exposure summaries will be presented: 
 Number and percentage of subjects and subject-years of exposure by 6-month time intervals 
(ie, >0, ≥6, ≥12, ≥18, ≥24, ≥30, ≥36, ≥42, ≥48, ≥54, and ≥60 months) and modal dose 
 Number and percentage of subjects within each LCM treatment duration category by modal 
dose and maximum daily dose. LCM treatment duration categories (days) are as follows: 1 to 
84; 85 to 168; 169 to 336; 337 to 504; 505 to 672; 673 to 1008; 1009 to 1344; 1345 to 1680; 
>1680; any duration (total of durations). 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 
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<200mg/day, ≥200 to <400mg/day, ≥400 to <600mg/day, ≥600 to 800mg/day, and 
≥800mg/day. 
Summary statistics will be presented for treatment duration (days), maximum daily dose (mg/day 
and mg/kg/day) and modal dose (mg/day and mg/kg/day). This analysis will be repeated for each 
subgroup as detailed in Section 4.8. 
Pediatric subjects with oral solution (mg/kg/day) and tablet (mg/day) dosing will be summarized 
two ways: raw (mg/kg/day and mg/day) and converted (mg/kg/day only).   
Detailed LCM exposure, LCM dosing, and drug accountability will be presented in subject data 
listings. In addition, a listing of subject numbers with exposure ≥800mg/day for adults, 
>600mg/day for pediatrics taking tablets and >12mg/kg/day for pediatrics taking oral solution at 
least once during the Treatment Period will be provided.  
10.2 
Adverse events 
Adverse events will be coded using MedDRA, tabulated by SOC and PT 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 in EP0012 and within 30 days following the last study 
medication dose or 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. Adverse 
events which were ongoing and treatment-emergent in SP0982 will remain treatment-emergent 
in EP0012 for rollover subjects. 
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. 
Only TEAEs that start on or after the date of Visit 1 will be summarized in tables (ie, ongoing 
AEs from the SP0982 study will not be considered treatment emergent). AEs that start in SP0982 
but worsen in EP0012 will be recorded in the EP0012 database with a new start date. 
The following summaries will be presented: 
 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 by intensity  
 Incidence of TEAEs by relationship  
 Incidence of serious TEAEs  
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 Incidence of serious TEAEs – Subject numbers 
 Incidence of TEAEs leading to discontinuation of subjects  
 Incidence in TEAEs leading to discontinuation of subjects – Subject numbers 
 Incidence of other significant TEAEs (See Section 11.2 for details) 
 Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 11.2 for 
details) 
 Incidence of TEAEs by 100 person-months of exposure during the study 
 Incidence of TEAEs by 3-month exposure period of TEAE onset 
 Incidence of TEAEs of interest related to epilepsy by 3-month exposure period of TEAE 
onset 
The 100 person-months of exposure calculation takes the incidence of subjects with TEAEs, 
divides it by the total exposure in months and multiplies by 100.  Exposure in days is divided by 
28 days to get exposure in months. 
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 by 3-month periods of TEAE onset: petit mal epilepsy, myoclonus, and myoclonic 
epilepsy. 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2. Adverse events of unknown dosing are those with no known dose or known 
dosing and partial AE start or stop dates. TEAEs which were ongoing from SP0982 will be 
presented for the dose the subject was taking on the date of first dose in EP0012. 
 Incidence of TEAEs by dose at onset 
 Incidence of Serious TEAEs by dose at onset 
 Incidence of TEAEs leading to discontinuation of subjects by 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 of subjects on the SS 
 Subjects experiencing adverse events leading to death on the ES 
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 11.5. 
10.3 
Clinical laboratory evaluations 
Clinical laboratory parameters are used in analyses if more than two subjects per visit have a 
result.  All clinical laboratory data appear in listings.  
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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. 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 results are those that are observed 
post-Baseline during the Treatment Period but 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 TEMA values for hematology and chemistry values can be 
found in Section 11.3. The number and percentage of subjects with at least 1 TEMA value will 
be presented by scheduled visit, Last Visit, Early Termination 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. A subject can be 
summarized in multiple minimum and maximum post-Baseline categories if the subject appears 
in multiple age categories (eg, Pediatric subjects) for the markedly abnormal criteria.   
A table summarizing the number of subjects meeting the potential drug induced liver injury 
(PDILI) criteria during the Treatment Period will also be presented. The categories for PDILI 
that will be presented are: 
 ≥3xULN in ALT or AST and ≥2xULN total bilirubin and ≥2xULN of alkaline phosphatase 
 ≥3xULN in ALT or AST and ≥2xULN total bilirubin 
 ≥5xULN in ALT or AST 
 ≥8xULN in ALT or AST 
 ≥3xULN in ALT or AST and the presence of symptoms 
 ≥3-<5xULN and baseline ≥2xULN in ALT or AST and <2xULN total bilirubin and no 
presence of symptoms 
 ≥5xULN and baseline ≥2xULN in ALT or AST and <2xULN total bilirubin. 
The National Cancer Institute common toxicity criteria (NCI CTC) version 4 can be found in 
Section 11.4. 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 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 
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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.  
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 (pulse rate, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), weight (kg), height (cm) and BMI (kg/m2)), 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. 
Treatment emergent abnormalities of vital signs, the criteria that do not involve a comparison to 
baseline, are those that were observed during the Treatment Period at scheduled visits and not 
reporting the abnormality during the Baseline Period. The number and percentage of subjects 
with at least 1 TEMA value will be presented at each post-Baseline visit, Last Visit, Early 
Termination Visit and minimum and maximum post-Baseline values obtained during the 
Treatment Period. Percentages will be relative to the number of subjects with a value at each 
time point.  
A subject can be summarized in multiple minimum and maximum post-Baseline categories if the 
subject appears in multiple age categories (eg. Pediatric subjects) for the TEMA criteria.   
All TEMA results summarized will be presented in a subject number listing. The abnormal vital 
sign criteria are defined in Section 11.3.3. 
A subject data listing of all vital signs data will be created, indicating any abnormal values. 
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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 
 
QTcB =
QT
√RR, where RR = 60/heart rate. 
The Fridericia corrected QT (QTcF) will be calculated as 
 
QTcF =
QT
√RR
3
, where RR = 60/heart rate. 
10.4.2.2 
Analysis of ECG parameters 
For quantitative ECG measurements (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
statistics of the actual values and change from Baseline (where Baseline is from SP0982 as 
defined in Section 0) will be summarized  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 and average value are listed. A subject can be summarized in multiple minimum 
and maximum post-Baseline categories if the subject appears in multiple age categories (eg, 
Pediatric subjects) for the continuous data. 
The number and percentage of subjects who met each of the TEMA criteria specified in 
Section 11.3.4 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 visits and Last Visit, Early Termination Visit, minimum and 
maximum post-Baseline values obtained during the Treatment Period. A subject can be 
summarized in multiple minimum and maximum post-Baseline categories if the subject appears 
in multiple age categories (eg, Pediatric subjects) for the TEMA criteria. 
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. 
The number and percentage of subjects with QT interval values classified as <450ms, 450 to 
<480ms, 480 to <500ms and ≥500ms and an increase from Baseline of <30ms, 30 to <60ms and 
≥60ms will be summarized for uncorrected QT, QTcB, and QTcF by visit. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
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10.4.3 
Physical examination 
A listing of abnormal physical examination findings will be provided. 
10.4.4 
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 1 or who 
will enter puberty during the course of the study). 
A shift table will be produced showing the change in Tanner stage (1 to 5) from Baseline to Last 
Visit during the first 2 years of the Treatment Period, by sex, for each of the 3-items. A shift 
table will also be produced for subjects enrolled > 2 years, showing the change in Tanner stage 
(1 to 5) from Baseline to Last Visit during the Treatment Period, by sex, for each of the 3-items. 
A listing of Tanner stage assessments will be provided. 
10.4.5 
Neurological examination 
Summaries of shift from Baseline to Last Visit will be provided by major neurological category 
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. 
10.4.6 
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 where questions 4 or 5 was answered ‘Yes’ will 
be provided since this is a study withdrawal criteria. No summaries of the C-SSRS data are 
planned. 
10.4.7 
Achenbach Child Behavior Checklist 
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. The Achenbach CBCL consists of the 
CBCL/1½-5 for children 4 years to 5 years and 11 months of age, and the CBCL/6-18 for 
children ≥6 years to <17 years of age. The version of the Achenbach CBCL appropriate to each 
subject’s age should be administered with the following exception: for subjects who completed 
the CBCL/1½-5 at the Baseline assessment of the previous study and turn 6 years of age within 1 
year after the Baseline assessment of the primary study, the CBCL/1½-5 should be completed for 
1 year after the Baseline assessment of the primary study, and subsequently the CBCL/6-18 
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should be completed. The Achenbach CBCL will only be administered in countries where a 
validated translated version is available. For each version of the CBCL, subjects must have at 
least 1 year of data before transitioning to the next age range. 
10.4.7.1 
Derivation of Achenbach variables 
The CBCL/1½-5 will be grouped according to syndrome scales in Table 1 and the CBCL/6-18 
will be grouped according to empirically based syndrome scales in Table 2. 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 1 
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 
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 2 
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 
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Syndrome Scale 
Questions 
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, raw 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 sex. Tables mapping each raw score 
to the appropriate T-score are provided in the CBCL Professional Manual and will be reproduced 
programmatically. 
10.4.7.2 
Analysis of Achenbach variables 
Only the syndrome scales presented in Tables 1 and 2 will be analyzed. Raw scores and change 
from Baseline for each CBCL/1 ½ -5 syndrome (aggressive behavior, anxious/depressed, 
attention problems, emotionally reactive, other problems, sleep problems, somatic complaints, 
and withdrawn) will be summarized for each visit, and Last Visit.  
Raw scores 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. If a subject has a baseline calculated for the CBCL/1 ½ -5 syndrome, that baseline 
should not be used for calculating change from baseline for the CBCL/6-18 syndrome. 
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 
problems, somatic complaints, and withdrawn) will be summarized for each visit, and Last Visit. 
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. 
Subject data listings of the data for the Achenbach CBCL will be provided containing the 
calculated T-scores, raw scores and change from Baseline. The means of the calculated T-score 
will be plotted by visit. 
10.4.8 
BRIEF-P and BRIEF assessment 
The BRIEF-P and BRIEF are validated tools that will be used for the evaluation of subjects ≥4 
years to <5 years of age, and ≥5 years of age, respectively. The BRIEF-P or BRIEF appropriate 
for each subject’s age should be completed, with the following exception: For subjects who 
completed the BRIEF-P at the Baseline assessment of the previous study and turn 5 years of age 
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within 1 year after the Baseline assessment of the primary study, the BRIEF-P should be 
completed for 1 year after the Baseline assessment of the primary study, and subsequently the 
BRIEF should be completed. The BRIEF-P and BRIEF will be used only in countries where a 
translated scale is available. For each developmentally appropriate version of the BRIEF subjects 
must have at least 1 year of data before transitioning to the next age range.  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. 
10.4.8.1 
BRIEF-P scores 
The BRIEF-P form comprises of 63 questions which can be answered as 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 3. 
Table 3 
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 sex. 
Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P 
Professional Manual and will be reproduced programmatically. 
Calculated T-score values and change from Baseline for the three index scores (Inhibitory self-
control, flexibility and emergent metacognition), the 5 individual component scores and GEC for 
the BRIEF-P questionnaire will be summarized at each visit, and Last Visit. 
All BRIEF-P assessment data will be listed including calculated T-scores, raw scores and 
changes from Baseline. The means of the BRIEF-P assessment data will be plotted by visit. 
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10.4.8.2 
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 4.  
Table 4 
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 
Behavioral Regulation Index (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, 28, 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 
Metacognition Index (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. 
T-score values and change from Baseline for the two indexed scores (BRI and MI), the GEC and 
the 8 individual component scores for the BRIEF questionnaire will be summarized at each visit, 
and Last Visit. If a subject has a baseline calculated for the BRIEF-P, that baseline should not be 
used for calculating change from baseline for the BRIEF. 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and sex. Tables that map each raw score to the appropriate T-
score are provided in the BRIEF Professional Manual and will be reproduced programmatically. 
All BRIEF assessment data will be listed including all scales/index scores (raw and T-scores, 
calculated and change from baseline). The means of the BRIEF assessment data will be plotted. 
10.4.9 
Safety Seizure Information 
All analyses will use the relevant data in the SS.  The analyses regarding Absence seizure 
information will be generated on the Absence subpopulation. The analyses regarding the 
Myoclonic seizure information will be generated on the Myoclonic subpopulation. 
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10.4.9.1 
New Seizure Type or Worsening Over Time 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period with absence or myoclonic, respectively, indicated by the 
Seizure History Classification, but not experienced in the Combined Baseline Period, as recorded 
in the diary, will be summarized overall and by LCM study drug status by 1-month period of 
seizure onset. 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period but not experienced in Combined Baseline Period or in 
seizure classification history, as recorded in the diary, will be summarized overall and by LCM 
study drug status by 1-month period of seizure onset. 
The number and percentage of subjects with new absence or myoclonic seizures in the Treatment 
Period, with absence or myoclonic, respectively, indicated by the Seizure History Classification 
but not experienced in the Combined Baseline Period as recorded in the diary in subjects with a 
history of absence or myoclonic seizures, respectively, or subjects with ≥50% increase in days 
with absence or myoclonic seizures, respectively, per 28 days as compared to Prospective 
Baseline Period (for those subjects with absence or myoclonic seizure data, respectively, 
reported in the Prospective Baseline Period in SP0982), will be summarized overall and by LCM 
study drug status by 1 month period of seizure onset. 
The number and percentage of subjects with ≥50% increase in days in absence or myoclonic 
seizures as compared to Prospective Baseline Period (for those subjects with absence or 
myoclonic seizure data, respectively, reported in the Prospective Baseline Period in SP0982) will 
be summarized by 1-month period of seizure onset.  
10.4.9.2 
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 8.3.1.1. 
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 (for those subjects with absence 
seizure data reported in the Prospective Baseline Period in SP0982) will be presented. 
10.4.9.3 
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 8.3.1.1. 
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 (for those subjects with 
myoclonic seizure data reported in the Prospective Baseline Period in SP0982) will be presented. 
11 
APPENDICES 
11.1 
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 
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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. 
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 = _____ 
Energy/Fatigue 
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      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 =        _____ 
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          ––            _____ 
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                                                                                                              TOTAL :     _____        ÷ 5 = _____ 
 
 
 
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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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11.2 
Appendix 2: Adverse Events 
11.2.1 
List of other significant AEs 
Table 5  
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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MedDRA Preferred Term 
Ventricular flutter 
Ventricular tachyarrhythmia 
Implantable defibrillator insertion 
Cardiac arrest 
Brugada syndrome 
Defect conduction intraventricular 
Electrocardiogram QT prolonged 
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 
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MedDRA Preferred Term 
Decreased appetite 
Diet refusal 
Hypophagia 
Food aversion 
Abnormal behaviour 
  *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’. 
11.2.2 
List of AEs for Potentially Drug Induced Liver Injury (PDILI) 
Table 6  
AEs for PDILI 
MedDRA Preferred Term for PDILI 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
Hyperbilirubinaemia 
Icterus index increased 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Ocular icterus 
Acute hepatic failure 
Asterixis 
Coma hepatic 
Cryptogenic cirrhosis 
Drug-induced liver injury 
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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 
Hepatitis toxic 
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Blood bilirubin abnormal 
Blood bilirubin increased 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
 
 
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11.3 
Appendix 3: Markedly abnormal values 
11.3.1 
Hematology 
Table 7  
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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11.3.2 
Chemistry 
Table 8  
Chemistry - Markedly Abnormal Values 
Parameter 
Age 
Range 
Unit 
(conventional) 
Abnormality 
Criteria 
(conventional) 
Unit 
(standard) 
Abnormality 
Criteria 
(standard) 
AST (SGOT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
ALT (SGPT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
Alkaline 
Phosphatase 
4y - <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 
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Parameter 
Age 
Range 
Unit 
(conventional) 
Abnormality 
Criteria 
(conventional) 
Unit 
(standard) 
Abnormality 
Criteria 
(standard) 
Creatinine 
Clearance* 
All 
mL/min 
<50 
mL/s 
<0.835 
Bicarbonate 
>1m - 
<17y 
mEq/L 
<15 
>38 
mmol/L 
<15 
>38 
≥17y 
<18 
>38 
<18 
>38 
Calcium 
1y - <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 
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Parameter 
Age 
Range 
Unit 
(conventional) 
Abnormality 
Criteria 
(conventional) 
Unit 
(standard) 
Abnormality 
Criteria 
(standard) 
Globulin 
≥1y 
g/dL 
<1.2 
>5.3 
g/L 
<12 
>53 
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. 
 
11.3.3 
Vital signs 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below: 
Table 9  
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  
 >100 a 
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 
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Parameter 
Age Range 
Abnormality Criteria 
<90 a  
>140 a 
 >160 a 
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)ba ≥7% change from Baseline (an 
increase or a decrease)a 
Abbreviations: m=month, y=year. 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/ 
 
 
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11.3.4 
ECG 
Abnormality criteria to be applied in the assessment of ECG parameter values are given below: 
Table 10  
ECGs Abnormality Criteria 
Parameter 
Age 
Abnormality Criteria 
QT interval (ms) 
1m-<12y 
>500 
>12y 
>500 or ≥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, >480 a, >500 or ≥60 increase from Baseline 
QTc(B) (ms) 
3y-<12y 
>450, or >15% increase from Baseline 
>12y- <17y 
>450, or >15% increase from Baseline 
≥17y 
>450, >480 a, >500 or ≥60 increase from Baseline 
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=months; 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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11.4 
Appendix 4: NCI CTC 
Table 11  
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 
<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) 
<800 -500/mm3 
<0.8 – 0.5x10e9/L (C) 
<500 - 200/mm3 
<0.5 – 0.2x10e9/L (C) 
<200mm3 
<0.2x10e9/L (C) 
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Medical Term 
Lab 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
<LLN-0.8G/L (S) 
<0.8 – 0.5G /L (S) 
<0.5 – 0.2G/L (S) 
<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) 
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) 
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Medical Term 
Lab 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
>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 
>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) 
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Medical Term 
Lab 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
 
 
Creatinine 
increased 
Creatinine 
>ULN - 1.5x ULN 
>1.5 - 3.0x ULN 
 
 >3.0 - 6.0 x ULN  
>6.0 x ULN 
C=Conventional units, LLN=lower limit of normal; S=Standard units, ULN=upper limit of normal.  
The cutoffs are according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: 28 May 2009 (v4.03: 14 June 2010). 
* In terms of the laboratory cut-offs, the criterion is the same as the preceding grade. 
** Fasting status will be ignored when programming this criteria. 
Note: Additional significant digits added to the mmol/L units (as published in Version 4.0) to be consistent with the umol/L units (UCB standard). 
 
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11.5 
Appendix 5: Tables required for Article 41 (EudraCT) 
Discontinuation due to AEs by Development 
11.6 
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. 
 
 
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12 
AMENDMENT TO THE STATISTICAL ANALYSIS PLAN 
12.1 
Amendment 1 
12.1.1 
Rationale for the amendment 
The SAP was amended to reflect changes adopted in SP0982 Protocol Amendment 5 and 
EP0012 Protocol Amendment 2. Here is a list of major changes: 
 Minor editorial corrections were made such as changing the reference of “PGTCS seizure” to 
“PGTCS” 
 The timing of completer cohort was changed from 6, 12 and 24 months to be in line with 
EP0012 visits at weeks 22, 46, and 94. 
 Adding a 75% responder in addition to the 50% responder for PGTCS and days with absence 
and myoclonic seizures. 
 Adding worsening in PGTCS and days with absence and myoclonic variables and analyses. 
 Updating the new absence and myoclonic seizure emergence analysis 
 Adding figures for QOLIE-31-P, PedsQL, EQ-5d-3L, BRIEF-P, BRIEF, Achenbach 
variables 
 Clarifying the analyses for hematology, clinical chemistry and ECGs 
 Adding and clarifying a few AE analyses 
 Updating the list of Other Significant AEs 
 Adding the list of AEs for potentially drug induced liver injury 
 Updating the ECG markedly abnormal criteria 
 Removing analyses intended to summarize study results for Years 1-2 and Years 3-5. 
12.1.2 
Modification and changes 
12.1.2.1 
Specific changes 
The information below was revised from: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
 
 
Has been changed to: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
 
 
2.3, Study Design and Conduct, the following text was added as the 3rd paragraph: 
For SP0982 subjects consented under Protocol Amendment 5, after the 125th event is confirmed, 
two classes of subjects will be allowed to enroll in EP0012.  Subjects who are being screened 
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will be allowed to directly enroll into EP0012, thus their screening and baseline data will be 
captured in SP0982 but their treatment information will be captured in EP0012; baseline 
information from SP0982 will be used for these subjects in EP0012.  For subjects who are 
concluding their LCM treatment and tapering in SP0982, these participants will be consented and 
complete their Safety Follow-Up (thus not receiving any LCM) in EP0012; the data captured in 
EP0012 will not be transferred to SP0982. 
2.4 Determination of Sample Size, the paragraph was revised from: 
The sample size of this open-label extension study will be determined by the parent SP0982 
study, where approximately 200 subjects are planned to be randomized.  SP0982 is an 
event-driven study. Up to 250 subjects may be enrolled to meet the required number of events.   
Baseline failures from SP0982 will also be eligible for EP0012, which may increase the sample 
size. 
Has been changed to: 
The sample size of this open-label extension study will be determined by the parent SP0982 
study.  SP0982 is an event-driven study. Up to 250 subjects may be enrolled to meet the required 
number of events.   Baseline failures from SP0982, subjects in screening at the end of SP0982 
and SP0982 subjects completing Safety follow-up in EP0012 will also be eligible for EP0012, 
which may increase the sample size. 
Section 3.1, General presentation of summaries and analyses, the following text was added to the 
end of the 2nd paragraph: 
for some parameters, Q1 and Q3 may also be displayed 
Section 3.1, the following sentence was changed from: 
 Minimum and maximum will have the same number of decimal places as the original value. 
Was changed to: 
 Minimum, Q1, Q3 and maximum will have the same number of decimal places as the 
original value. 
Section 3.2.1.1, Analysis periods, the 2nd bullet was modified from: 
 Post-Treatment Period: The Post-Treatment Period is defined as the treatment free 
observational phase after the Treatment Period. It starts on the day after the end date of the 
Treatment Period and ends on the date of the final visit or date of last contact with the 
subject, whichever is later.  
Was changed to: 
 Post-Treatment Period: The Post-Treatment Period is defined as the treatment free 
observational phase after the Treatment Period, for the subjects who take LCM in EP0012. It 
starts on the day after the end date of the Treatment Period and ends on the date of the final 
visit or date of last contact with the subject, whichever is later. For the subjects from SP0982 
who are completing their Safety Follow-up in EP0012, their entire time in EP0012 will be 
deemed to be in the Post-Treatment Period due to the subjects not taking LCM in EP0012.   
Section 3.2.1.4, Month, the following text was added: 
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A month is defined as 28 days. 
Section 3.2.1.5, Completer Cohort, the section was revised from: 
A completer cohort will be defined as the subset of subjects in the Full Analysis Set (FAS) that 
were enrolled and treated with LCM for a specified duration of time. For example, a 6 month 
completer cohort consists of subjects enrolled and treated with LCM for at least 6 months where 
a month is defined as 28 days. 
Subjects will be classified as belonging to one or more of the following completer cohorts for the 
purpose of subgroup analyses: 
 6 months 
 12 months 
 24 months 
 >24 months. 
Has been changed to: 
A completer cohort will be defined as the subset of subjects in the Full Analysis Set (FAS) that 
were enrolled, treated with LCM for a specified duration of time, and have efficacy data 
available for the duration of the cohort. For example, a 22-week completer cohort consists of 
subjects from the FAS, treated with LCM for at least 22 weeks and have efficacy data through at 
least 22 weeks of exposure. 
Subjects will be classified as belonging to one or more of the following completer cohorts for the 
purpose of subgroup analyses: 
 22 weeks 
 46 weeks 
 94 weeks. 
Section 3.2.3, Seizure cluster, was modified from: 
If a seizure cluster is reported, it will be assigned to the most dominant International League 
Against Epilepsy (ILAE) seizure type and the frequency will be set to 2 times the number of 
clusters reported. 
Was changed 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 3.3, Definition of Baseline values, the 2nd paragraph has been revised from: 
For absence and myoclonic seizure data, the Prospective Baseline Period is defined as the 4-
week Prospective Baseline Period from the SP0982 study. This Period starts the date of Visit 1 
of the SP0982 study and ends the day before Visit 2 of the SP0982 study. 
Has been changed to: 
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For absence and myoclonic seizure data in order to determine Responder Status and worsening, 
the Prospective Baseline Period is defined as the 4-week Prospective Baseline Period from the 
SP0982 study. This Period starts the date of Visit 1 of the SP0982 study and ends the day before 
Visit 2 of the SP0982 study. In order to determine emergence of new seizure type, the Combined 
Baseline Period will be used. 
Section 3.4, Protocol deviations, the section was changed from: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on either the primary efficacy or key safety outcomes for an individual 
subject. The criteria for identifying important protocol deviations and the classification of 
important protocol deviations will be defined within the project Data Cleaning Plan. To the 
extent feasible, rules for identifying protocol deviations will be defined without review of the 
data and without consideration of the frequency of occurrence of such deviations. Whenever 
possible, criteria for identifying important protocol deviations will be implemented 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock to confirm exclusion from analysis sets. 
Was changed to: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for identifying 
important protocol deviations and the classification of important protocol deviations will be 
defined within the project Data Cleaning Plan. To the extent feasible, rules for identifying 
protocol deviations will be defined without review of the data and without consideration of the 
frequency of occurrence of such deviations. Whenever possible, criteria for identifying important 
protocol deviations will be implemented algorithmically to ensure consistency in the 
classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. 
Section 4.2.1, Missing seizure diary days, this section has been revised from: 
For evaluations based on seizure diary data, imputation for missing data will not be performed. 
For the purpose of the derivation of 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. 
The calculation of average 28-day seizure frequency accounts for missing data in the first 2 years 
by only evaluating days for which data are available. A subject will only be considered seizure-
free for absence or myoclonic seizures in the first 2 years if the subject had <10% of days during 
the time period being analyzed reported as “not done”. For years 3-5, when subjects are only 
required to enter days when seizures occur, days not reported are assumed to be seizure free. 
Has been changed to: 
For evaluations based on seizure diary data, imputation for missing data will not be performed. 
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For the purpose of the derivation of PGTC seizure-free status, in the first 2 years, 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. For years 3-5, when subjects are only required to enter days when PGTCS 
occurred, days not reported are assumed to be PGTCS free; if seizure information is known to be 
missing, then the subject is not PGTCS free. The calculation of average 28-day PGTCS 
frequency accounts for missing data in the first 2 years by only evaluating days for which data 
are available. For years 3-5, the calculation of average 28-day PGTCS frequency uses the seizure 
information reported since “not done” information is no longer gathered; if there is a known non-
compliance in recording seizures and the unevaluable days can be identified, then the average 
28-day PGTCS frequency will use only evaluable days. 
A subject will only be considered seizure-free for absence or myoclonic seizures in the first 2 
years if the subject had <10% of days during the time period being analyzed reported as “not 
done”. For years 3-5, when subjects are only required to enter days when absence or myoclonic 
seizures occur, days not reported are assumed to be seizure free. 
Section 4.3, Interim analyses and data monitoring, this section was revised from: 
No formal interim analysis is planned for this study. Interim data from EP0012 may be 
summarized to support a regulatory submission, regular safety signal detection monitoring, 
publications, and annual reports to regulatory agencies. For any interim data summaries, all 
available data as of the time of the database snapshot will be included. Subjects ongoing at the 
time of an interim data summary will be assumed to be treated up until the date of the clinical 
data cut-off. No Data Monitoring Committee is planned.  
Has been changed to: 
No formal interim analysis is planned for this study. Interim data from EP0012 may be 
summarized to support a regulatory submission, regular safety signal detection monitoring, 
publications, and annual reports to regulatory agencies. For any interim data summaries, all 
available data as of the time of the clinical cut-off date will be included. Subjects ongoing at the 
time of an interim data summary will be assumed to be treated up to and including the date of the 
clinical data cut-off. No Data Monitoring Committee is planned. 
Section 4.8, Examination of subgroups, the Region subgroup was revised from: 
 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. 
Separate subgroupings are used for the purpose of summarizing the following scales: 
Has been changed to: 
 Region 
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 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. 
The following scales are assessed by specific age subgroupings. The following age subgroupings 
are used for the purpose of summarizing the following scales: 
Section 6.2, Analysis of other Baseline Characteristics, the following was revised from: 
 SP0982 exit status (Baseline failure, 24-week completer, met exit criteria). 
Has been changed to: 
 LCM study drug status (continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982)) 
 SP0982 exit status (Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up). 
Section 6.4, Medical history and concomitant diseases, the first sentence was modified from: 
Previous and ongoing medical history conditions will be summarized by system organ class 
(SOC) and preferred term (PT) for the SS. 
Was changed to: 
Previous and ongoing medical history conditions, initially reported in SP0982 and potentially 
updated for EP0012, will be summarized by system organ class (SOC) and preferred term (PT) 
for the SS. 
Section 6.5, Prior and concomitant medications, the following sentence was added to the end of 
the first paragraph: 
Prior AEDs, benzodiazepines and other medications are not summarized for the EP0012 
subjects. 
Section 8.2.2, Analysis of secondary efficacy variable, this section was revised from: 
The percent change in PGTC seizure frequency during the Treatment Period by completer cohort 
will be summarized with descriptive statistics. The percent change in PGTC seizure frequency 
during the Treatment Period by completer cohort will also be summarized separately for subjects 
that are in the study for 1-2 years and subjects that are in the study for 3-5 years. 
All PGTC seizure frequency per 28 days data will be listed. 
Has been changed to: 
The percent change in PGTCS frequency during the Treatment Period by completer cohort will 
be summarized with descriptive statistics.  
All PGTCS frequency per 28 days data will be listed. 
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Section 8.3.1.2, Variables: Responder status – reduction in PGTCS frequency, this section was 
revised from: 
A responder is defined as a subject experiencing ≥50% reduction in PGTC seizure frequency per 
28 days from Combined Baseline to the period of interest. Response to treatment will be based 
on the percent change in seizure frequency, calculated as described in Section 8.2.1. 
Has been changed to: 
A 50% responder is defined as a subject experiencing ≥50% reduction in PGTCS frequency per 
28 days from Combined Baseline Period to the period of interest. Response to treatment will be 
based on the percent change in PGTCS frequency, calculated as described in Section 8.2.1. A 
75% responder is defined as a subject experiencing ≥75% reduction in PGTCS frequency per 28 
days from Combined Baseline Period to the period of interest. 
Section 8.3.1.3, Variables: Responder status – reduction in days with absence seizures, this 
section was revised from: 
A responder is defined as a subject experiencing ≥50% reduction in the number of days with 
absence seizures per 28 days from Prospective Baseline to the Treatment Period. Response to 
treatment will be based on the percent change in the number of days with absence seizures per 28 
days, calculated as described in Section 8.3.1.1. 
Has been changed to: 
A 50% responder is defined as a subject experiencing ≥50% reduction in the number of days 
with absence seizures per 28 days from Prospective Baseline Period to the period of interest, for 
the subjects reporting absence seizures during the Prospective Baseline Period from SP0982. 
Response to treatment will be based on the percent change in the number of days with absence 
seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% responder is defined as a 
subject experiencing ≥75% reduction in the number of days with absence seizures per 28 days 
from Prospective Baseline Period to the period of interest, for the subjects reporting absence 
seizures during the Prospective Baseline Period from SP0982. 
Section 8.3.1.4, Variables: Responder status – reduction in days with myoclonic seizures, this 
section was revised from: 
A responder is defined as a subject experiencing ≥50% reduction in the number of days with 
myoclonic seizures per 28 days from Prospective Baseline to the Treatment Period. Response to 
treatment will be based on the percent change in the number of days with myoclonic seizures per 
28 days, calculated as described in Section 8.3.1.1. 
Has been changed to: 
A 50% responder is defined as a subject experiencing ≥50% reduction in the number of days 
with myoclonic seizures per 28 days from Prospective Baseline Period to the period of interest, 
for the subjects reporting myoclonic seizures during the Prospective Baseline Period from 
SP0982. Response to treatment will be based on the percent change in the number of days with 
myoclonic seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% responder is 
defined as a subject experiencing ≥75% reduction in the number of days with myoclonic seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
myoclonic seizures during the Prospective Baseline Period from SP0982. 
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Section 8.3.1.5, Variables: Seizure-free status, this section was revised from: 
For years 1-2, the following definitions will be used: 
A PGTC seizure-free day will be defined as a day where no PGTC seizures were reported in 
the seizure diary and seizures were assessed (ie, “no seizures” is marked or number is entered as 
zero). Days in the seizure diary which are marked as “not done” on the CRF will be counted as a 
PGTC seizure free day. 
Seizure-free status will be determined for a particular time period. A subject will have PGTC 
seizure freedom (seizure free status=yes) for the time period if the subject completed the time 
period and reported “no seizures” or “not done” for all days during the time period.  
A generalized seizure-free day will be defined as a day where no generalized 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 not be counted as a generalized seizure free day. 
A subject will have seizure freedom (seizure free status=yes) for all generalized seizure types 
for the applicable time period if the subject completed the time period and reported zero 
generalized seizures for all days during the time period when the number of seizures was 
available, and had <10% of days during the time period with seizure data reported as “not done”. 
For years 3-5, the following definitions will be used: 
A PGTC seizure-free day will be defined as a day where no PGTC seizures were reported in 
the seizure diary. 
Seizure-free status will be determined for a particular time period. A subject will have PGTC 
seizure freedom (seizure free status=yes) for the time period if the subject completed the time 
period and no seizures were reported during the time period.  
A generalized seizure-free day will be defined as a day where no generalized seizures were 
reported in the seizure diary. 
A subject will have seizure freedom (seizure free status=yes) for all generalized seizure types 
for the applicable time period if the subject completed the time period and reported zero 
generalized seizures during the time period. 
Has been changed to: 
For years 1-2, the following definitions will be used: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in 
the seizure diary and seizures were assessed (ie, “no seizures” is marked or number is entered as 
zero). Days in the seizure diary which are marked as “not done” on the CRF will be counted as a 
seizure-free day from PGTCS. 
Seizure-free status will be determined for a particular time period. A subject will have 
seizure-free status from PGTCS for the time period if the subject completed the time period and 
reported “no PGTC seizures” or “not done” for all days during the time period.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary and seizures were assessed. Days in 
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the seizure diary which are marked as “not done” on the CRF will not be counted as a seizure 
free day. 
A subject will have seizure-free status from all generalized seizure types for the applicable 
time period if the subject completed the time period and reported zero generalized seizures for all 
days during the time period when the number of generalized seizures was available, and had 
<10% of days during the time period with seizure data reported as “not done”. 
For years 3-5, the following definitions will be used: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in 
the seizure diary. 
Seizure-free status from PGTCS will be determined for a particular time period. A subject 
will have seizure-free status from PGTCS for the time period if the subject completed the time 
period and no PGTCS were reported during the time period.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
A subject will have seizure-free status from all generalized seizure types for the applicable 
time period if the subject completed the time period and reported zero seizures during the time 
period. 
Section 8.3.1.6, Variable: Worsening of PGTCS, this section was added: 
Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.2.1. Seizure worsening is defined as a subject experiencing ≥50% increase 
in PGTCS frequency per 28 days from Combined Baseline Period to the period of interest. 
Section 8.3.1.7, Variable: Worsening of days with absence seizures, this section was added: 
Response to treatment will be based on the percent change in days with absence seizures, as 
calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% increase in 
days with absence seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting absence seizures during the Prospective Baseline Period from 
SP0982. 
Section 8.3.1.8, Variable: Worsening of days with myoclonic seizures, this section was added: 
Response to treatment will be based on the percent change in days with myoclonic seizures, as 
calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% increase in 
days with myoclonic seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting myoclonic seizures during the Prospective Baseline Period 
from SP0982. 
Section 8.3.2.2, Analysis: Responder status – reduction in PGTCS frequency, this was revised 
from: 
The number and percentage of responders will be summarized for the Treatment Period with 
descriptive statistics. 
Has been changed to: 
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The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Section 8.3.2.3, Analysis: Responder status – reduction in days with absence seizures, this was 
revised from: 
The number and percentage of responders will be summarized for the Treatment Period with 
descriptive statistics. 
Has been changed to: 
The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Section 8.3.2.4, Analysis: Responder status – reduction in days with myoclonic seizures, this was 
revised from: 
The number and percentage of responders will be summarized for the Treatment Period with 
descriptive statistics. 
Has been changed to: 
The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Section 8.3.2.5, Analysis: Seizure-free status, this was revised from: 
The number and percentage of subjects with seizure-free status (yes/no) will be summarized by 
completer cohort for the following types of seizures: 
 Seizure-free status (yes, no) for PGTC seizures  
 Seizure-free status (yes, no) for all generalized seizure types 
Has been changed to: 
The number and percentage of subjects with seizure-free status (yes/no) will be summarized by 
completer cohort and Treatment Period for the following types of seizures: 
 Seizure-free status (yes, no) for PGTCS  
 Seizure-free status (yes, no) for all generalized seizure types.  
Section 8.3.2.6, Analysis: PGTCS worsening, this section was added: 
The number and percentage of subjects with seizure worsening, ≥50% increase in PGTCS 
frequency per 28 days, will be summarized by completer cohort and Treatment Period. 
Section 8.3.2.7, Analysis: Worsening in days with absence seizures, this section was added: 
The number and percentage of subject with ≥50% increase in days with absence seizures per 28 
days will be summarized by completer cohort and Treatment Period. 
Section 8.3.2.8, Analysis: Worsening in days with myoclonic seizures, this section was added: 
The number and percentage of subjects with ≥50% increase in days with myoclonic seizures per 
28 days will be summarized by completer cohort and Treatment Period. 
Section 8.4.2.1, QOLIE-31-P variables, the following paragraph was inserted: 
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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 at the end of this 
section: 
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 at the end of this section: 
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 was added at the end of this 
section: 
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 bullet point was revised from: 
 Number and percentage of subjects within each LCM treatment duration category by modal 
dose and maximum daily dose. LCM treatment duration categories (days) are as follows: 1 to 
84; 85 to 168; 169 to 336; 337 to 504; 505 to 672; 673 to 1008; 1009 to 1344; 1345 to 1680; 
>1680; any duration (total of durations) 
Has been changed to: 
 Number and percentage of subjects within each LCM treatment duration category by modal 
dose and maximum daily dose. LCM treatment duration categories (days) are as follows: 1 to 
84; 85 to 168; 169 to 336; 337 to 504; 505 to 672; 673 to 1008; 1009 to 1344; 1345 to 1680; 
>1680; any duration (total of durations). 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 tables 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, has been revised from: 
Adverse events will be coded using MedDRA, and tabulated by SOC and PT 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 in EP0012 and within 30 days following the last study 
medication dose or 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 
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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. 
Only TEAEs that start on or after the date of Visit 1 will be summarized in tables i.e. ongoing 
AEs from the SP0982 study will not be considered treatment emergent. AEs that start in SP0982 
but worsen in EP0012 will be recorded in the EP0012 database with a new start date. 
The following summaries will be presented: 
 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 by intensity  
 Incidence of TEAEs by relationship  
 Incidence of serious TEAEs  
 Incidence of serious TEAEs– Subject numbers 
 Incidence of TEAEs leading to discontinuation  
 Incidence in TEAEs leading to discontinuation– Subject numbers 
 Incidence of other significant TEAEs (See Section 11.2 for details) 
 Incidence of TEAEs by 100 person-months of exposure during the study 
The following summaries will be presented by dose at onset (Unknown/Missed, >0 to 
<4mg/kg/day, ≥4 to <8mg/kg/day, ≥8 to <12mg/kg/day and ≥12mg/kg/day, >0 to <200mg/day, 
≥200 to <300mg/day, ≥300 to <400mg/day, and ≥400mg/day). Adverse events of unknown 
dosing are not summarized but those taken where LCM dose is 0mg/kg/day or 0mg/day are in 
the applicable column. Adverse events of unknown dosing are those with UNK as the dose or 
known dosing and partial AE start or stop dates. 
 Incidence of TEAEs by dose at onset 
 Incidence of Serious TEAEs by dose at onset 
 Incidence of TEAEs leading to discontinuation by 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 
A glossary of AEs will be presented showing the mapping of investigator terms to coded SOC 
and PTs. 
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A list of further AE tables required for EudraCT and clinicaltrials.gov is provided in 
Section 11.5. 
Has been changed to: 
Adverse events will be coded using MedDRA, and tabulated by SOC and PT 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 in EP0012 and within 30 days following the last study 
medication dose or 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. 
Only TEAEs that start on or after the date of Visit 1 will be summarized in tables (ie, ongoing 
AEs from the SP0982 study will not be considered treatment emergent). AEs that start in SP0982 
but worsen in EP0012 will be recorded in the EP0012 database with a new start date. 
The following summaries will be presented: 
 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 by intensity  
 Incidence of TEAEs by relationship  
 Incidence of serious TEAEs  
 Incidence of serious TEAEs – Subject numbers 
 Incidence of TEAEs leading to discontinuation  
 Incidence in TEAEs leading to discontinuation – Subject numbers 
 Incidence of other significant TEAEs (See Section 11.2 for details) 
 Incidence of TEAEs for potential drug-induced liver injury (PDILI) (See Section 11.2 for 
details) 
 Incidence of TEAEs by 100 person-months of exposure during the study 
 Incidence of TEAEs by 3-month exposure period of TEAE onset 
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 Incidence of TEAEs of interest related to epilepsy by 3-month exposure period of TEAE 
onset 
The 100 person-months of exposure calculation takes the incidence of subjects with TEAEs, 
divides it by the total exposure and multiplies by 100. 
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 by 3-month periods of TEAE onset: petit mal epilepsy, myoclonus, and myoclonic 
epilepsy. 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2 . Adverse events of unknown dosing are those with no known dose or known 
dosing and partial AE start or stop dates. 
 Incidence of TEAEs by dose at onset 
 Incidence of Serious TEAEs by dose at onset 
 Incidence of TEAEs leading to discontinuation by 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 11.5. 
Section 10.3, Clinical laboratory evaluations, this section has been revised from: 
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. 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. 
Markedly abnormal (MA) values indicate significant deviations from the expected range of age-
appropriate values. Marked laboratory abnormalities observed post-Baseline during the 
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Treatment Period but not present at Baseline are considered treatment emergent. Markedly 
abnormal 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 11.3. 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria will also be presented. 
The National Cancer Institute common toxicity criteria (NCI CTC) can be found in Section 11.4. 
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 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. 
Subject data listings of all laboratory data will also be presented.  
Any additional lab data will be listed, including positive pregnancy test results listed by subject. 
Has been changed to: 
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. 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 results are those that are observed 
post-Baseline during the Treatment Period but 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 TEMA values for hematology and chemistry values can be 
found in Section 11.3. The number and percentage of subjects with at least 1 TEMA value will 
be presented 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. 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria will also be presented. 
The National Cancer Institute common toxicity criteria (NCI CTC) can be found in Section 11.4. 
The number and percentage of subjects with treatment emergent laboratory abnormalities of NCI 
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CTC grade 2 or higher (hematology and clinical chemistry) will be summarized by 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.  
Any additional lab data will be listed, including positive pregnancy test results listed by subject. 
Section 10.4.1, Vital signs, the 2nd paragraph has been revised from: 
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high 
value, at each post-Baseline visit up to Visit 10, for which SBP, DBP and pulse rate 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. The abnormal vital sign criteria are defined in 
Section 11.3.3. 
Has been changed to: 
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high 
value, at each post-Baseline visit up to Visit 10, for which SBP, DBP and pulse rate 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 11.3.3. 
Section 10.4.2.2, Analysis of ECG parameters, this section has been revised 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 at enrollment 
groups. 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 with QT interval values classified as <450ms, 450 to 
<480ms, 480 to <500ms and ≥500ms and an increase from Baseline of <30ms, 30 to <60ms and 
≥60ms will be summarized for uncorrected QT, QTcB, and QTcF by visit. 
The number and percentage of subjects who met each of the criteria specified in Section 11.3.4 
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 interval. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
Has been changed to: 
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For quantitative ECG measurements (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
statistics of the actual values and change from Baseline (where Baseline is from SP0982 as 
defined in Section 0) will be summarized  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 11.3.4 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 visits 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. 
Detailed information on the quantitative and qualitative ECG findings will be presented in 
subject data listings. 
Section 10.4.7.2, Analysis of Achenbach variables, the following sentence was added to the end 
of this section: 
The means of the calculated T-score will be plotted by visit. 
Section 10.4.8.1, BRIEF-P scores, the following sentence was added to the end of this section: 
The means of the BRIEF-P assessment data will be plotted by visit. 
Section 10.4.8.2, BRIEF scores, the following sentence was added to the end of this section: 
The means of the BRIEF assessment data will be plotted. 
Section 10.4.9, Safety Seizure Information, this section changed from: 
10.4.9.1 New Seizure Type 
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. 
 
10.4.9.2 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 for the first 2 years of treatment, calculated as 
described in Section 8.3.1.1. 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 first 2 years of the Treatment Period compared to the Prospective Baseline 
will be presented. 
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10.4.9.3 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 for the first 2 years of treatment, calculated 
as described in Section 8.3.1.1. 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 first 2 years of the Treatment Period compared to the Prospective 
Baseline will be presented. 
Has been changed to: 
10.4.9.1 New Seizure Type or Worsening Over Time 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period with absence or myoclonic, respectively, indicated by the 
Seizure History Classification, but not experienced in the Combined Baseline Period, as recorded 
in the diary, will be summarized overall and by LCM study drug status by 1-month period of 
seizure onset. 
The number and percentage of subjects with new absence or myoclonic seizure types 
experienced in the Treatment Period but not experienced in Combined Baseline Period or in 
seizure classification history, as recorded in the diary, will be summarized overall and by LCM 
study drug status by 1-month period of seizure onset. 
The number and percentage of subjects with new absence or myoclonic seizures in the Treatment 
Period, with absence or myoclonic, respectively, indicated by the Seizure History Classification 
but not experienced in the Combined Baseline Period as recorded in the diary in subjects with a 
history of absence or myoclonic seizures, respectively, or subjects with ≥50% increase in days 
with absence or myoclonic seizures, respectively, per 28 days as compared to Prospective 
Baseline (for those subjects with absence or myoclonic seizure data, respectively, reported in the 
Prospective Baseline Period in SP0982), will be summarized overall and by LCM study drug 
status by 1 month period of seizure onset. 
The number and percentage of subjects with ≥50% increase in days in absence or myoclonic 
seizures as compared to Prospective Baseline Period (for those subjects with absence or 
myoclonic seizure data, respectively, reported in the Prospective Baseline Period in SP0982), 
will be summarized by 1-month period of seizure onset.  
10.4.9.2 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 8.3.1.1. 
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 (for those subjects with absence 
seizure data reported in the Prospective Baseline Period in SP0982) will be presented. 
10.4.9.3 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 8.3.1.1. 
The number and percentage of subjects experiencing an increase of up to 25%, >25% to 50%, 
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>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 (for those subjects with 
myoclonic seizure data reported in the Prospective Baseline Period in SP0982) will be presented. 
Section 11.2.1, List of other significant AEs, this table has been updated. 
Section 11.2.2, List of AEs for potentially drug induced liver injury, this table has been added. 
Section 11.3.4, ECG Abnormality Criteria, some of the criteria have been updated. 
Section 11.5, Appendix 5, the table titles have been updated in this section. 
Section 11.6, the section has been added. 
12.2 
Amendment 2 
12.2.1 
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. 
12.2.2 
Modification and changes 
 Analyses involving post-treatment vital sign and QTc measurements were added 
The following item was clarified:    
 Algorithm for identifying rescue medications 
The following items were added: 
 An analysis of subjects withdrawing from background AEDs to monotherapy with LCM 
 A new listing of rescue medications 
 New variable identifying Asian sites 
 
 
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12.2.2.1 
 Specific changes 
The information below was revised from: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
Has been revised to: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
 
Section 3.1, General presentation of summaries and analyses, the following text was added to the 
end of the section: 
Efficacy analyses will be performed on data reported during analysis treatment period. PGTCS 
analyses will be done on PGTCS data captured while the subject is taking LCM (gaps 3 days or 
less are permitted); if a subject experiences an LCM gap > 3 days, any PGTCS reported during 
the gap will not be included in PGTCS summaries. Safety analyses will be performed on data 
reported during the analysis treatment period. All data reported in the study will be listed in 
subject data listings. 
Section 3.2.1.5, Completer cohorts, the following sentence was modified from: 
A completer cohort will be defined as the subset of subjects in the Full Analysis Set (FAS) that 
were enrolled, treated with LCM for a specified duration of time, and have efficacy data 
available for the duration of the cohort. 
Was revised to: 
A completer cohort will be defined as the subset of subjects in the Full Analysis Set (FAS) that 
were enrolled, treated with LCM for the specified duration of time (allowing gaps of 3 days or 
less), and have efficacy data available for the duration of the cohort. 
Section 3.2.1.6, Time Period, the following section was added: 
The time periods for the Treatment Period seizure analysis are “0 to 22 Weeks”, “>22 to 46 
Weeks”, “>46 to 94 Weeks”, “>94 to 142 Weeks”, “>142 to 190 Weeks”, “>190 to 238 Weeks”, 
“0 to 46 Weeks”, “0 to 46 Weeks (> 22 Weeks)”, “0 to 94 Weeks”, “0 to 94 Weeks (> 46 
Weeks)”, “0 to 142 Weeks”, “0 to 142 Weeks (>94 Weeks)”,  “0 to 190 Weeks”, and “0 to 238 
Weeks”. Additional time periods will be added based on the visit schedule as subjects progress 
through the study. 
The time periods include all data in the time window of the time period of interest including 
early termination and end of taper visit data. A calculation may be needed using dates to 
determine what time period the early termination and end of taper visit data fit into for each 
subject. 
Section 3.2.4, the following text was changed from: 
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Antiepileptic drugs (AEDs) and benzodiazepines will be collected on the concomitant and prior 
medication case report form (CRF) for AEDs. New concomitant AEDs can be added at any time. 
Stable use of benzodiazepines is allowed as concomitant AEDs. Intermittent use of 
benzodiazepines is allowed as rescue medication for epilepsy indications with a maximum of 1 
dose per week. Benzodiazepines used as rescue medication will be flagged with “RESCUE” in 
the indication field on the CRF. Rescue benzodiazepines will also be identified programmatically 
as any benzodiazepines taken intermittently as 1 dose per week. 
Was revised to: 
Antiepileptic drugs (AEDs) and benzodiazepines will be collected on the concomitant and prior 
medication case report form (CRF) for AEDs. New concomitant AEDs can be added at any time. 
Stable use of benzodiazepines is allowed as concomitant AEDs. Intermittent use of 
benzodiazepines is allowed as rescue medication for epilepsy indications with a maximum of 1 
dose per week. Benzodiazepines used as rescue medication will be flagged with “RESCUE” in 
the indication field on the CRF. Rescue AEDs will also be identified programmatically as any 
AED with an epilepsy or seizure related indication taken intermittently as 1 dose per week. 
Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days 
prior to Visit 1. 
Section 4.2, Handling of dropouts or missing data, the following text was added to the beginning 
of the section: 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who transitioned from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data not reported for V1 in EP0012. 
• 
for subjects who are baseline failures or incomplete screen failures in SP0982 who enrolled 
in EP0012, baseline data will be used from EP0012 V1 (if prior to first EP0012 dose) or the 
latest data from the screening and baseline visits in SP0982 can be used (also if prior to first 
EP0012 dose). 
Section 4.2.1, Missing seizure diary days, the following text was changed from: 
A subject will only be considered seizure-free for absence or myoclonic seizures in the first 2 
years if the subject had <10% of days during the time period being analyzed reported as “not 
done”. For years 3-5, when subjects are only required to enter days when absence or myoclonic 
seizures occur, days not reported are assumed to be seizure free. 
Was revised to: 
For all seizure types, any missing day in the seizure diary during years 1-2 renders a subject to be 
not seizure-free due to the lack of information. 
Absence or myoclonic subjects will be considered for seizure-free evaluation from all 
generalized seizure types in years 1-2 for the applicable time period if the subject  had <10% of 
days during the time period with seizure data reported as “not done”. 
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For years 3-5, when subjects are only required to enter days when generalized seizures occur, a 
subject will be considered seizure-free for generalized seizures if the subject has no days 
reported with generalized seizures (seizure type=II). 
Section 4.9, Data Handling Method of Textual Results in Laboratory Data, the following section 
was added: 
For laboratory data analysis, any textual data above the upper LOQ (eg. “>n.nnn”) will be set to 
the upper LOQ and used when determining the maximum. 
The original value will be displayed in subject data listings. 
Section 6.2.2, Analysis of other Baseline characteristics, the following text was changed from: 
 SP0982 exit status (Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up). 
Was revised to: 
 SP0982 exit status (Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation). 
Section 6.5, Prior and concomitant medications, the following text was added to the end of the 
section: 
AEDs flagged as rescue medications will also be listed in subject data listings. 
The number of subjects withdrawing to Monotherapy during the Treatment Period will be 
summarized.  Withdrawing to monotherapy means the subject has documentation that all 
background AEDs [except LCM] were discontinued during Treatment Period) will be 
summarized. A record for the discontinued AED must be present in the concomitant AED data. 
Section 8. Efficacy Analyses, the following text was changed from: 
Analyses of the efficacy variables will be performed using the FAS and will be descriptive in 
manner only. 
All seizure diary data will be listed. A listing of subjects excluded from the FAS will also be 
produced. 
Was revised to: 
Analyses of the efficacy variables will be performed using the FAS (unless otherwise stated) and 
will be descriptive in manner only. Efficacy analyses will be performed on data reported during 
analysis treatment period. PGTCS analyses will be done on PGTCS data captured while the 
subject is taking LCM (gaps 3 days or less are permitted); if a subject experiences an LCM gap > 
3 days, any PGTCS reported during the gap will not be included in PGTCS summaries. 
All seizure diary data will be listed. A listing of subjects excluded from the FAS will also be 
produced. 
 Section 8.2.2 Analysis of secondary efficacy variable, the following text was changed from: 
The percent change in PGTCS frequency during the Treatment Period by completer cohort will 
be summarized with descriptive statistics.  
All PGTCS frequency per 28 days data will be listed. 
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Was revised to: 
The percent change in PGTCS frequency during the Treatment Period by Completer Cohort and 
Time Period will be summarized with descriptive statistics.  
The percent change in PGTCS frequency over the Treatment Period by Time Period will be 
summarized with descriptive statistics.  
All PGTCS frequency per 28 days data will be listed. 
Section 8.3, Analysis of seizure related other efficacy variables, the following text was added to 
the beginning of the section: 
All seizure data recorded during the treatment period will be summarized and listed for the 
seizure related other efficacy variables.  
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 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 treatment period. 
Section 8.3.1.5 Variables: Seizure-free status, the following text was added: 
For all seizure types, any missing day in the seizure diary during years 1-2 renders a subject to be 
not seizure-free due to the lack of information. 
Section 8.3.1.5 Variables: Seizure-free status, the following text was changed from: 
Seizure-free status will be determined for a particular time period. A subject will have seizure-
free status from PGTCS for the time period if the subject completed the time period and reported 
“no PGTC seizures” or “not done” for all days during the time period.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) 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 not be counted as a seizure 
free day. 
A subject will have seizure-free status from all generalized seizure types for the applicable 
time period if the subject completed the time period and reported zero generalized seizures for all 
days during the time period when the number of generalized seizures was available, and had 
<10% of days during the time period with seizure data reported as “not done”. 
For years 3-5, the following definitions will be used: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in 
the seizure diary. 
Seizure-free status from PGTCS will be determined for a particular time period. A subject 
will have seizure-free status from PGTCS for the time period if the subject completed the time 
period and no PGTCS were reported during the time period.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
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A subject will have seizure-free status from all generalized seizure types for the applicable 
time period if the subject completed the time period and reported zero seizures during the time 
period. 
Was revised to: 
PGTCS free status will be determined for a particular time period. A subject will have seizure-
free status from PGTCS for the time period if the subject completed the time period and reported 
only a combination of “no PGTC seizures” or “not done” for all days during the time period. If 1 
or more PGTCS are reported in the time period or if the seizure data is missing, then the subject 
does not have PGTCS free status=Yes for the time period. 
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary and seizures were assessed. An 
absence or myoclonic subject will be considered for seizure-free evaluation for generalized 
seizure-free status in years 1-2 for the applicable time period if the subject had <10% of days 
during the time period with seizure data reported as “not done”. If 1 or more seizure type=II 
seizures are reported in the time period, if there is missing data or if there are 10% or more “Not 
done” days for an absence and/or myoclonic seizure subject, then the subject does not have 
generalized seizure-free status=Yes for the time period. 
For years 3-5, the following definitions will be used: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary. 
Seizure-free status from PGTCS will be determined for a particular time period. A subject will 
have seizure-free status from PGTCS for the time period if the subject completed the time period 
and no PGTCS were reported during the time period. If 1 or more PGTCS are reported in the 
time period, then the subject does not have PGTC seizure-free status=Yes for the time period. 
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
A subject will have seizure-free status from all generalized seizure types for the applicable time 
period if the subject completed the time period and reported zero seizure type=II seizures during 
the time period. If 1 or more seizure type=II seizures are reported in the time period, then the 
subject does not have generalized seizure-free status=Yes for the time period. 
Section 8.3.1.7 Variable: Worsening of days with absence seizures, the following text was 
changed from: 
Response to treatment will be based on the percent change in days with absence seizures, as 
calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% increase in 
days with absence seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting absence seizures during the Prospective Baseline Period from 
SP0982. 
Was revised to: 
Response to treatment will be based on the percent change in days with absence seizures per 28 
days, as calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% 
increase in days with absence seizures per 28 days from Prospective Baseline Period to the 
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period of interest, for the subjects reporting absence seizures during the Prospective Baseline 
Period from SP0982. 
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% to the period of interest, for the 
subjects reporting absence seizures during the Prospective Baseline Period from SP0982. 
Section 8.3.1.8 Variable: Worsening of days with myoclonic seizures, the following text was 
changed from: 
Response to treatment will be based on the percent change in days with myoclonic seizures, as 
calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% increase in 
days with myoclonic seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting myoclonic seizures during the Prospective Baseline Period 
from SP0982. 
Was revised to: 
Response to treatment will be based on the percent change in days with myoclonic seizures per 
28 days, as calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% 
increase in days with myoclonic seizures per 28 days from Prospective Baseline Period to the 
period of interest, for the subjects reporting myoclonic seizures during the Prospective Baseline 
Period from SP0982. 
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% to the period of interest, for the 
subjects reporting myoclonic seizures during the Prospective Baseline Period from SP0982. 
Section 8.3.2 Analysis of seizure-related other efficacy variables – throughout this section, it was 
clarified which analysis would be performed on the SS. 
Section 8.3.2.1 Analysis: Days with seizures per 28 days, the following text was changed from: 
The following data will be summarized with descriptive statistics only: 
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Baseline age in SP0982 and completer cohort  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and completer cohort  
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and completer cohort  
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Baseline age in SP0982 and completer cohort. 
All seizure days data for absence and myoclonic seizures will be listed. 
Was revised to: 
The following data will be summarized with descriptive statistics only: 
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Baseline age in SP0982 and Completer Cohort  
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 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Baseline age in SP0982 and Time Period  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Completer Cohort  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Time Period 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Completer Cohort  
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Time Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Baseline age in SP0982 and Completer Cohort. 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Baseline age in SP0982 and Time Period 
All seizure days data for absence and myoclonic seizures will be listed. 
Section 8.3.2.2 Analysis: Responder status – reduction in PGTCS frequency, the following text 
was changed from: 
 The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Was revised to: 
The number and percentage of ≥50% and ≥75% responders will be summarized Time Period and 
Treatment Period. 
Section 8.3.2.3 Analysis: Responder status – reduction in days with absence seizures, the 
following text was changed from: 
The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Was revised to: 
The number and percentage of ≥50% and ≥75% responders will be summarized by Time Period 
and Treatment Period. 
Section 8.3.2.4 Analysis: Responder status – reduction in days with myoclonic seizures, the 
following text was changed from: 
The number and percentage of ≥50% and ≥75% responders will be summarized by completer 
cohort and Treatment Period. 
Was revised to: 
The number and percentage of ≥50% and ≥75% responders will be summarized by Time Period 
and Treatment Period. 
Section 8.3.2.6 Analysis: PGTCS worsening, the following text was changed from: 
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The number and percentage of subjects with seizure worsening, ≥50% increase in PGTCS 
frequency per 28 days, will be summarized by completer cohort and Treatment Period.  
Was revised to: 
The number and percentage of subjects with seizure worsening, ≥50% increase in PGTCS 
frequency per 28 days, will be summarized by Time Period and Treatment Period.  
Section 8.3.2.7 Analysis: Worsening in days with absence seizures, the following text was 
changed from: 
The number and percentage of subject with ≥50% increase in days with absence seizures per 28 
days will be summarized by completer cohort and Treatment Period. 
Was revised to: 
The number and percentage of subject with ≥50% increase in days with absence seizures per 28 
days will be summarized by Time Period and Treatment Period. 
Section 8.3.2.8 Analysis: Worsening in days with myoclonic seizures, the following text was 
changed from: 
The number and percentage of subjects with ≥50% increase in days with myoclonic seizures per 
28 days will be summarized by completer cohort and Treatment Period. 
Was revised to: 
The number and percentage of subject with ≥50% increase in days with myoclonic seizures per 
28 days will be summarized by Time Period and Treatment Period. 
Section 10.2 Adverse events, the following rest was changed from: 
The 100 person-months of exposure calculation takes the incidence of subjects with TEAEs, 
divides it by the total exposure and multiplies by 100. 
Was revised to: 
The 100 person-months of exposure calculation takes the incidence of subjects with TEAEs, 
divides it by the total exposure in months and multiplies by 100.  Exposure in days is divided by 
28 days to get exposure in months. 
Section 10.3 
Clinical laboratory evaluations, the following text was changed from: 
The definition of TEMA values for hematology and chemistry values can be found in 
Section 11.3. The number and percentage of subjects with at least 1 TEMA value will be 
presented 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. 
Was revised to: 
The definition of TEMA values for hematology and chemistry values can be found in 
Section 11.3. The number and percentage of subjects with at least 1 TEMA value will be 
presented by scheduled visit, Last Visit, Early Termination 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. A subject can be summarized 
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in multiple minimum and maximum post-Baseline categories if the subject appears in multiple 
age categories (eg, Pediatric subjects) for the markedly abnormal criteria. 
Section 10.4 
Vital signs, physical findings, and other observations related to safety, the 
following text was changed from: 
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high 
value, at each post-Baseline visit up to Visit 10, for which SBP, DBP and pulse rate 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 11.3.3. 
Was revised to: 
The number and percentage of subjects with at least 1 TEMA value will be presented at each 
post-Baseline visit, Last Visit, Early Termination Visit and minimum and maximum post-
Baseline values obtained during the Treatment Period. Percentages will be relative to the number 
of subjects with a value at each time point.  
A subject can be summarized in multiple minimum and maximum post-Baseline categories if the 
subject appears in multiple age categories (eg. Pediatric subjects) for the TEMA criteria.  
Section 10.4.2.2 Analysis of ECG parameters, the following text was changed from: 
The number and percentage of subjects who met each of the TEMA criteria specified in 
Section 11.3.4 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 visits 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. 
Was revised to: 
The number and percentage of subjects who met each of the TEMA criteria specified in Section 
11.3.4 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 visits and Last Visit, Early Termination Visit, minimum and 
maximum post-Baseline values obtained during the Treatment Period. A subject can be 
summarized in multiple minimum and maximum post-Baseline categories if the subject appears 
in multiple age categories (eg, Pediatric subjects) for the TEMA criteria. 
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. 
The number and percentage of subjects with QT interval values classified as <450ms, 450 to 
<480ms, 480 to <500ms and ≥500ms and an increase from Baseline of <30ms, 30 to <60ms and 
≥60ms will be summarized for uncorrected QT, QTcB, and QTcF by visit. 
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Section 10.4.8.2 
BRIEF scores, Table 4, question 28 was added to the list of items used for 
scoring of Plan/Organize individual component score 
Section 11.3.1 Hematology, the following table was changed from: 
Table 12  
Hematology Markedly Abnormal Values 
Parameter 
UNIT 
(conventional) 
abnormality 
Criteria 
(conventional 
unit) 
unit 
(standard) 
Abnormality 
Criteria (standard 
unit) 
Hematocrit 
% 
 
≤85% of LLN 
≥115% of ULN 
% 
≤85% of LLN 
≥115% of ULN 
Hemoglobin 
g/dL 
 
≤85% of LLN 
≥115% of ULN 
g/L 
≤85% of LLN 
≥115% of ULN 
WBC/Leukocytes 
109/L 
≤3.0 
≥16.0 
G/L 
≤3.0 
≥16.0 
Platelets 
109/L 
≤100 
≥600 
G/L 
≤100 
≥600 
RBC/ 
Erythrocytes 
1012/L 
<3.5 
T/L 
<3.5 
Abbreviations: LLN=lower limit of normal, ULN=upper limit of normal.  
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Was revised to: 
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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Section 11.3.2 Chemistry, the following table was changed from: 
Table 13  
Chemistry - Markedly Abnormal Values 
Parameter 
UNIT 
(conventional) 
Abnormality Criteria 
(conventional) 
Unit 
(standard) 
Abnormality 
Criteria 
(standard) 
AST (SGOT) 
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) 
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 
U/L 
≥3.0 x ULN 
U/L 
≥3.0 x ULN 
GGT 
U/L 
≥3.0 x ULN 
U/L 
≥3.0 x ULN 
Total Bilirubin 
mg/dL 
≥2.0 
umol/L 
≥34.208 
Total Protein 
g/dL 
<4.3 
>13.0 
g/L 
<43 
>130 
Albumin 
g/dL 
<2.6 
g/L 
<26 
BUN 
mg/dL 
≥40 
mmol/L 
≥14.28 
Creatinine 
mg/dL 
≥2.0 
umol/L 
≥176.8 
Creatinine 
Clearance* 
mL/min 
<50 
mL/s 
<0.835 
Bicarbonate 
mEq/L 
<18 
>38 
mmol/L 
<18 
>38 
Calcium 
mg/dL 
≤7.6 
≥11.0 
mmol/L 
≤1.9 
≥2.75 
Chloride 
mEq/L 
≤90 
≥112 
mmol/L 
≤90 
≥112 
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Parameter 
UNIT 
(conventional) 
Abnormality Criteria 
(conventional) 
Unit 
(standard) 
Abnormality 
Criteria 
(standard) 
Phosphorous 
mg/dL 
≤2.0 
≥6.0 
mmol/L 
≤0.646 
≥1.938 
Potassium 
mEq/L 
≤3.0 
≥6.0 
mmol/L 
≤3.0 
≥6.0 
Sodium 
mEq/L 
<127 
>151 
mmol/L 
<127 
>151 
Glucose 
mg/dL 
<50 
≥200 
mmol/L 
<2.775 
≥11.1 
Uric Acid 
mg/dL 
>9.5 
umol/L 
>565.06 
Abbreviations: ALT=alanine aminotransferase; AS =aspartate aminotransferase; BUN=blood urea nitrogen; 
GGT=gamma-glutamyltransferase; ULN=upper limit of normal;  
*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. 
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Was revised to: 
Parameter 
Age 
Range 
UNIT 
(conventional) 
abnormality 
Criteria 
(conventional) 
unit 
(standard) 
Abnormality 
Criteria 
(standard) 
AST (SGOT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
ALT (SGPT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
Alkaline 
Phosphatase 
4y - <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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Parameter 
Age 
Range 
UNIT 
(conventional) 
abnormality 
Criteria 
(conventional) 
unit 
(standard) 
Abnormality 
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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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. 
 
Section 11.3.3 Vital signs, the following table was changed from: 
Table 14  
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 
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 
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 
Abbreviations: m=month, y=year. A month is defined as 30 days; a year is defined as 365.25 days.  
 asource: http://www.cdc.gov/growthcharts/ 
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Was revised to: 
Table 15  
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  
 >100 a 
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 
<90 a  
>140 a 
 >160 a 
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 
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Parameter 
Age Range 
Abnormality Criteria 
Body Weight 
1m - <17y 
<3% or  97% of the normal body weight growth 
curve ranges based on gender and the age of subject 
on date of weight assessmenta 
≥17y 
≥ 10% change from Baseline (an increase or a 
decrease)ba ≥7% change from Baseline (an increase 
or a decrease)a 
Abbreviations: m=month, y=year. 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/ 
Section 11.3.4 ECG, the following table was changed from: 
Table 16  
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 
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 
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 
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>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 
Was revised to: 
Table 17  
ECGs Abnormality Criteria 
Parameter 
Age 
Abnormality Criteria 
QT interval (ms) 
1m-<12y 
>500 
>12y 
>500 or ≥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, >480 a, ≥500 or ≥60 increase from Baseline 
QTc(B) (ms) 
3y-<12y 
>450, or >15% increase from Baseline 
>12y- <17y 
>450, or >15% increase from Baseline 
≥17y 
>450, >480 a, ≥500 or ≥60 increase from Baseline 
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) 
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 Section 11.5,  Appendix 5: Tables required for Article 41 (EudraCT), clinicaltrials.gov and 
Article 46 (European Pediatric Regulation), the following text was changed from: 
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: 
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 
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective 
Baseline by Development  
 Increase in Days with Myoclonic Seizures During the Treatment Period Compared to 
Prospective Baseline by Development  
Study Medication Duration by Development 
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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 
Tables in this section are not referred to in the body of the SAP.  Tables summarizing 
Development may show columns for Pediatrics and Adults where Pediatrics are the subjects in 
EP0012 aged 17 or less and Adults are the subjects in EP0012 aged 18 or more or the table may 
be generated by Pediatrics and Adults. 
Section 11.6, Additional Subgroups to be programmed in ADSL, the following text was added to 
the end of the section: 
Subjects enrolled at Asian study sites (Asian, non-Asian) – Asian sites are those in Taiwan, 
South Korea, China and Japan. 
12.3 
Amendment 3 
12.3.1 
Rationale for the amendment 
SAP Amendment 3 was issued because  
 Protocol Amendments #4 and #5 occurred, 
 CRFs were added to the clinical database (i.e. related to COVID-19, medical history, 
seizure classification), 
 Text was added to address handling COVID-19, 
 for seizures, a database change of documenting missing seizure data as “Not Done” for 
all missing days in the data, in addition to the “Not Done” as reported by the subject; this 
prompted the changing of the efficacy algorithm for counting PGTCS to no longer 
assume zero PGTCS for reports of “Not Done” 
 new analyses were added involving generalized seizure and all seizure types and 
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 other analysis items throughout the SAP were also clarified. 
12.3.2 
Modification and changes 
12.3.2.1 
Specific changes 
The information below was revised from  
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
Has been revised to: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
SAP Amendment #3 
15 Nov 2021 
The following list of abbreviations were added: 
COVID-19 
Coronavirus disease 2019 
II  
 
 
generalized seizures 
IIA  
 
 
absence seizures 
IIB  
 
 
myoclonic seizures 
IIE  
 
 
primary generalized tonic-clonic seizures 
IPD 
 
 
important protocol deviation 
MA 
 
 
markedly abnormal 
SAE 
 
 
serious adverse event 
SPD 
 
 
specification of protocol deviations 
Section 1 Introduction 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for protocol 
number EP0012.   
Has been revised to: 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for protocol 
number EP0012, through protocol amendment #5; the data summarized will be from EP0012 
unless otherwise stated.  Since EP0012 is an open-label extension of SP0982, the SP0982 SAP 
Amendment #4 should be consulted for how variables were calculated for the randomized 
subjects rolling into EP0012.  
Section 2.2.1.1 Primary safety variables,  
The primary safety variables are: 
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 Adverse events (AEs) as reported spontaneously by the subject and/or caregiver or observed 
by the investigator 
 Subject withdrawals 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 days with 
absence seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline Period 
 Subjects with an increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with 
myoclonic seizures per 28 days during the Treatment Period as compared to the Prospective 
Baseline Period 
Has been revised to: 
The primary safety variables are: 
 The incidence of TEAEs over the duration of the Treatment Period 
 Subject withdrawals due to TEAEs 
 Incidence of new appearance of absence of absence and/or myoclonic seizures during the 
Treatment Period 
 An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with absence 
seizures per 28 days during the Treatment Period as compared to the Prospective Baseline 
Period 
 An increase of up to 25%, >25% to 50%, >50% to 75%, and >75% in days with myoclonic 
seizures per 28 days during the Treatment Period as compared to the Prospective Baseline 
Period 
 At least 50% worsening in days with absence seizures 
 At least 50% worsening in days with myoclonic seizures 
Section 2.2.1.2 Secondary safety variables 
Secondary safety variables are: 
 Changes in hematology, chemistry, and urinalysis parameters 
 Changes in 12-lead electrocardiogram (ECG) 
 Changes in vital sign measurements (ie, blood pressure (BP) and pulse rate), including body 
mass index (BMI) and physical (including neurological) examination findings 
Has been revised to: 
Secondary safety variables are: 
 Percentage of treatment-emergent marked abnormalities in hematology and chemistry 
parameters 
 Percent of treatment-emergent marked abnormalities in 12-lead electrocardiogram (ECG) 
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Percentage of treatment-emergent marked abnormalities in vital sign measurements (ie, blood 
pressure (BP) and pulse rate) 
Section 2.2.1.3 Other safety variables 
Other safety variables are: 
 Achenbach Child Behavior Checklist (CBCL)1½-5 or CBCL/6-18 
 Cognitive function assessment Behavior Rating Inventory of Executive Function 
(BRIEF)/BRIEF-P 
Has been revised to: 
Other safety variables are: 
 Changes in hematology, chemistry, and urinalysis parameters 
 Changes in 12-Lead ECGs 
 Changes in vital sign measurements (ie. BP and pulse rate), including weight and height and 
physical (including neurological) examination findings 
 Achenbach Child Behavior Checklist (CBCL)1½-5 or CBCL/6-18 (for pediatric subjects 
only) 
 Cognitive function assessment Behavior Rating Inventory of Executive Function 
(BRIEF)/BRIEF-P (for pediatric subjects only) 
Section 2.2.2.3 Other efficacy variables: 
The other efficacy variables are: 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period 
 Percentage of subjects with at least a 50% reduction in PGTCS frequency compared to the 
Combined Baseline Period 
 Percentage of subjects with at least a 50% reduction in myoclonic seizure days compared to 
the Prospective Baseline Period 
 Percentage of subjects with at least a 50% reduction in absence seizure days compared to the 
Prospective Baseline Period 
 Seizure-free status (yes/no) for PGTCS 
 Seizure-free status (yes/no) for all generalized seizure types 
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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 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 for the first two years of treatment 
 Change from Baseline in the EQ-5D-3L visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age) for the first two 
years of treatment 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
for the first two years of treatment 
 Number of working or school days lost by subject due to epilepsy for the first two years of 
treatment 
 Number of days with help from a caregiver due to epilepsy for the first two years of 
treatment 
Has been revised to: 
The other efficacy variables are: 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period 
 At least a 50% reduction in PGTCS frequency compared to the Combined Baseline Period 
 At least a 50% reduction in myoclonic seizure days compared to the Prospective Baseline 
Period 
 At least a 50% reduction in absence seizure days compared to the Prospective Baseline 
Period 
 Seizure-free status (yes/no) for PGTCS 
 Seizure-free status (yes/no) for all generalized seizure types 
 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 
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Functioning, Emotional Functioning, Social Functioning, and School Functioning) and total 
scores in subjects <18 years of age for the first two years of treatment 
 Change from Baseline in the EQ-5D-3L visual analogue scale (VAS) score and change in 
utility as converted from the 5 dimensions (for subjects ≥12 years of age) for the first two 
years of treatment 
 Healthcare resource use: medical procedures, hospitalizations, and healthcare provider visits 
for the first two years of treatment 
 Number of working or school days lost by subject due to epilepsy for the first two years of 
treatment 
 Number of days with help from a caregiver due to epilepsy for the first two years of 
treatment 
Section 2.2.2.4 Additional efficacy variables was added: 
Additional other efficacy variables that will be analyzed in this SAP are: 
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period 
 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period 
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period 
 At least a 50% reduction in generalized seizure days compared to the Prospective Baseline 
Period 
 At least a 50% reduction in all seizure days compared to the Prospective Baseline Period 
 Seizure-free status (yes/no) for all seizure types 
 Duration of PGTCS free intervals 
 Duration of all generalized seizure-free intervals 
 Duration of all seizure-free intervals 
Section 2.3 Study design and conduct: 
This is a multicenter, open-label extension study to assess the long-term safety and change in 
seizure frequency associated with long-term adjunctive oral LCM for uncontrolled PGTCS in 
subjects ≥4 years of age with IGE. This study will enroll consenting subjects, or subjects whose 
legal representatives have given consent, who have completed the LCM SP0982 study as well as 
eligible Baseline failures from SP0982. 250 subjects from 150 sites are planned to be enrolled in 
EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, study completers from SP0982 who are eligible for inclusion in EP0012 are defined as:  
SP0982 Baseline failures 
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 Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry criteria 
except the minimum PGTCS criteria required for randomization (Baseline failures) 
Randomized subjects meeting SP0982 exit criteria 
 Subjects who completed the first 6 weeks of the Treatment Period (after randomization) of 
SP0982 and experienced ≥2 PGTCS during that time or 
 Subjects who experience a second PGTCS after the first 6 weeks of the Treatment Period of 
SP0982 
SP0982 completers 
 Subjects who experience <2 PGTCS within the 24-week Treatment Period of SP0982 
For SP0982 subjects consented under SP0982 Protocol Amendment 5, after the 125th event is 
confirmed, two classes of subjects will be allowed to enroll in EP0012.  Subjects who are being 
screened will be allowed to directly enroll into EP0012, thus their screening and baseline data 
will be captured in SP0982 but some of their baseline data may be captured in EP0012.  For 
subjects who are concluding their LCM treatment and tapering in SP0982, these participants will 
be consented and complete their Safety Follow-Up (thus not receiving any LCM) in EP0012; the 
data captured in EP0012 will not be transferred to SP0982. 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final Clinic 
Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria.  Eligible 
Baseline failures from SP0982 who choose to enter this study will undergo a complete Visit 1.   
The study duration and the total number of clinic visits will vary for each subject.  For each 
subject, the study will last from study entry until LCM is approved for use in the subject’s 
country for the treatment of PGTCS in subjects with IGE, or until UCB has determined that the 
clinical development program for the indication will be formally discontinued, or until the 
sponsor decides to close the study.  It is anticipated that at least 2 years of treatment will be 
performed to allow for the collection of long-term safety data.  If LCM is not approved for use in 
the subject’s country at the time the sponsor closes the study, access to LCM will be provided 
according to local laws. 
The following study periods are defined: 
 A Treatment Period lasting at least 2 years. 
 An up to 4-week Taper Period and a 30-day Safety Follow-Up Period. 
 Subjects continuing LCM treatment with commercially available LCM will transition to a 
dose determined by the investigator. 
 Subjects tapering off LCM will do so over a period of up to 4 weeks. 
 An End of Taper Visit will occur after the final LCM dose for subjects who taper off 
LCM. 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. 
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The end of the study is defined as the date of the last visit/telephone contact of the last subject in 
the study. 
Has been revised to: 
This is a multicenter, open-label extension study to assess the long-term safety, tolerability and 
change in seizure frequency associated with long-term adjunctive oral LCM for uncontrolled 
PGTCS (seizure type=IIE) in subjects ≥4 years of age with IGE. This study will enroll 
consenting subjects, or subjects whose legal representatives have given consent, who have 
completed the LCM SP0982 study (or have left the primary study at the time of the 125th event, 
whichever came first) as well as eligible Baseline failures from SP0982. Then, some subjects 
who tapered in SP0982 after the 125th event may enter EP0012 for the Safety Follow-up only 
(ICF to be signed beforehand). Up to 250 subjects from 150 to 180 study sites are planned to be 
enrolled in EP0012. 
For the purposes of this study, Baseline failures, randomized subjects who meet SP0982 exit 
criteria, study completers from SP0982 who are eligible for inclusion in EP0012, SP0982 Safety 
Follow-up subjects, and Others are defined as:  
SP0982 Baseline failures 
 Subjects who complete the Prospective Baseline Period of SP0982 and meet all entry criteria 
except the minimum PGTCS criteria required for randomization (Baseline failures) 
Randomized subjects meeting SP0982 exit criteria 
 Subjects who completed the first 6 weeks of the Treatment Period (after randomization) of 
SP0982 and experienced ≥2 PGTCS during that time or 
 Subjects who experience a second PGTCS after the first 6 weeks of the Treatment Period of 
SP0982 
SP0982 completers 
 Subjects who experience <2 PGTCS within the 24-week Treatment Period of SP0982 
 Subjects who were ongoing in SP0982 when the 125th event occurred 
SP0982 Safety Follow-Up subjects 
 Subjects tapered in SP0982 after the 125th event occurs will enter EP0012 for the Safety 
Follow-Up only; these subjects take no study medication in EP0012 and their EP0012 reason 
for discontinuation is that they are completing SP0982 Follow-up in EP0012. 
Other 
 Subjects that enrolled in EP0012 that did not fall into the above categories 
For SP0982 subjects consented under SP0982 Protocol Amendment 5, after the 125th event is 
confirmed, two classes of SP0982 subjects will be allowed to enroll in EP0012.  Subjects who 
are being screened in SP0982, at the time of the 125th event, will be allowed to directly enroll 
into EP0012, thus their screening and baseline data will be captured in SP0982 but some of their 
baseline data may be captured in EP0012; their treatment information will be captured in 
EP0012.  For subjects who are concluding their SP0982 LCM treatment and tapering, these 
SP0982 participants will be consented to enroll in EP0012 and complete their Safety Follow-Up 
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(thus not receiving any LCM) in EP0012; the data captured in EP0012 will not be transferred to 
SP0982. 
EP0012 will last at least 2 years and consists of a Treatment Period, an up to 4-week Taper 
Period, and a 30-day Safety Follow-Up Period. Visit 1 of EP0012 is the same as the Final Clinic 
Visit of SP0982 for completers and subjects who meet the SP0982 exit criteria.  Eligible 
Baseline failures from SP0982 who choose to enter this study will undergo a complete Visit 1.   
For adult subjects, treatment will continue for at least 2 years.  Once 2 years of participation are 
reached, adult subjects will continue to participate until 1 of the 2 following conditions are met: 
 LCM is approved for use for the treatment of PGTCS in subjects with IGE in the subject’s 
country or  
 until the latest approval is granted either by EMA, FDA or PMDA. 
For pediatric subjects, treatment will continue until 1 of the following 2 conditions are met: 
 up to 5 years of participation or 
 until the approval of the extension of indication to cover the target age group is granted. 
Adult and pediatric subjects are completers if they continue in the study for the maximum 
duration in their respective region. 
The following study periods for the EP0012 protocol (not for the analysis) are defined: 
 A Treatment Period lasting at least 2 years for adults enrolled into EP0012 (may be shorter 
for adults leaving the study when the PGTCS indication approvals are obtained during the 
course of the study). 
 A Treatment Period lasting at least 5 years (238 weeks) for the population less than 18 years 
old at enrollment in EP0012 (may be shorter as some participants leave the study when the 
PGTCS indication approvals are obtained during the course of the study). 
 An up to 4-week Taper Period and a 30-day Safety Follow-Up Period. 
 Subjects continuing LCM treatment with commercially available LCM will transition to a 
dose determined by the investigator and do not have to perform the tapering (Taper Visit 
and SFU). 
 Subjects tapering off LCM will do so over a period of up to 4 weeks. 
 An End of Taper Visit (latest 3 days after the final dose) will occur after the final LCM 
dose for subjects who taper off LCM. 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 same design will apply to some of the subjects 
tapered in SP0982 at the time of the 125th event and who entered EP0012 for the Safety 
Follow-Up Visit only and to subjects who entered EP0012 for a Safety Follow-Up Visit 
after discontinuing SP0982 due to the study stopping. 
The end of the study is defined as the date of the last visit/telephone contact of the last subject in 
the study. 
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Subjects who entered EP0012 as <18 years and become adults (18 years and older) during the 
study will remain in the study for at least 5 years (238 weeks). 
Section 3.1 General presentation of summaries and analyses, new 2nd paragraph: 
All appropriate tables, figures and listings will present the study results by All Subjects, 
Pediatrics (>=4 to <18 years old in EP0012), and Adults (>=18 years old in EP0012).  Study 
results for assessments given only to pediatric subjects will present information by All Subjects. 
A pediatric subject is less than 18 years old at EP0012 Visit 1. 
Section 3.1 General presentation of summaries and analyses, last 3 paragraphs: 
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. 
Efficacy analyses will be performed on data reported during analysis treatment period. PGTCS 
analyses will be done on PGTCS data captured while the subject is taking LCM (gaps 3 days or 
less are permitted); if a subject experiences an LCM gap > 3 days, any PGTCS reported during 
the gap will not be included in PGTCS summaries.  
Safety analyses will be performed on data reported during the analysis treatment period. All data 
reported in the study will be listed in subject data listings. 
Has been revised to: 
By-visit summaries will not include data from unscheduled clinic visits unless otherwise stated. 
Data provided at all visits will be included in subject data listings.  A complete set of data 
listings containing all reported and documented study data and all calculated data (eg, change 
from Baseline) will be generated, in most cases, for the analysis population of interest. 
Efficacy analyses will be performed on data reported during the analysis Treatment Period see 
Section 3.2.1.1) on the Full Analysis Set (FAS). PGTCS analyses will be done on PGTCS data 
captured while the subject is taking LCM (gaps 3 days or less are permitted); if a subject 
experiences an LCM gap > 3 consecutive days, any PGTCS reported during the gap will not be 
included in PGTCS summaries.  
Safety analyses (which include analyses on absence (seizure type=IIA) and/or myoclonic 
seizures (seizure type=IIB)) will be performed on data reported during the analysis Treatment 
Period for the Safety Set (SS). 
Section 3.2.1.1 Analysis periods,  
The following analysis periods are defined: 
 Treatment Period: The Treatment Period starts at the time of first dose of study medication 
during the EP0012 study and ends on the date of last dose of study medication or the date of 
ET Visit or Termination Visit, whichever is later. The Treatment Period includes the 
protocol-defined Taper Period (see Section 3.2.2) if the subject completes it. 
 Post-Treatment Period: The Post-Treatment Period is defined as the treatment free 
observational phase after the Treatment Period, for the subjects who take LCM in EP0012. It 
starts on the day after the end date of the Treatment Period and ends on the date of the final 
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visit or date of last contact with the subject, whichever is later. For the subjects from SP0982 
who are completing their Safety Follow-up in EP0012, their entire time in EP0012 will be 
deemed to be in the Post-Treatment Period due to the subjects not taking LCM in EP0012. 
Has been revised to: 
The following analysis periods are defined: 
 Treatment Period (this analysis Treatment Period differs from the protocol-defined treatment 
period): The Treatment Period starts at the time of first dose of study medication during the 
EP0012 study and ends on the date of last dose of study medication or the date of ET Visit or 
Termination Visit, whichever is later. The Treatment Period includes the protocol-defined 
Taper Period (see Section 3.2.2) if the subject completes it. In essence, the Treatment Period 
contains all data between the dates when the subject is being treated with study medication.  
 An efficacy analysis Treatment Period must be calculated for the PGTCS-related 
analyses. This time period starts at the time of first dose of study medication during the 
EP0012 study and ends on the date of last dose of study medication. 
 Post-Treatment Period: The Post-Treatment Period is defined as the treatment free (ie no 
study medication) observational phase after the Treatment Period (in SP0982 or EP0012) 
where study is taken. It starts on the day after the end date of the Treatment Period and ends 
on the date of the final visit or date of last contact with the subject, whichever is later. For the 
subjects from SP0982 who are completing their Safety Follow-up in EP0012, their entire 
time in EP0012 will be deemed to be in the Post-Treatment Period due to the subjects not 
taking study medication in EP0012. 
If the date of last dose of study medication is missing, see imputation rules in Section 4.2.4.  
Section 3.2.1.5 Completer cohort: 
A completer cohort will be defined as the subset of subjects in the Full Analysis Set (FAS) that 
were enrolled, treated with LCM for the specified duration of time (allowing gaps of 3 days or 
less), and have efficacy data available for the duration of the cohort. For example, a 22-week 
completer cohort consists of subjects from the FAS, treated with LCM for at least 22 weeks and 
have efficacy data through at least 22 weeks of exposure. 
Subjects will be classified as belonging to one or more of the following completer cohorts for the 
purpose of subgroup analyses: 
 22 weeks 
 46 weeks 
 94 weeks. 
Has been revised to: 
A completer cohort will be defined as the subset of subjects in the FAS that were enrolled, 
treated with LCM for the specified duration of time (allowing gaps of 3 days or less), and have 
efficacy data available for the duration of the treatment exposure stated in the name of the 
cohort. For example, a 22-week completer cohort consists of subjects from the FAS, treated with 
LCM for at least 22 weeks and have efficacy data through at least 22 weeks of exposure (Visit 
5). 
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Subjects will be classified as belonging to one or more of the following completer cohorts for the 
purpose of subgroup analyses: 
 22 weeks 
 46 weeks 
 94 weeks. 
 142 Weeks 
 190 Weeks 
 238 Weeks 
Section 3.2.1.5.1 Use of ET or Termination Visit when Scheduled Visits are missing 
An adult subject is considered a completer of EP0012 if Visit 11 (Week 94) or ET or 
Termination visit is completed instead of Visit 11 (and there are no other treatment visits 
completed) within the window stated below. Visit 11 or Week 94 was chosen as the visit where 
subjects could complete the study because it was the closest visit occurring to 2 years given the 6 
month visit schedule. Subjects also may be deemed completers of EP0012 when they leave the 
study due to LCM being approved in their region.  
If the visit that corresponds to the completer cohort is missing, then ET or Termination visit will 
be checked to see if this data can be used for the missing visit and to complete the data needed 
for the completer cohort. 
For assessing the 22 and 46 Week completer cohorts, respectively, assess whether the ET visit 
was completed instead of Visit 5 or Visit 8, respectively; the Termination visit may not be an 
option for some subjects for the 22 Week or 46 Week Completer cohorts since subjects can only 
complete the study after 2 years or approval in their region. 
Since subjects can complete EP0012 at Week 94 for the 94 Week completer cohort (and for later 
completer cohorts), if the Week 94 (Visit 11) is missing, then assess whether the Termination or 
ET visit was completed instead of Visit 11.     
The assessment of using Termination or ET visit to determine whether a subject completes a 
cohort occurs when the subject is missing visit for XX Week Completer Cohort (Week 22 – Visit 
5, Week 46 – Visit 8, Week 94 – Visit 11, Week 142 – Visit 13, Week 190 - Visit 15, and Week 
238 – Visit 17) and there are no other later protocol-scheduled visits indicating the subject was 
exposed longer in the study.  Review the Protocol’s Schedule of Study Assessments to determine 
the number of weeks (and calculate the expected date) from the prior visit that the Termination 
or ET visit is expected.  The Termination or ET visit must not be any more than 7 days earlier 
than expected date for XX Week Completer Cohort, as protocol visit windows are ±7 days; if the 
ET or Termination visit date is too early, the subject did not complete enough exposure to be 
included in XX Week Completer Cohort. 
Subjects in the completer cohort may have their data further presented by smaller time periods 
within the duration of the completer cohort as presented in Section 3.2.1.6.  When a subject 
qualifies for a particular completer cohort, the subject has data for the entire completer cohort; 
this means that the subject has data for the smaller time periods within the completer cohort. 
Section 3.2.1.6 Time Period 
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The time periods for the Treatment Period seizure analysis are “0 to 22 Weeks”, “>22 to 46 
Weeks”, “>46 to 94 Weeks”, “>94 to 142 Weeks”, “>142 to 190 Weeks”, “>190 to 238 Weeks”, 
“0 to 46 Weeks”, “0 to 46 Weeks (> 22 Weeks)”, “0 to 94 Weeks”, “0 to 94 Weeks (> 46 
Weeks)”, “0 to 142 Weeks”, “0 to 142 Weeks (>94 Weeks)”,  “0 to 190 Weeks”, and “0 to 238 
Weeks”. Additional time periods will be added based on the visit schedule as subjects progress 
through the study. 
The time periods include all data in the time window of the time period of interest including 
early termination and end of taper visit data. A calculation may be needed using dates to 
determine what time period the early termination and end of taper visit data fit into for each 
subject. 
Has been revised to: 
Some time period labels are used for completer cohort tables as well as non-completer cohort 
tables.  When the tables present time periods within a completer cohort, the subject, by 
definition, has data for the entire time period whereas for the non-completer cohort tables, the 
subject may not have data for the entire time period. 
The time periods for the Treatment Period seizure analysis are “0 to 22 Weeks”, “>22 to 46 
Weeks”, “>46 to 94 Weeks”, “>94 to 142 Weeks”, “>142 to 190 Weeks”, “>190 to 238 Weeks”, 
“0 to 46 Weeks”, “0 to 46 Weeks (> 22 Weeks)”, “0 to 94 Weeks”, “0 to 94 Weeks (> 46 
Weeks)”, “0 to 142 Weeks”, “0 to 142 Weeks (>94 Weeks)”,  “0 to 190 Weeks”,  “0 to 238 
Weeks” and entire “Treatment Period”. Additional time periods will be added based on the visit 
schedule as subjects progress through the study.  All tables displaying Time Period should show 
all time periods. 
The time periods for the Treatment Period include all data in the time window of the time period 
of interest including termination, early termination and end of taper visit data. A calculation may 
be needed using dates to determine what time period the termination, early termination and end 
of taper visit data fit into for each subject. While completer cohorts and their time periods 
involve subjects having data for the entire cohort or time period, when it comes to non-completer 
cohort tables, subjects do not have to have data for the whole Treatment period or time period 
within the Treatment period. 
For example, for non-completer cohort tables, “0 to 46 Weeks” contains all data from all subjects 
in 0-46 weeks, where Week 46 is Visit 8, if present; if a subject discontinues the study at Visit 4, 
the subject is still summarized in “0 to 46 Weeks”. “0 to 46 Weeks (>22 Weeks)” contains all 
data for all subjects who have data through at least Visit 5 (Week 22).  If a subject only has data 
up to Week 14 (Visit 4), the subject will appear in “0 to 46 Weeks” but not in “0 to 46 Weeks 
(>22 Weeks)”. 
Section 3.2.1.7 Visit Algorithm was added: 
In determining the date of visits, which is specifically helpful in determining whether patients are 
members of completer cohorts, the in-clinic date of the visit will be used instead of visit dates 
from SDTM.SV (the Study Visits SDTM dataset which contain in-clinic and non-clinic visit 
dates).  In-clinic visit dates, firstly from SDTM.VS (Vital Signs), will be used as the date of 
protocol-specified visits.  If a visit is missing in SDTM.VS, then the in-clinic visit date from 
SDTM.DA (Drug Accountability) will be used as the date of the protocol-specified visit. If a 
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visit is missing in SDTM.VS and SDTM.DA, then the in-clinic visit date from SDTM.LB 
(Laboratory Results) will be used as the data of the protocol-specified visit. 
Section 3.2.4 AEDs and Benzodiazepines 
Antiepileptic drugs (AEDs) and benzodiazepines will be collected on the concomitant and prior 
medication case report form (CRF) for AEDs. New concomitant AEDs can be added at any time. 
Stable use of benzodiazepines is allowed as concomitant AEDs. Intermittent use of 
benzodiazepines is allowed as rescue medication for epilepsy indications with a maximum of 1 
dose per week. Benzodiazepines used as rescue medication will be flagged with “RESCUE” in 
the indication field on the CRF. Rescue AEDs will also be identified programmatically as any 
AED with an epilepsy or seizure related indication taken intermittently as 1 dose per week. 
Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days 
prior to SP0982 Visit 1. 
Was revised to: 
Antiepileptic drugs (AEDs) and benzodiazepines will be collected on the concomitant and prior 
medication case report form (CRF) for AEDs. New concomitant AEDs can be added at any time. 
Benzodiazepines are AEDs. The UCB study physician will review a listing of all medications 
and flag which ones are to be summarized as AEDs and benzodiazepines since AEDs may be 
entered on the wrong medication case report form.  
Concomitant AEDs at Study entry, concomitant benzodiazepine use at SP0982 entry, and 
Lifetime AEDs and Benzodiazepines for subjects randomized in SP0982 are already calculated 
and carried forward into EP0012. These variables will be summarized. 
For EP0012 direct enrollers, concomitant AEDs at study entry are defined as AEDs where the 
start date is on or before 28 days prior to EP0012 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 EP0012  (direct enrollers) Visit 1; ongoing AEDs are not 
counted as a lifetime AED. Concomitant benzodiazepine use at EP0012 entry is the use of any 
benzodiazepine at EP0012 Visit 1. 
Stable use of benzodiazepines is allowed as concomitant AEDs. Intermittent use of 
benzodiazepines is allowed as rescue medication for epilepsy indications with a maximum of 1 
dose per week. Benzodiazepines used as rescue medication will be flagged with “RESCUE” in 
the indication field on the CRF. Rescue AEDs will also be identified programmatically as any 
AED with an epilepsy or seizure related indication taken for 1 or 2 days, at any frequency.  
If a subject is unable to take study medication, commercial lacosamide can be taken instead in 
order to fill the gaps in exposure.  In this instance, the commercial lacosamide usage is 
considered a substitute for study medication in determining whether a subject has > 3 day LCM 
gap and counting PGTCS occurring in such a gap; no exposure records will be created to add 
commercial lacosamide to study medication exposure. The start and end date of commercial 
LCM usage will be calculated and stored in ADSL for use in PGTCS analyses.  
The preferred term reported on the concomitant medication CRF is lacosamide. 
Section 3.2.4.1 Phenytoin use was added: 
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The following preferred terms will be grouped as “Phenytoin”: phenytoin, phenytoin sodium, 
ethotoin, fosphenytoin, fosphenytoin sodium, and zentronal. 
Section 3.2.4.2 Valproate use was added: 
The following preferred terms will be grouped as “Valproate”: valproic acid, valproate 
semisodium, valproate sodium, valproate magnesium, ergenyl chrono, and valproate. 
Section 3.2.4.3 Phenobarbital use was added: 
The following preferred terms will be grouped as “Phenobarbital”: phenobarbital, phenobarbital 
sodium, methylphenobarbital, and primidone. 
Section 3.3 Definition of Baseline Values 
For PGTCS data, the Combined Baseline Period is defined as the combined 12-week Historical 
and 4-week Prospective Baseline Periods from the SP0982 study. This Period starts 84 days prior 
to Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 study. 
For absence and myoclonic seizure data in order to determine Responder Status and worsening, 
the Prospective Baseline Period is defined as the 4-week Prospective Baseline Period from the 
SP0982 study. This Period starts the date of Visit 1 of the SP0982 study and ends the day before 
Visit 2 of the SP0982 study. In order to determine emergence of new seizure type, the Combined 
Baseline Period will be used. 
For all other data, Baseline values are defined as follows; 
 For Baseline failures from SP0982, data collected at Visit 1 prior to the first dose of study 
medication 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 data not collected at Visit 1 
prior to the first dose of study medication, the last data collected in SP0982 will be used as 
Baseline values, if available.  
For non-Baseline failures from SP0982, the last non-missing value prior to the first dose of study 
medication in the SP0982 study will be used as the Baseline value. 
Was revised to: 
The baseline data for randomized SP0982 subjects in EP0012 will not recalculated. For subjects 
who directly enrolled into EP0012, some baseline variables may be calculated in SP0982 but 
these calculations need to be reassessed as detailed below. 
For PGTCS data, the Combined Baseline Period is defined as the combined 12-week Historical 
and 4-week Prospective Baseline Periods from the SP0982 study. The Combined Baseline Period 
starts 84 days prior to Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 
study. This means that for subjects who directly enrolled into EP0012 (were not randomized in 
SP0982), the baseline PGTCS (before first dose in EP0012) data from SP0982 is combined with 
any reported baseline seizure information from EP0012 to recalculate the subject’s baseline 
variables such as PGTCS frequency. 
Data from Combined Baseline is used for analyses involving PGTCS since the CRF was specific 
in asking for PGTCS counts.  Other seizure type data recorded in Historical Baseline are deemed 
less reliable.  For seizure calculations involving Absence, Myoclonic, Generalized (seizure 
type=II) and All seizure types (seizure types = I, II and III), Prospective Baseline data is used; 
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that means for generalized and all seizure type calculations specifically, PGTCS data in 
Prospective Baseline will only be used (not the Combined Baseline data) along with the other 
seizure types. 
For absence, myoclonic, generalized and all seizure data, the Prospective Baseline Period is 
defined as the 4-week Prospective Baseline Period from the SP0982 study. This Period starts the 
date of Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 study. This 
means that for the subjects who directly enrolled into EP0012 (were not randomized in SP0982), 
the baseline absence, myoclonic, generalized or all (respectively) seizure data from SP0982’s 
Prospective Baseline period is combined with any reported baseline absence, myoclonic, 
generalized or all (respectively) seizure information from EP0012 (reported before first dose in 
EP0012) to recalculate the subject’s baseline variables such as days with absence, myoclonic, 
generalized or all seizures per 28 days. 
In order to determine emergence of new seizure type, the Combined Baseline Period as well as 
any seizures reported prior to first dose in EP0012 will be used. 
For all other data, Baseline values are defined as follows; 
 For Baseline failures from SP0982, data collected at Visit 1 prior to the first dose of study 
medication 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 data not collected at Visit 1 but 
still prior to the first dose of study medication, the last data collected in SP0982 will be used 
as Baseline values, if available.  
 For non-Baseline failures from SP0982, the last non-missing value prior to the first dose of 
study medication in the SP0982 study will be used as the Baseline value.  
For quantitative ECG assessments, if repeat measurements pre-first dose, then the average 
value is used as the Baseline value. 
Section 3.4 Protocol Deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for identifying 
important protocol deviations and the classification of important protocol deviations will be 
defined within the project Data Cleaning Plan. To the extent feasible, rules for identifying 
protocol deviations will be defined without review of the data and without consideration of the 
frequency of occurrence of such deviations. Whenever possible, criteria for identifying important 
protocol deviations will be implemented algorithmically to ensure consistency in the 
classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. 
Was revised to: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on key safety outcomes for an individual subject. The criteria for identifying 
important protocol deviations and the classification of important protocol deviations will be 
defined in the Specification of Protocol Deviation (SPD) document. To the extent feasible, rules 
for identifying protocol deviations will be defined without review of the data and without 
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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. 
In general, protocol deviations will be considered according to the following general categories: 
 Inclusion criteria 
 Exclusion criteria 
 Withdrawal criteria 
 LCM dosing regimen 
 Prohibited concomitant medications 
 Procedural non-compliance 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. A list of subjects with important protocol deviations will be agreed upon during 
the quarterly IPD meetings and will be documented in the IPD meeting minutes. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus 
disease 2019 (covid-19) will be documented. Important protocol deviations related to COVID-19 
will be included in the important protocol deviations.  
Section 3.5.1 Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have a signed Informed Consent/Assent 
form.  
Was revised to: 
The Enrolled Set (ES) will consist of all subjects who have a signed Informed Consent/Assent 
form.  Subjects completing SP0982 Safety Follow-up are contained in this analysis population 
because no study medication is administered to them.  
Section 3.5.2 Safety Set 
The Safety Set (SS) is a subset of the ES and consists of all subjects who received at least 1 dose 
of LCM during EP0012. 
Was revised to: 
The Safety Set (SS) is a subset of the ES and consists of all subjects who received at least 1 dose 
of LCM during EP0012. All safety analyses will be performed on the SS. 
Section 3.5.3 Full Analysis Set 
The FAS is a subset of the SS and consists of all subjects with seizure diary data for at least 1 
day during EP0012. 
Was revised to: 
The FAS is a subset of the SS and consists of all subjects with seizure diary data for at least 1 
day during EP0012. PGTCS-related analyses will be performed on the FAS. 
Section 3.6 Treatment assignment and treatment groups, first sentence: 
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All subjects will receive LCM.   
Has been revised to: 
All subjects, except those enrolled to complete Safety-Follow-up in EP0012, will receive LCM.   
Section 3.9 Changes to protocol-defined analyses: 
There are no changes to analyses specified in the protocol. 
Has been revised to: 
There are no changes to analyses specified in the protocol however there are additional variables 
defined in the SAP which are detailed in Section 2.2.2.4 that will be analyzed. 
Section 4.2 Handling of dropouts or missing data: 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who transitioned from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data not reported for V1 in EP0012. 
• 
for subjects who are baseline failures or incomplete screen failures in SP0982 who enrolled 
in EP0012, baseline data will be used from EP0012 V1 (if prior to first EP0012 dose) or the 
latest data from the screening and baseline visits in SP0982 can be used (also if prior to first 
EP0012 dose). 
Has been revised to: 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who transitioned from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data not reported for V1 in EP0012. 
• 
for subjects who are baseline failures or incomplete screen failures in SP0982 who enrolled 
in EP0012, baseline data will be used from EP0012 V1 or unscheduled V1 (if prior to first 
EP0012 dose) or the latest data from the screening and baseline visits in SP0982 can be used 
(also if prior to first EP0012 dose). 
Section 4.2.1 Missing seizure days 
For evaluations based on seizure diary data, imputation for missing data will not be performed. 
For the purpose of the derivation of PGTC seizure-free status, in the first 2 years, 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. For years 3-5, when subjects are only required to enter days when PGTCS 
occurred, days not reported are assumed to be PGTC seizure-free; if seizure information is 
known to be missing, then the subject is not PGTC seizure-free.  
The calculation of average 28-day PGTCS frequency accounts for missing data in the first 2 
years by only evaluating days for which data are available. For years 3-5, the calculation of 
average 28-day PGTCS frequency uses the seizure information reported since “not done” 
information is no longer gathered; if there is a known non-compliance in recording seizures and 
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the unevaluable days can be identified, then the average 28-day PGTCS frequency will use only 
evaluable days. 
For all seizure types, any missing day in the seizure diary during years 1-2 renders a subject to be 
not seizure-free due to the lack of information. 
Absence or myoclonic subjects will be considered for seizure-free evaluation from all 
generalized seizure types in years 1-2 for the applicable time period if the subject had <10% of 
days during the time period with seizure data reported as “not done”. 
For years 3-5, when subjects are only required to enter days when generalized seizures occur, a 
subject will be considered seizure-free for generalized seizures if the subject has no days 
reported with generalized seizures (seizure type=II). 
Has been revised to: 
For evaluations based on seizure diary data, imputation for missing data will not be performed.  
This means, for example, for an analysis for an interim data cut or for the final analysis, only 
seizure data for completed visits can be used in the analyses (i.e. study participants should not be 
assumed to have zero seizures between the time of the last-known visit and the interim cutoff; 
the subject will appear as having missing seizure information). The calculation of average 28-day 
seizure frequency or days with seizure per 28 days accounts for missing data by only evaluating 
days for which the data are available. Additionally for PGTC seizure calculations, PGTCS are 
not counted during gaps when LCM is not taken > 3 consecutive days. 
Section 4.8 Examination of subgroups, the following was added: 
 Development (in EP0012) (≥ 4 to <18 years of age, ≥18) 
Section 4.10 Use of safety subset of subjects was added: 
For absence seizure analyses, the population analyzed will be further restricted to the subset of 
subjects  
 who reported a seizure classification history of absence seizures in either SP0982 or 
EP0012, or 
 who reported absence seizures during Combined Baseline Period, the Treatment Period 
or Transition Period of SP0982 or  
 who reported absence seizures at any time prior to Safety Follow-up in EP0012.   
These subjects are hereby referred to as the “Absence subpopulation” because this subgroup only 
contain subjects who have had or who are having absence seizures. 
For myoclonic seizure analyses, the population analyzed will be further restricted to the subset of 
subjects  
 who reported a seizure classification history of myoclonic seizures in either SP0982 or 
EP0012, or 
 who reported myoclonic seizures during Combined Baseline period, the Treatment Period 
or Transition Period of SP0982 or  
 who reported myoclonic seizures at any time prior to Safety Follow-up in EP0012.   
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These subjects are hereby referred to as the “Myoclonic subpopulation” because this subgroup 
only contain subjects who have had or who are having myoclonic seizures. 
Section 5.1 Subject disposition 
The study eligibility criteria and those subjects who did not meet it will be listed for the ES. All 
disposition data for the ES will be presented in subject data listings.  
The number of subjects in the SS and FAS 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 and FAS including number and percentages for each reason for 
discontinuation. The completion of the study is defined as the completion of the Termination 
Visit. Discontinuation is defined as the completion of the ET Visit. This summary will be 
repeated for each subgroup 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. 
Has been revised to: 
The study eligibility criteria and those subjects who did not meet it will be listed for the ES. All 
disposition data for the ES will be presented in subject data listings.  
The number of subjects in the SS and FAS 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 number and percentage of subjects in the ES, SS and FAS will be presented by age at 
Baseline in SP0982 as well as for all subjects. 
The overall number and percentage of subjects who completed and discontinued from the study 
will be presented for the SS and FAS by age at baseline in SP0982 as well as all subjects 
including number and percentages for each reason for discontinuation. The completion of the 
study is defined as the completion of the Termination Visit. Discontinuation is defined as the 
completion of the ET Visit. The number and percentage of subjects who switch to commercial 
Vimpat use will be presented. The study termination information will be presented in the subject 
data listings. 
The number and percentages of subjects impacted by COVID-19 will be presented for each visit, 
overall and by impact category, for all subjects in the SS.  These data will be presented in subject 
data listings. 
A by-subject listing will be presented to show all visit dates and the associated relative day. 
Section 6.1.2 Analysis of demographic variables: 
Baseline demographics will be summarized for the SS and include gender, race, ethnicity, age, 
age category, height (cm), weight (kg) and BMI (kg/m2). Race and ethnicity will be from the 
SP0982 study but all other demographic variables will be from EP0012. 
Demographics will be listed for all subjects screened. 
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Has been changed to: 
Baseline demographics will be summarized for the SS and include gender, race, ethnicity, age, 
age category, height (cm), weight (kg) and BMI (kg/m2); age is calculated in the SDTM as age at 
enrollment into EP0012 and that variable should be used for defining age category. Race and 
ethnicity will be from the SP0982 study but all other demographic variables will be from 
EP0012. 
Demographics will be listed for all subjects enrolled. 
Section 6.2.2 Analysis of other Baseline characteristics: 
The following Baseline characteristics will be presented: 
 Time since first diagnosis at date of consent for SP0982 
 Age at diagnosis of the disease 
 ILAE Seizure classification history from SP0982 
 Classification of epileptic syndrome from SP0982 
 Lifetime AEDs and Benzodiazepines at SP0982 entry (0, 1-3, 4-6, 7+) 
 Baseline PGTCS frequency from SP0982 per 28 days (as continuous data) 
 Baseline PGTCS frequency at SP0982 entry (≤2, >2 per 28 days) from Interactive Response 
Technology (IRT) 
 Baseline PGTCS frequency at SP0982 entry (≤2, >2 per 28 days) from CRF 
 Concomitant AEDs at SP0982 entry (1, 2, 3). 
 Concomitant AEDs at EP0012 entry (0, 1, 2, 3, 4) 
 Concomitant benzodiazepine use at SP0982 entry (yes, no)  
 Concomitant benzodiazepine use at EP0012 entry (yes, no) 
 LCM study drug status (continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982)) 
 SP0982 exit status (Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation). 
All Baseline characteristics will be presented in data listings. All reproductive potential and birth 
control information will be presented in data listings. 
Was revised to: 
For director enrollers in EP0012, the baseline characteristic variables can represent a 
combination of baseline data stored in SP0982 as well as EP0012; the subjects continuing from 
SP0982 are included but their baseline data is from SP0982 only.   
Subjects randomized in SP0982 will appear in summaries below denoted as being from “SP0982 
entry”. All subjects enrolled in EP0012 will appear in rows that have no reference to SP0982 and 
the rows denoted as being from “EP0012 entry” or “EP0012”. 
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The following Baseline characteristics will be presented: 
 Time since first diagnosis at date of consent  – Time since first diagnosis calculated for all 
EP0012 subjects; this data is stored in SP0982 
 Age at diagnosis of the disease – age at diagnosis calculated for all EP0012 subjects; this data 
is stored in SP0982ILAE Seizure classification history  – see below 
 Classification of epileptic syndrome  – see below 
 Lifetime AEDs and Benzodiazepines (SP0982) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of randomized SP0982 subjects in EP0012; this data is stored 
in SP0982 
 Lifetime AEDs and Benzodiazepines (EP0012) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of all EP0012 subjects 
 Combined Baseline PGTCS frequency per 28 days (as continuous data) – baseline PGTCS 
seizure frequency from CRF of all EP0012 subjects; SP0982 IRT data is not used in EP0012. 
 Combined Baseline PGTCS frequency categories (≤2, >2 per 28 days)  – baseline PGTCS 
seizure frequency categorized from CRF of all EP0012 subjects 
 Concomitant AEDs at SP0982 entry (0, 1, 2, 3, 4) – categorical representation of concomitant 
AEDs of randomized SP0982 subjects in EP0012; this data is stored in SP0982 
 Concomitant AEDs at EP0012 entry (0, 1, 2, 3, 4) – categorical representation of 
concomitant AEDs of all EP0012 subjects 
 Concomitant benzodiazepine use at SP0982 entry (yes, no, missing) – Yes/No to concomitant 
Benzo use of randomized SP0982 subjects in EP0012; this data is stored in SP0982  
 Concomitant benzodiazepine use at EP0012 entry (yes, no) – Yes/No to concomitant Benzo 
use of all EP0012 subjects 
 LCM study drug status  - continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982 or other) 
 SP0982 exit status  - Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation. 
ILAE Seizure Classification History (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information. 
Classification of Epileptic Syndromes (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information.  
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All Baseline characteristics will be presented in data listings. All reproductive potential and birth 
control information will be presented in data listings. 
Section 6.4 Medical history and concomitant diseases: 
Previous and ongoing medical history conditions, initially reported in SP0982 and potentially 
updated for EP0012, 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. 
Was revised to: 
Previous and ongoing medical history conditions, initially reported in SP0982 and potentially 
updated for EP0012, will be summarized by system organ class (SOC) and preferred term (PT) 
for the subjects in the SS. For medical history events, meaning they are not ongoing, if the same 
coded condition is reported in both SP0982 and EP0012, only the EP0012 condition will be 
summarized; if the coded conditions are differently reported in SP0982 and EP0012, then both 
sets of conditions will be summarized. If no new conditions are reported in EP0012, then only 
SP0982 conditions will be summarized. A similar summary will be provided for concomitant 
diseases for the SS. Concomitant diseases are medical history events which are ongoing at the 
SP0982 Screening Visit or reported as ongoing in EP0012 on the medical history CRF page. 
The SP0982 and EP0012 data for the subjects in EP0012, 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. 
Section 6.5 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. Prior AEDs, benzodiazepines 
and other medications are not summarized for the EP0012 subjects. 
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. 
Concomitant AEDs and benzodiazepines taken during the Treatment Period will be summarized 
by ATC level 4 and PT for the SS. 
Concomitant medications (excluding AEDs and benzodiazepines) will be summarized by ATC 
level 1 (anatomical main group) and ATC level 2 (therapeutic subgroup) for the SS. 
All concomitant medications will be listed. A glossary of ATC codes and associated 
investigator’s terms for all AEDs or benzodiazepines and all other medications (excluding AEDS 
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and benzodiazepines) will be listed separately in subject 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. 
The number of subjects withdrawing to Monotherapy during the Treatment Period will be 
summarized.  Withdrawing to monotherapy means the subject has documentation that all 
background AEDs [except LCM] were discontinued during Treatment Period) will be 
summarized. A record for the discontinued AED must be present in the concomitant AED data. 
Has been revised to: 
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. Prior AEDs, benzodiazepines 
and other medications are not summarized for the EP0012 subjects. 
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. 
Concomitant AEDs and benzodiazepines taken during the Treatment Period will be summarized 
by ATC level 4 and PT for the SS. 
Concomitant medications (excluding AEDs and benzodiazepines) will be summarized by ATC 
level 1 (anatomical main group) and ATC level 2 (therapeutic subgroup) for the SS. 
All medications will be listed. 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 subject 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. 
The number of subjects withdrawing to Monotherapy during the Treatment Period will be 
identified.  Withdrawing to monotherapy means the subject has documentation that all 
background AEDs [except LCM] were discontinued during Treatment Period. A record for the 
discontinued background AEDs must be present in the concomitant AED data and study 
medication must be taken continuously (>3 day gaps are not allowed). For the subjects who 
withdrew to monotherapy, the following results will be listed: 
 Treatment Duration 
 Monotherapy Start Date 
 Monotherapy End Date 
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 Duration (days) of monotherapy 
 AEDs that were discontinued 
 Period when monotherapy starts (0 to Week 46 (V8), >Week 46 to Week 94 (V11), 
>Week 94 to Week 142 (V13), >Week 142 to Week 190 (V15), >Week 190 (V15)). 
The Monotherapy period and the cutoffs are determined for any visit falling within the Treatment 
Period, after using the definition of Treatment Period from Section 3.2.1.1 and the visit algorithm 
from Section 3.2.1.7.  The start of the Monotherapy period is mapped to the period based on the 
subject’s visit schedule as denoted in the period cutoffs (V8, V11, V13, and V15). 
Section 8 Efficacy Analyses: 
Analyses of the efficacy variables will be performed using the FAS (unless otherwise stated) and 
will be descriptive in manner only. Efficacy analyses will be performed on data reported during 
analysis treatment period. PGTCS analyses will be done on PGTCS data captured while the 
subject is taking LCM (gaps 3 days or less are permitted); if a subject experiences an LCM gap > 
3 days, any PGTCS reported during the gap will not be included in PGTCS summaries. 
All seizure diary data will be listed. A listing of subjects excluded from the FAS will also be 
produced. 
Was revised to: 
Analyses of the efficacy variables (i.e. PGTCS-related variables) will be performed using the 
FAS (unless otherwise stated) and will be descriptive in manner only. Efficacy analyses will be 
performed on data reported during the efficacy analysis Treatment Period. PGTCS analyses will 
be performed on PGTCS data captured while the subject is taking LCM (gaps 3 days or less are 
permitted); if a subject experiences an LCM gap > 3 days, any PGTCS reported during the gap 
will not be included in PGTCS summaries. 
Subject seizure information will be imputed with all dates between the start and end of the 
efficacy Treatment Period; for years 3-5, all days are assumed zero seizure days except those 
with Not Dones or non-zero counts. Seizure frequency and seizure days will be calculated over 
non-missing (or evaluable) seizure diary days. Diary days captured as Not Done will not be 
considered in the calculation of seizure frequency or days with seizure (i.e. unevaluable).  
Because the evaluation of efficacy is not the primary objective of this study, and because in an 
uncontrolled study in a variable setting, which allows individualized optimization of study 
medication and concomitant AEDs, no summaries assessing the impact of missing seizure diary 
days are planned. 
Other seizure variables are considered safety variables and the analysis will be performed using 
the SS spanning the Treatment Period. 
All seizure diary data will be listed. A listing of subjects excluded from the FAS will also be 
produced. 
Section 8.2.1 Derivation of secondary efficacy variable: 
The secondary efficacy variable is percent change in PGTCS frequency per 28 days from 
Combined Baseline Period. In order to account for potential differences in the durations of the 
study periods for individuals, seizure data will be normalized to 28 days. For years 1-2, seizure 
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information is collected every day, but for years 3-5 only days with a seizure are recorded. 
Therefore, from (and including) the day after Visit 11 date to the (and including) date of 
completion/discontinuation will be assumed to be seizure free days if no seizures are recorded. 
For years 1-2, only days with a seizure record are considered evaluable 
The 28-day PGTCS frequency (SF) will be calculated for the Combined Baseline Period and 
Treatment Periods as: 
SF =  
(# PGTCS in the relative period/# days in relative period with evaluable seizure data)*28 
The percent change (PCH) in PGTCS frequency per 28 days from Combined Baseline Period 
(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. 
Was revised to: 
The secondary efficacy variable, calculated on the FAS, is percent change in PGTCS frequency 
per 28 days from Combined Baseline Period for PGTCS data where there is no >3 day LCM gap. 
In order to account for potential differences in the durations of the study periods for individuals, 
seizure data will be normalized to 28 days. For years 1-2, (up to and including Visit 11 date), 
seizure information is collected every day, but for years 3-5 only days with a seizure are 
recorded. Therefore, from the day after Visit 11 date (inclusive) to the date of the end of the 
efficacy Treatment Period (inclusive) will be assumed to be seizure free days  unless non-zero 
seizure counts are recorded or the seizure diaries are recorded as being Not Done for those days. 
For years 1-2, only days with a seizure record other than Not Done are considered evaluable.  
Also see Section 4.2.1. 
The 28-day PGTCS frequency (SF) will be calculated for the Combined Baseline Period and 
Treatment Periods as: 
SF =  
(# PGTCS in the relative period on days with evaluable seizure data/# days in relative period 
with evaluable seizure data)*28 
The percent change (PCH) in PGTCS frequency per 28 days from Combined Baseline Period 
(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. 
Section 8.2.2 Analysis of secondary efficacy variable: 
The percent change in PGTCS frequency during the Treatment Period by Completer Cohort and 
Time Period will be summarized with descriptive statistics.  
The percent change in PGTCS frequency over the Treatment Period by Time Period will be 
summarized with descriptive statistics. 
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Was revised to: 
The percent change in PGTCS frequency during the efficacy Treatment Period by Completer 
Cohort and Time Period will be summarized with descriptive statistics. All calculated completer 
cohorts and time periods will be summarized. 
The percent change in PGTCS frequency over the efficacy Treatment Period by Time Period will 
be summarized with descriptive statistics. All calculated time period results will be summarized. 
Section 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.  
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 Treatment Period of SP0982 or EP0012.   
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 Treatment Period of SP0982 or EP0012. 
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 the other efficacy variables (i.e. absence, 
myoclonic, generalized and/or all seizure related variables) will be performed using the SS and 
will be descriptive in manner only. These analyses will be performed on data reported during the 
Treatment Period. 
In section 8.3.1.1 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 Period and Treatment Periods as: 
D = ([# days with absence seizures in the relative period] / [# days in relative period with 
evaluable seizure data])*28. 
For years 1-2, only days with a seizure record are considered evaluable. However, for years 3-5, 
from (and including) the day after Visit 11 date to the (and including) date of 
completion/discontinuation will be assumed to be seizure free days if no seizures are recorded. 
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 Prospective Baseline 
Period (PB) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DPB) / DPB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DPB corresponds to the number of days with absence seizures per 28 days 
during the Prospective Baseline Period from SP0982. If DPB is zero, then PCH will be missing 
and any such subjects will be excluded from the percent change summary. 
Similarly, the percent change in the number of days with myoclonic seizures per 28 days from 
the Prospective Baseline Period will be calculated. 
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Have been revised to: 
All calculations involving days with seizures per 28 days will be on the SS. 
The number of days with absence seizures per 28 days (D) will be calculated separately for the 
Prospective Baseline Period and Treatment Periods as: 
D = ([# days with absence seizures in the relative period on days with evaluable seizure data] / [# 
days in relative period with evaluable seizure data])*28. 
For years 1-2 (up to and including Visit 11 date), only days with a seizure record other than Not 
Done are considered evaluable. However, for years 3-5, from the day after Visit 11 date 
(inclusive) to the date of the end of the efficacy Treatment period (inclusive) will be assumed to 
be seizure free days if no seizures are recorded or the seizure diaries are not recorded as being 
Not Done for those days.. 
Similarly, the number of days with myoclonic, generalized and all seizures per 28 days will be 
calculated. 
The percent change (PCH) in days with absence seizures per 28 days from Prospective Baseline 
Period (PB) to the appropriate analysis period (T) is defined as: 
PCH = [(DT – DPB) / DPB] x 100 
where DT corresponds to the number of days with absence seizures per 28 days during the 
relative period and DPB corresponds to the number of days with absence seizures per 28 days 
during the Prospective Baseline Period. If DPB is zero, then PCH will be missing and any such 
subjects will be excluded from the percent change summary. 
Similarly, the percent change in the number of days with myoclonic, generalized and all seizures 
per 28 days from the Prospective Baseline Period will be calculated. 
Section 8.3.1.2 Variables: Responder status – reduction in PGTCS frequency: 
A 50% responder is defined as a subject experiencing ≥50% reduction in PGTCS frequency per 
28 days from Combined Baseline Period to the period of interest. Response to treatment will be 
based on the percent change in PGTCS frequency, calculated as described in Section 8.2.1. A 
75% responder is defined as a subject experiencing ≥75% reduction in PGTCS frequency per 28 
days from Combined Baseline Period to the period of interest. 
Has been revised to: 
These variables are calculated on the FAS. A 50% responder is defined as a subject experiencing 
≥50% reduction in PGTCS frequency per 28 days from Combined Baseline Period to the period 
of interest. Response to treatment will be based on the percent change in PGTCS frequency, 
calculated as described in Section 8.2.1. A 75% responder is defined as a subject experiencing 
≥75% reduction in PGTCS frequency per 28 days from Combined Baseline Period to the period 
of interest. 
Section 8.3.1.3 Variables: Responder status – reduction in days with absence seizures: 
A 50% responder is defined as a subject experiencing ≥50% reduction in the number of days 
with absence seizures per 28 days from Prospective Baseline Period to the period of interest, for 
the subjects reporting absence seizures during the Prospective Baseline Period from SP0982. 
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Response to treatment will be based on the percent change in the number of days with absence 
seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% responder is defined as a 
subject experiencing ≥75% reduction in the number of days with absence seizures per 28 days 
from Prospective Baseline Period to the period of interest, for the subjects reporting absence 
seizures during the Prospective Baseline Period from SP0982. 
Has been revised to: 
These variables are calculated on the Absence subpopulation of the SS. A 50% responder is 
defined as a subject experiencing ≥50% reduction in the number of days with absence seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
absence seizures during the Prospective Baseline Period. Response to treatment will be based on 
the percent change in the number of days with absence seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
reduction in the number of days with absence seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting absence seizures during the Prospective 
Baseline Period. 
Section 8.3.1.3 Variables: Responder status – reduction in days with myoclonic seizures: 
A 50% responder is defined as a subject experiencing ≥50% reduction in the number of days 
with myoclonic seizures per 28 days from Prospective Baseline Period to the period of interest, 
for the subjects reporting myoclonic seizures during the Prospective Baseline Period from 
SP0982. Response to treatment will be based on the percent change in the number of days with 
myoclonic seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% responder is 
defined as a subject experiencing ≥75% reduction in the number of days with myoclonic seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
myoclonic seizures during the Prospective Baseline Period from SP0982. 
Has been revised to: 
These variables are calculated on the Myoclonic subpopulation of the SS. A 50% responder is 
defined as a subject experiencing ≥50% reduction in the number of days with myoclonic seizures 
per 28 days from Prospective Baseline Period to the period of interest, for the subjects reporting 
myoclonic seizures during the Prospective Baseline Period. Response to treatment will be based 
on the percent change in the number of days with myoclonic seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
reduction in the number of days with myoclonic seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting myoclonic seizures during the 
Prospective Baseline Period. 
Section 8.3.1.5, Variables: Responder status – reduction in days with generalized seizures is 
new: 
These variables are calculated on the SS. A 50% responder is defined as a subject experiencing 
≥50% reduction in the number of days with generalized (all type II) seizures per 28 days from 
Prospective Baseline Period to the period of interest, for the subjects reporting generalized 
seizures during the Prospective Baseline Period. Response to treatment will be based on the 
percent change in the number of days with generalized seizures per 28 days, calculated as 
described in Section 8.3.1.1. A 75% responder is defined as a subject experiencing ≥75% 
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reduction in the number of days with generalized seizures per 28 days from Prospective Baseline 
Period to the period of interest, for the subjects reporting generalized seizures during the 
Prospective Baseline Period. 
Section 8.3.1.6, Variables: Responder status – reduction in days with all seizures is new: 
These variables are calculated on the SS. A 50% responder is defined as a subject experiencing 
≥50% reduction in the number of days with all types of seizures per 28 days from Prospective 
Baseline Period to the period of interest, for the subjects reporting any seizures during the 
Prospective Baseline Period. Response to treatment will be based on the percent change in the 
number of days with all seizures per 28 days, calculated as described in Section 8.3.1.1. A 75% 
responder is defined as a subject experiencing ≥75% reduction in the number of days with all 
seizures per 28 days from Prospective Baseline Period to the period of interest, for the subjects 
reporting any seizures during the Prospective Baseline Period. 
Section 8.3.1.5 Variable seizure-free status: 
For years 1-2, the following definitions will be used: 
For all seizure types, any missing day in the seizure diary during years 1-2 renders a subject to be 
not seizure-free due to the lack of information. 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary and seizures were assessed (ie, “no seizures” is marked or number is entered as 
zero). Days in the seizure diary which are marked as “not done” on the CRF will be counted as a 
seizure-free day from PGTCS.  
PGTCS free status will be determined for a particular time period. A subject will have seizure-
free status from PGTCS for the time period if the subject completed the time period and reported 
only a combination of “no PGTC seizures” or “not done” for all days during the time period. If 1 
or more PGTCS are reported in the time period or if the seizure data is missing, then the subject 
does not have PGTCS free status=Yes for the time period. 
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary and seizures were assessed. An 
absence or myoclonic subject will be considered for seizure-free evaluation for generalized 
seizure-free status in years 1-2 for the applicable time period if the subject had <10% of days 
during the time period with seizure data reported as “not done”. If 1 or more seizure type=II 
seizures are reported in the time period, if there is missing data or if there are 10% or more “Not 
done” days for an absence and/or myoclonic seizure subject, then the subject does not have 
generalized seizure-free status=Yes for the time period. 
For years 3-5, the following definitions will be used: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary. 
Seizure-free status from PGTCS will be determined for a particular time period. A subject will 
have seizure-free status from PGTCS for the time period if the subject completed the time period 
and no PGTCS were reported during the time period. If 1 or more PGTCS are reported in the 
time period, then the subject does not have PGTC seizure-free status=Yes for the time period. 
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A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
A subject will have seizure-free status from all generalized seizure types for the applicable time 
period if the subject completed the time period and reported zero seizure type=II seizures during 
the time period. If 1 or more seizure type=II seizures are reported in the time period, then the 
subject does not have generalized seizure-free status=Yes for the time period. 
Has been revised to: 
For all seizure types and all subjects, any missing or Not Done day in the seizure diary renders a 
subject to be not seizure-free on that day due to the lack of information. 
Section 8.3.1.7.1 Variable: PGTCS free status is new: 
A seizure-free day from PGTCS will be defined as a day where no PGTCS were reported in the 
seizure diary and seizures were assessed (ie, “no seizures” is marked or number is entered as 
zero). Days in the seizure diary which are marked as “not done” on the CRF will not be counted 
as a seizure-free day from PGTCS.  A subject with a >3 day LCM gap within the period of 
interest will not be PGTCS-free for that period. 
PGTCS free status will be summarized by completer cohort on the FAS. A subject will have 
seizure-free status from PGTCS for a completer cohort if the subject are in the completer cohort 
and reported only “no PGTC seizures” for all days during the completer cohort period. If 1 or 
more PGTCS are reported in the completer cohort or if the seizure data is Not Done, then the 
subject has PGTCS free status=No for the completer cohort. 
Section 8.3.1.7.2 Variable: Generalized seizure-free status is new: 
If missing data is reported, then the subject is not seizure-free from generalized seizures for those 
missing days.  
A seizure-free day from generalized seizures will be defined as a day where no generalized 
seizures (seizure type=II) were reported in the seizure diary. 
A subject will have seizure-free status from all generalized seizure types for the applicable time 
period if the subject completed the time period and reported zero seizure type=II seizures and no 
“Not Done” days during the time period for the SS. If 1 or more seizure type=II seizures are 
reported or if there are “Not Done” seizure diary days in the time period, then the subject has 
generalized seizure-free status=No for the time period. 
Section 8.3.1.8 Variables: all seizure-free status is new: 
A seizure-free day from all seizures will be defined as a day where no seizures (seizure type=I, II 
or III) were reported in the seizure diary. 
A subject will have seizure-free status from all seizure types for the applicable time period if the 
subject completed the time period and reported zero seizures, with no “Not Done” days, during 
the time period for the SS. If 1 or more seizures are reported or if there are “Not Done” seizure 
diary days in the time period, then the subject has all seizure-free status=No for the time period. 
Section 8.3.1.9 Variable: Worsening of PGTCS: 
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Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.2.1. Seizure worsening is defined as a subject experiencing ≥50% increase 
in PGTCS frequency per 28 days from Combined Baseline Period to the period of interest. 
Has been revised to: 
Response to treatment will be based on the percent change in PGTCS frequency, calculated as 
described in Section 8.2.1 on the FAS. PGTCS worsening is defined as a subject experiencing 
≥50% increase in PGTCS frequency per 28 days from Combined Baseline Period to the period of 
interest. 
Section 8.3.1.10 Variable: Worsening of days with absence seizures: 
Response to treatment will be based on the percent change in days with absence seizures per 28 
days, as calculated in Section 8.3.1.1. Worsening is defined as a subject experiencing ≥50% 
increase in days with absence seizures per 28 days from Prospective Baseline Period to the 
period of interest, for the subjects reporting absence seizures during the Prospective Baseline 
Period from SP0982. 
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% to the period of interest, for the 
subjects reporting absence seizures during the Prospective Baseline Period from SP0982. 
Has been revised to: 
Response to treatment will be based on the percent change in days with absence seizures per 28 
days on the Absence subpopulation, as calculated in Section 8.3.1.1 on the SS. Worsening is 
defined as a subject experiencing ≥50% increase in days with absence seizures per 28 days from 
Prospective Baseline Period to the period of interest, for the subjects reporting absence seizures 
during the Prospective Baseline Period. 
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% to the period of interest, for the 
subjects reporting absence seizures during the Prospective Baseline Period. 
Section 8.3.1.12 Worsening of days with generalized seizures is new: 
Response to treatment will be based on the percent change in days with generalized seizures per 
28 days, as calculated in Section 8.3.1.1 on the SS. Worsening is defined as a subject 
experiencing ≥50% increase in days with generalized seizures per 28 days from Prospective 
Baseline Period to the period of interest, for the subjects reporting generalized seizures during 
the Prospective Baseline Period. 
Section 8.3.1.13 Worsening of days with all seizures is new: 
Response to treatment will be based on the percent change in days with all seizures per 28 days, 
as calculated in Section 8.3.1.1 on the SS. Worsening is defined as a subject experiencing ≥50% 
increase in days with all seizures per 28 days from Prospective Baseline Period to the period of 
interest, for the subjects reporting all seizures during the Prospective Baseline Period. 
Section 8.3.1.14 PGTCS free intervals was added: 
PGTCS-free intervals will only be assessed for periods not containing >3 day LCM gap. If the 
>3 day LCM gap appears in the period of interest, the subject is not PGTCS-free for the interval. 
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For the FAS, subjects who are PGTCS-free from the date of Visit 1 will be identified as having a 
PGTCS-free interval from Visit 1.  The duration of the PGTCS-free interval will be calculated as 
date of last day of consecutive PGTCS freedom – date of Visit 1 +1. 
To determine the longest interval of PGTCS-freedom, all PGTCS-free intervals will be identified 
with a calculation of date of last day of PGTCS freedom for Nth interval – date of the first day of 
PGTCS freedom for the Nth interval + 1. The largest duration of all N intervals will be identified 
as the longest interval of PGTCS freedom. 
To determine the total duration of PGTCS-freedom, all N PGTCS-free intervals will be summed. 
Section 8.3.1.15 Generalized seizure free intervals was added: 
For the SS, subjects who are generalized seizure-free from the date of Visit 1 will be identified as 
having a generalized seizure-free interval from Visit 1.  The duration of the generalized seizure-
free interval will be calculated as date of last day of consecutive generalized seizure freedom – 
date of Visit 1 +1. 
To determine the longest interval of generalized seizure free, all generalized seizure-free 
intervals will be identified with a calculation of date of last day of consecutive generalized 
seizure freedom for Nth interval – date of the first day of generalized seizure freedom for the Nth 
interval + 1. The largest duration of all N intervals will be identified as the longest interval of 
generalized seizure freedom. 
To determine the total duration of generalized seizure freedom, all N generalized seizure-free 
intervals will be summed. 
Section 8.3.1.16 All seizure-free intervals was added: 
For the SS, subjects who are all seizure-free from the date of Visit 1 will be identified as having 
an all seizure-free interval from Visit 1.  The duration of the all seizure-free interval will be 
calculated as date of last day of consecutive all seizure freedom – date of Visit 1 +1. 
To determine the longest interval of all seizure free, all seizure-free intervals will be identified 
with a calculation of date of last day of consecutive all seizure freedom for Nth interval – date of 
the first day of all seizure freedom for the Nth interval + 1. The largest duration of all N intervals 
will be identified as the longest interval of all seizure freedom. 
To determine the total duration of all seizure freedom, all N all seizure-free intervals will be 
summed. 
Section 8.3.2.1 Analysis: Days with seizures per 28 days: 
The following data will be summarized on the SS with descriptive statistics only: 
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Baseline age in SP0982 and Completer Cohort  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Baseline Age in SP0982 and Time Period  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Completer Cohort  
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 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Baseline Age in SP0982 and Time Period 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Baseline age in SP0982 and Completer Cohort  
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Baseline Age in SP0982 and Time Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Baseline age in SP0982 and Completer Cohort. 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Baseline Age in SP0982 and Time Period 
All seizure days data for absence and myoclonic seizures will be listed. 
Was revised to: 
The following data will be summarized on the SS by all periods calculated for the Time Period 
or Completer Cohort with descriptive statistics only: 
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with absence seizures per 28 days relative to the Prospective Baseline Period 
by Age at Baseline in SP0982 and Time Period  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Percent change in days with absence seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with myoclonic seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Completer Cohort. 
 Percent change in days with myoclonic seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Time Period 
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort  
 Change in days with generalized seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Completer Cohort. 
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 Percent change in days with generalized seizures per 28 days relative to the Prospective 
Baseline Period by Age at Baseline in SP0982 and Time Period 
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period by 
Age at Baseline in SP0982 and Completer Cohort  
 Change in days with all seizures per 28 days relative to the Prospective Baseline Period by 
Age at Baseline in SP0982 and Time Period 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Completer Cohort. 
 Percent change in days with all seizures per 28 days relative to the Prospective Baseline 
Period by Age at Baseline in SP0982 and Time Period 
All seizure days data for absence, myoclonic, generalized and all seizures will be listed. 
Analyses of the absence seizure related variables will summarize the Absence subpopulation.  
Analyses of the myoclonic seizure related variables will summarize the Myoclonic 
subpopulation. 
Section 8.3.2.2 Analysis: Responder status – reduction in PGTCS frequency: 
The number and percentage of ≥50% and ≥75% responders will be summarized by Time Period 
and Treatment Period. 
Has been revised to: 
The number and percentage of ≥50% and ≥75% responders in PGTCS will be summarized on 
the FAS by Time Period and Treatment Period. 
Section 8.3.2.3 Responder status – reduction in days with absence seizures was updated to be on 
the Absence subpopulation 
Section 8.3.2.4 Responder status – reduction in days with myoclonic seizures was updated to be 
on the Myoclonic subpopulation 
Section 8.3.2.5 Responder status – reduction in days with generalized seizures was added: 
The number and percentage of ≥50% and ≥75% responders will be summarized on the SS by 
Time Period and Treatment Period. 
Section 8.3.2.6 Responder status – reduction in days with all seizures was added: 
The number and percentage of ≥50% and ≥75% responders will be summarized on the SS by 
Time Period and Treatment Period. 
Section 8.3.2.7 Seizure-free status: 
The number and percentage of subjects with seizure-free status (yes/no) will be summarized on 
the SS by Completer Cohort and Treatment Period for the following types of seizures: 
 Seizure-free status (yes, no) for PGTCS  
 Seizure-free status (yes, no) for all generalized seizure types.  
Was revised to: 
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The number and percentage of subjects with seizure-free status (yes/no) will be summarized by 
Completer Cohort for the following types of seizures: 
 Seizure-free status (yes, no) for PGTCS on the FAS 
 Seizure-free status (yes, no) for all generalized seizure types on the SS 
 Seizure-free status (yes, no) for all seizure types on the SS. 
Section 8.3.2.7.1 PGTCS free intervals was added: 
The duration of the following PGTCS-free intervals during the Treatment Period on the FAS will 
be summarized with descriptive statistics: 
 1st PGTCS free interval from Visit 1 
 Longest PGTCS-free interval 
 All PGTCS-free intervals 
Section 8.3.2.7.2 Generalized seizure-free intervals was added: 
The duration of the following generalized seizure-free intervals during the Treatment period will 
be summarized with descriptive statistics:  
 1st generalized seizure- free interval from Visit 1 
 Longest generalized seizure-free interval 
 All generalized seizure-free intervals 
 Section 8.3.2.7.3 All seizure-free intervals was added: 
The duration of the following all seizure-free intervals during the Treatment period on the SS 
will be summarized with descriptive statistics:  
 1st all seizure-free interval from Visit 1 
 Longest all seizure-free interval 
 All seizure-free intervals 
Section 8.3.2.8 Analysis: PGTCS worsening was updated to be on the FAS. 
Section 8.3.2.9 Worsening in days with absence seizures was updated to be on the Absence 
subpopulation 
Section 8.3.2.10 Worsening in days with myoclonic seizures was updated to be on the Myoclonic 
subpopulation 
Section 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 
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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 
Was revised to: 
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. Only 
whole year ages are used. 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 PedsQL Measurement Model includes 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. For each subject, the same version that is used at 
Baseline should be used for 12 months and thereafter the appropriate age versions should be 
used. 
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. For 
versions intended for subjects >8 years of age, Physical Functioning refers to questions 
 
 Emotional Functioning refers to questions 
 Social 
Functioning refers to questions 
 School Functioning refers to 
questions 
 
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. 
Item transformed score = 100 – (item raw score x 25) 
Each PedsQL scale or dimension score is then calculated as the mean of the transformed item 
scores from items of the considered dimension. In the case of item-level missing data, these will 
be replaced by the average of non-missing item scores from the considered dimension, if at least 
50% of the items from that dimension are non-missing. 
The above algorithm will also be used to calculate the PedsQL total score (all items), the 
psychosocial health summary score (a combination of the emotional, social and school 
functioning items), and the physical health summary score (the physical functioning items) for 
each subject. These summary scores will be missing if any of the scale scores contributing to 
their calculation is missing. 
Section 10 Safety analyses was updated with: 
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Any data that appears in the database (in UCB Findings, Clinical Events, or Findings About) and 
is not covered by the sections below, will be listed. 
Section 10.1.1 Derivation of exposure variables, the following was added: 
For pediatric subjects who take both LCM formulations, their tablet dosing in mg/day will be 
converted to mg/kg/day by dividing the total daily dose in mg/day by the most recently available 
(relative to the dosing date) body weight in kg. Should a subject receive both oral solution and an 
oral tablet on the same day, then the individual tablet dose in mg is converted to mg/kg by 
dividing by the most recently available (relative to the dosing date) body weight, and then the 
individual dose of oral solution in mg/kg is added to the tablet dose in mg/kg to obtain a total 
daily dose in mg/kg/day. 
Section 10.1.2 Analysis of exposure variables, the following was added: 
Pediatric subjects with oral solution (mg/kg/day) and tablet (mg/day) dosing will be summarized 
two ways: raw (mg/kg/day and mg/day) and converted (mg/kg/day only).   
Section 10.2 Adverse events, the following listing was added: 
 Subjects experiencing adverse events leading to death on the ES 
Section 10.3 Clinical laboratory evaluations, this first paragraph was added: 
Clinical laboratory parameters are used in analyses if more than two subjects per visit have a 
result.  All clinical laboratory data appear in listings 
Section 10.3 Clinical laboratory evaluations: 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria will also be presented. 
was revised to: 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria during the Treatment Period will also be presented. 
 Section 10.4.2.2 Analysis of ECG parameters: 
For quantitative ECG measurements (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
statistics of the actual values and change from Baseline (where Baseline is from SP0982 as 
defined in Section 0) will be summarized  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. 
Was revised to: 
For quantitative ECG measurements (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and corrected QT intervals using Bazett and Fridiricia correction methods), summary 
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statistics of the actual values and change from Baseline (where Baseline is from SP0982 as 
defined in Section 0) will be summarized  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 and average value are listed. A subject can be summarized in multiple minimum 
and maximum post-Baseline categories if the subject appears in multiple age categories (eg, 
Pediatric subjects) for the continuous data. 
Section 10.4.6 Assessment of suicidality: 
Subject data listings of the data for the C-SSRS will be provided. No summaries of the C-SSRS 
data are planned. 
Was changed to: 
Subject data listings of the data for the C-SSRS where questions 4 or 5 was answered ‘Yes’ will 
be provided. No summaries of the C-SSRS data are planned. 
Section 10.4.7.2 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 
problems, somatic complaints, and withdrawn) will be summarized for each visit, and Last Visit. 
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. 
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. 
Was changed to: 
Only the syndrome scales presented in Tables 1 and 2 will be analyzed.  Raw scores and change 
from Baseline for each CBCL/1 ½ -5 syndrome (aggressive behavior, anxious/depressed, 
attention problems, emotionally reactive, other problems, sleep problems, somatic complaints, 
and withdrawn) will be summarized for each visit, and Last Visit.  
Raw scores 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. 
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 
problems, somatic complaints, and withdrawn) will be summarized for each visit, and Last Visit. 
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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. 
Subject data listings of the data for the Achenbach CBCL will be provided containing the 
calculated T-scores, raw scores and change from Baseline. The means of the calculated T-score 
will be plotted by visit. 
Section 10.4.8.1 BRIEF-P Scores: 
The 2-subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 3. 
 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and sex. 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. 
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All BRIEF-P assessment data will be listed. The means of the BRIEF-P assessment data will be 
plotted by visit. 
Was revised to: 
The 3-subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 3. 
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 
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 sex. 
Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P 
Professional Manual and will be reproduced programmatically. 
Calculated T-score values and change from Baseline for the three index scores (Inhibitory self-
control, flexibility and emergent metacognition), the 5 individual component scores and GEC for 
the BRIEF-P questionnaire will be summarized at each visit, and Last Visit. 
All BRIEF-P assessment data will be listed including calculated T-scores, raw scores and 
changes from Baseline. The means of the BRIEF-P assessment data will be plotted by visit. 
Section 10.4.8.2 BRIEF scores, after Table 4: 
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 sex. 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. 
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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. 
All BRIEF assessment data will be listed. The means of the BRIEF assessment data will be 
plotted. 
Was revised to: 
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. 
T-score values and change from Baseline for the two indexed scores (BRI and MI), the GEC and 
the 8 individual component scores for the BRIEF questionnaire will be summarized at each visit, 
and Last Visit. 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and sex. Tables that map each raw score to the appropriate T-
score are provided in the BRIEF Professional Manual and will be reproduced programmatically. 
All BRIEF assessment data will be listed including all scales/index scores (raw and T-scores, 
calculated and change from baseline). The means of the BRIEF assessment data will be plotted. 
Section 10.4.9 Safety Seizure Information was updated with: 
All analyses will use the relevant data in the SS.  The analyses regarding Absence seizure 
information will be generated on the Absence subpopulation. The analyses regarding the 
Myoclonic seizure information will be generated on the Myoclonic subpopulation. 
Section 11.2.1 List of other significant AEs, the following were added: 
Cardiac arrest 
Brugada syndrome 
Defect conduction intraventricular 
Electrocardiogram QT prolonged 
Section 11.2.2 List of AEs for PDILI, the following were added: 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Section 11.4 Appendix 4: NCI CTC, the following footnote was added: 
** Fasting status will be ignored when programming this criteria. 
Section 11.5 Appendix 5: Tables required for Article 41, 46 and clinicaltrials.gov: 
Disposition and Discontinuation Reasons by Development 
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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 
Increase in Days with Absence Seizures During the Treatment Period Compared to Prospective 
Baseline by Development  
 Increase in Days with Myoclonic Seizures During the Treatment Period Compared to 
Prospective Baseline 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 
 
Tables in this section are not referred to in the body of the SAP.  Tables summarizing 
Development may show columns for Pediatrics and Adults where Pediatrics are the subjects in 
EP0012 aged 17 or less and Adults are the subjects in EP0012 aged 18 or more or the table may 
be generated by Pediatrics and Adults. 
Was revised to Section 11.5 Appendix 5: Tables required for Article 41 (EudraCT): 
Discontinuation due to AEs by Development 
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12.4 
Amendment 4 
12.4.1 
Rationale for the amendment 
SAP Amendment 4 was issued because  
 Because EP0012 directly enrolled subjects as well as those who rolled over from SP0982, 
the handling of their data for analysis needed to be clarified and 
 A few other analysis items were clarified. 
12.4.2 
Modification and changes 
12.4.2.1 
Specific changes 
The information below was revised from  
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
SAP Amendment #3 
15 Nov 2021 
Has been revised to: 
SAP/Amendment Number Date 
Final SAP 
20 Dec 2016 
SAP Amendment #1 
10 Dec 2018 
SAP Amendment #2 
10 Oct 2019 
SAP Amendment #3 
15 Nov 2021 
SAP Amendment #4 
09 Sep 2022 
Section 2.3, Study design and conduct, the following: 
 Subjects that enrolled in EP0012 that did not fall into the above categories 
Was updated to: 
 Subjects that enrolled in EP0012 that did not fall into the above categories, like those who 
were incomplete screeners 
The following sentence from the protocol text: 
Eligible Baseline failures from SP0982 who choose to enter this study will undergo a complete 
Visit 1.   
Was updated to: 
Eligible Baseline failures and incomplete screeners from SP0982 who choose to enter this study 
will undergo a complete Visit 1. 
Section 2.3.1 EP0012 entry status was added: 
Subjects who enter EP0012 are either rollovers from SP0982 or direct enrollers in EP0012. 
Section 2.3.1.1 Rollover subjects was added: 
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The subjects enrolled in EP0012 who were randomized in SP0982 and entered EP0012 after 
discontinuation or completion of SP0982. All study data captured in EP0012 prior to the Safety 
Follow-up period will be summarized as on-treatment (or during the treatment period) for these 
subjects, even if the procedure was done before the 1st dose of EP0012 study medication. 
Section 2.3.1.2 Direct enrollers was added: 
The subjects enrolled in EP0012 who were baseline failures or incomplete screeners in SP0982 
who were never randomized to take SP0982 study medication. 
Section 2.3.2 Protocol visit windows was added: 
Protocol visit windows are ±7 days. 
Section 3.2.1.1, Treatment period definition: 
The following analysis periods are defined: 
 Treatment Period (this analysis Treatment Period differs from the protocol-defined treatment 
period): The Treatment Period starts at the time of first dose of study medication during the 
EP0012 study and ends on the date of last dose of study medication or the date of ET Visit or 
Termination Visit, whichever is later. The Treatment Period includes the protocol-defined 
Taper Period (see Section 3.2.2) if the subject completes it. In essence, the Treatment Period 
contains all data between the dates when the subject is being treated with study medication. 
 An efficacy analysis Treatment Period must be calculated for the PGTCS-related 
analyses. This time period starts at the time of first dose of study medication during the 
EP0012 study and ends on the date of last dose of study medication. 
Was modified to: 
The following analysis periods are defined: 
 Treatment Period (this analysis Treatment Period differs from the protocol-defined treatment 
period): The Treatment Period, which will apply to all non-efficacy analyses, starts at the 
time of first dose of study medication during the EP0012 study for the direct enrollers (date 
of first visit for rollover subjects) and ends on the date of last dose of study medication or the 
date of last protocol-defined visit before SFU visit or death date, whichever is later. The 
Treatment Period includes the protocol-defined Taper Period (see Section 3.2.2) if the subject 
completes it. 
 An efficacy analysis Treatment Period must be calculated for the PGTCS-related 
analyses. This time period starts at the time of first dose of study medication during the 
EP0012 study (date of first visit for rollover subjects) and ends on the date of last dose of 
study medication or death date, whichever is later. 
Section 3.2.1.2 Relative day: 
Relative day will be calculated as the current date minus the date of first dose of study 
medication in EP0012 plus 1 for days on or after the day of first dose of study medication and 
prior to or on the day of last study medication dose (eg, the day of first dose will be Day 1). 
Relative day will be calculated as date of first dose of study medication in EP0012 minus the 
current date for days prior to the first dose of study medication (the day prior to first dose will be 
Day -1). For days after the last dose of study medication, relative day will be calculated as the 
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current date minus the date of last dose of study medication including a “+” to denote post 
treatment days (eg, the day after the last dose will be Day +1). Relative day will not be calculated 
for partial dates. 
Was modified to: 
Relative day will be calculated as the current date minus the date of first dose of study 
medication in EP0012 for direct enrollers (first visit date for rollover subjects) plus 1 for days on 
or after the day of first dose of study medication and prior to or on the day of last study 
medication dose (eg, the day of first dose or first visit will be Day 1). Relative day will be 
calculated as date of first dose of study medication for direct enrollers or first visit for rollovers 
in EP0012 minus the current date for days prior to the first dose of study medication (the day 
prior to first dose or first visit will be Day -1). For days after the last dose of study medication, 
relative day will be calculated as the current date minus the date of last dose of study medication 
including a “+” to denote post treatment days (eg, the day after the last dose will be Day +1). 
Relative day will not be calculated for partial dates. 
Section 3.2.1.5 Completer cohort: 
A completer cohort will be defined as the subset of subjects in the FAS that were enrolled, 
treated with LCM for the specified duration of time (allowing gaps of 3 days or less), and have 
efficacy data available for the duration of the treatment exposure stated in the name of the 
cohort. For example, a 22-week completer cohort consists of subjects from the FAS, treated with 
LCM for at least 22 weeks and have efficacy data through at least 22 weeks of exposure (Visit 
5). 
Was revised to: 
A completer cohort will be defined as the subset of subjects in the FAS that were enrolled, 
treated with LCM for the specified duration of time (allowing gaps of 3 days or less), and have 
efficacy data available for the duration of the treatment exposure stated in the name of the cohort 
minus the visit window (7 days). For example, a 22-week completer cohort consists of subjects 
from the FAS, treated with LCM for at least 22 weeks minus 7 days and have efficacy data 
through at least 22 weeks minus 7 days of exposure (Visit 5 or ET visit). 
Section 3.2.1.5.1 Use of ET or Termination Visit when Scheduled Visits are missing: 
An adult subject is considered a completer of EP0012 if Visit 11 (Week 94) or ET or 
Termination visit is completed instead of Visit 11 (and there are no other treatment visits 
completed) within the window stated below. Visit 11 or Week 94 was chosen as the visit where 
subjects could complete the study because it was the closest visit occurring to 2 years given the 6 
month visit schedule. Subjects also may be deemed completers of EP0012 when they leave the 
study due to LCM being approved in their region.  
If the visit that corresponds to the completer cohort is missing, then ET or Termination visit will 
be checked to see if this data can be used for the missing visit and to complete the data needed 
for the completer cohort. 
For assessing the 22 and 46 Week completer cohorts, respectively, assess whether the ET visit 
was completed instead of Visit 5 or Visit 8, respectively; the Termination visit may not be an 
option for some subjects for the 22 Week or 46 Week Completer cohorts since subjects can only 
complete the study after 2 years or approval in their region. 
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Since subjects can complete EP0012 at Week 94 for the 94 Week completer cohort (and for later 
completer cohorts), if the Week 94 (Visit 11) is missing, then assess whether the Termination or 
ET visit was completed instead of Visit 11.     
The assessment of using Termination or ET visit to determine whether a subject completes a 
cohort occurs when the subject is missing visit for XX Week Completer Cohort (Week 22 – Visit 
5, Week 46 – Visit 8, Week 94 – Visit 11, Week 142 – Visit 13, Week 190 - Visit 15, and Week 
238 – Visit 17) and there are no other later protocol-scheduled visits indicating the subject was 
exposed longer in the study.  Review the Protocol’s Schedule of Study Assessments to determine 
the number of weeks (and calculate the expected date) from the prior visit that the Termination 
or ET visit is expected.  The Termination or ET visit must not be any more than 7 days earlier 
than expected date for XX Week Completer Cohort, as protocol visit windows are ±7 days; if the 
ET or Termination visit date is too early, the subject did not complete enough exposure to be 
included in XX Week Completer Cohort. 
Was revised to: 
A subject is considered a completer of EP0012 if Visit 11 (Week 94 = 658 days minus 7 days) or 
ET or Termination visit is completed instead of Visit 11. Visit 11 or Week 94 was chosen as the 
visit where subjects could complete the study because it was the closest visit occurring to 2 years 
given the 6 month visit schedule. Subjects also may be deemed completers of EP0012 when they 
leave the study due to LCM being approved in their region.  
If the visit that corresponds to the completer cohort is missing, then ET or Termination visit will 
be checked to see if this data can be used for the missing visit and to complete the data needed 
for the completer cohort. 
For assessing the 22 and 46 Week completer cohorts, respectively, assess whether the ET visit 
was completed instead of Visit 5 (minus 7 days) or Visit 8 (minus 7 days), respectively; the 
Termination visit may not be an option for some subjects for the 22 Week or 46 Week Completer 
cohorts since subjects can only complete the study after 2 years or approval in their region. 
Since subjects can complete EP0012 at Week 94 (minus 7 days) for the 94 Week completer 
cohort (and for later completer cohorts), if the Week 94 (Visit 11) is missing, then assess whether 
the Termination or ET visit was completed instead of Visit 11.     
The assessment of using Termination or ET visit to determine whether a subject completes a 
cohort occurs when the subject is missing visit for XX Week Completer Cohort (Week 22 – Visit 
5(minus 7 days), Week 46 – Visit 8 (minus 7 days), Week 94 – Visit 11 (minus 7 days), Week 
142 – Visit 13 (minus 7 days), Week 190 - Visit 15 (minus 7 days), and Week 238 – Visit 17 
(minus 7 days)) and there are no other later protocol-scheduled visits indicating the subject was 
exposed longer in the study.  Review the Protocol’s Schedule of Study Assessments to determine 
the number of weeks (and calculate the expected date) from the prior visit that the Termination 
or ET visit is expected.  The Termination or ET visit must not be any more than 7 days earlier 
than expected date for XX Week Completer Cohort, as protocol visit windows are ±7 days; if the 
ET or Termination visit date is too early, the subject did not complete enough exposure to be 
included in XX Week Completer Cohort. 
Section 3.2.1.6 Time Period, 3rd paragraph: 
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The time periods for the Treatment Period include all data in the time window of the time period 
of interest including termination, early termination and end of taper visit data. A calculation will 
be needed using dates to determine what time period the termination, early termination and end 
of taper visit data fit into for each subject. While completer cohorts and their time periods 
involve subjects having data for the entire cohort or time period, when it comes to non-completer 
cohort tables, subjects may not have data for the whole Treatment period or time period within 
the Treatment period. 
Was revised to: 
The time periods for the Treatment Period include all data in the time window of the time period 
of interest including termination, early termination and end of taper visit data, taking into 
account the 7 day visit window. A calculation will be needed using dates to determine what time 
period the termination, early termination and end of taper visit data fit into for each subject, 
adjusting for the 7 day visit window. While completer cohorts and their time periods involve 
subjects having data for the entire cohort or time period, when it comes to non-completer cohort 
tables, subjects may not have data for the whole Treatment period or time period within the 
Treatment period. 
Section 3.2.2 Protocol defined study periods, Taper Period: 
up to 4-week period following the Treatment Period for subjects who discontinue from the study 
at any time.  The Taper Period starts the day after the Treatment Period ends and continues until 
the date of last dose of study medication. 
Was revised to: 
up to 4-week period following the Treatment Period for subjects who discontinue from the study 
at any time.  The Taper Period starts the day after the Treatment Period ends and continues until 
the date of last dose of study medication or the End of Taper Visit. 
Section 3.2.2 Protocol defined study periods, Safety Follow-up Period: 
30-day period following the Taper Period. The Safety Follow-up Period starts the day after the 
last dose of study medication and continues until the Safety Follow-up telephone contact date. 
Was revised to: 
30-day period following the Taper Period. The Safety Follow-up Period starts the day after the 
last dose of study medication or End of Taper Visit and continues until the Safety Follow-up 
telephone contact date. 
Section 3.2.4 AEDs and benzodiazepines: 
Concomitant AEDs at Study entry, concomitant benzodiazepine use at SP0982 entry, and 
Lifetime AEDs and Benzodiazepines for subjects randomized in SP0982 are already calculated 
and carried forward into EP0012. These variables will be summarized. 
For EP0012 direct enrollers, concomitant AEDs at study entry are defined as AEDs where the 
start date is on or before 28 days prior to EP0012 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 EP0012 (direct enrollers) Visit 1; ongoing AEDs are not counted 
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as a lifetime AED. Concomitant benzodiazepine use at EP0012 entry is the use of any 
benzodiazepine at EP0012 Visit 1. 
Was revised to: 
Concomitant AEDs at SP0982 entry, concomitant benzodiazepine use at SP0982 entry, and 
Lifetime AEDs and Benzodiazepines for the rollover subjects are already calculated and carried 
forward into EP0012.  
For EP0012 direct enrollers, concomitant AEDs at study entry are defined as AEDs where the 
start date is on or before 28 days prior to EP0012 Visit 1 and the medication was still ongoing on 
the date of Visit 1. The concomitant AEDs for the rollover and direct enroller subjects will be 
presented as Concomitant AEDs at the start of study medication dosing. 
Lifetime AEDs are defined as AEDs taken in the subject’s history and stopped at least 28 days 
prior to EP0012 (direct enrollers) Visit 1; ongoing AEDs are not counted as a lifetime AED. The 
lifetime AEDs for direct enrollers and rollover subjects will be presented as Lifetime AEDs and 
Benzodiazepines prior to start of study medication dosing  
Concomitant benzodiazepine use at EP0012 entry is the use of any benzodiazepine at EP0012 
Visit 1. The concomitant benzodiazepine use for direct enrollers and rollover subjects will be 
presented as Concomitant benzodiazepine use at the start of study medication dosing. 
Section 3.3 Baseline values, 1st paragraph: 
The baseline data for randomized SP0982 subjects in EP0012 will not recalculated. For subjects 
who directly enrolled into EP0012, some baseline variables may be calculated in SP0982 but 
these calculations need to be reassessed as detailed below. 
Was revised to: 
The baseline data for rollover subjects in EP0012 will not recalculated. For subjects who are 
direct enrollers, some baseline variables may be calculated in SP0982 but these calculations need 
to be reassessed as detailed below. 
Section 3.3 Baseline values, 4th paragraph: 
For absence, myoclonic, generalized and all seizure data, the Prospective Baseline Period is 
defined as the 4-week Prospective Baseline Period from the SP0982 study. This Period starts the 
date of Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 study. This 
means that for the subjects who directly enrolled into EP0012 (were not randomized in SP0982), 
the baseline absence, myoclonic, generalized or all (respectively) seizure data from SP0982’s 
Prospective Baseline period is combined with any reported baseline absence, myoclonic, 
generalized or all (respectively) seizure information from EP0012 (reported before first dose in 
EP0012) to recalculate the subject’s baseline variables such as days with absence, myoclonic, 
generalized or all seizures per 28 days. 
Was revised to: 
For absence, myoclonic, generalized and all seizure data, the Prospective Baseline Period is 
defined as the 4-week Prospective Baseline Period from the SP0982 study. This Period starts the 
date of Visit 1 of the SP0982 study and ends the day before Visit 2 of the SP0982 study. This 
means that for the subjects who directly enrolled into EP0012 (were not randomized in SP0982), 
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the baseline absence, myoclonic, generalized or all (respectively) seizure data from SP0982’s 
Prospective Baseline period is combined with any reported baseline absence, myoclonic, 
generalized or all (respectively) seizure information in the daily seizure diary from EP0012 
(reported before first dose in EP0012) to recalculate the subject’s baseline variables such as days 
with absence, myoclonic, generalized or all seizures per 28 days. 
Section 3.3 Baseline values, 6th paragraph: 
For all other data, Baseline values are defined as follows; 
 For Baseline failures from SP0982, data collected at Visit 1 prior to the first dose of study 
medication 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 data not collected at Visit 1 but 
still prior to the first dose of study medication, the last data collected in SP0982 will be used 
as Baseline values, if available.  
 For non-Baseline failures from SP0982, the last non-missing value prior to the first dose of 
study medication in the SP0982 study will be used as the Baseline value. 
For quantitative ECG assessments, if repeat measurements pre-first dose, then the average value 
is used as the Baseline value. 
Was revised to: 
For all other data, Baseline values are defined as follows; 
 For direct enrollers from SP0982, data collected at Visit 1 prior to the first dose of study 
medication 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 data not collected at Visit 1 but 
still prior to the first dose of study medication, the last data collected in SP0982 will be used 
as Baseline values, if available.  
 For rollover subjects from SP0982, the last non-missing value prior to the first dose of study 
medication in the SP0982 study will be used as the Baseline value.  
For quantitative ECG assessments, if repeat measurements pre-first dose, then the average value 
is used as the Baseline value. 
For direct enrollers, data that is used as the Baseline will be labelled as such.  In general, change 
from baseline for these subjects will be calculated from Visit 2 onward, if the subject has a 
calculated baseline. 
For rollover subjects, change from baseline for these subjects will be calculated from Visit 1 
onward, if the subject has a baseline calculation from SP0982. 
Section 3.6, paragraphs 2 and 3: 
At Visit 1, subjects who completed SP0982 will start on a dose of LCM as follows; 
 10mg/kg/day for pediatric subjects weighing <30kg,  
 8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg,  
 400mg/day (200mg twice a day (bid)) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg.   
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Subjects who are eligible Baseline failures from SP0982 will start at Visit 1 on a dose of LCM as 
follows; 
Were revised to: 
At Visit 1, rollover subjects will start on a dose of LCM as follows; 
 10mg/kg/day for pediatric subjects weighing <30kg,  
 8mg/kg/day for pediatric subjects weighing ≥30kg to <50kg,  
 400mg/day (200mg twice a day (bid)) for adult subjects (≥18 years of age) or pediatric 
subjects weighing ≥50kg.   
Subjects who are direct enrollers into EP0012 will start at Visit 1 on a dose of LCM as follows; 
Section 4.2 Handling of dropouts or missing data: 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who transitioned from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data not reported for V1 in EP0012. 
• 
for subjects who are baseline failures or incomplete screen failures in SP0982 who enrolled 
in EP0012, baseline data will be used from EP0012 V1 or unscheduled V1 (if prior to first 
EP0012 dose) or the latest data from the screening and baseline visits in SP0982 can be used 
(also if prior to first EP0012 dose). 
Was revised to: 
For subjects missing data at the first visit in EP0012, data from SP0982 will be checked as 
follow:  
• 
for subjects who are rollovers from SP0982 to EP0012, final clinic visit data in SP0982 will 
be checked for data expected and not reported for V1 in EP0012. 
• 
for subjects who are direct enrollers in EP0012, baseline data will be used from EP0012 V1 
or any unscheduled visit (if prior to first EP0012 dose) or the latest data from the screening and 
baseline visits in SP0982 can be used (also if prior to first EP0012 dose). 
Section 4.2.1.1 Week 94 visit – seizure data was added: 
At Week 94, subjects switch from using daily seizure diaries (where every date is entered) to 
using a seizure log (where only non-zero seizures are logged by date).  For subjects who 
continue past Week 94 in the study, if the date of the Week 94 visit is not logged on the daily 
seizure diary with a non-zero seizure count and it does not appear on the seizure log with a non-
zero count, then it can be assumed that 0 seizures occurred on that date. 
Section 4.2.3 Incomplete dates for adverse events and concomitant medications, 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 1st of the month. 
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 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 1 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. 
Was modified to: 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollovers is not the same as the month and year of the start date, 
then use the 1st of the month. 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollovers is the same as the month and year of the start, then use the 
date of first dose for direct enrollers or first visit for rollover subjects. 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is not the same as the year of the start date, then use January 1 of the year of 
the start date. 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is the same as the year of the start date, then use the date of first dose for 
direct enrollers or first visit for rollover subjects. 
 If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose for direct enrollers or first visit for rollover subjects, then use the date of first 
dose for direct enrollers or first visit for rollover subjects. 
Section 4.2.3 Incomplete dates for adverse events and concomitant medications, 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 1st 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 1 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 
Modified to: 
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 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollover subjects is not the same as the month and year of onset, 
then use the 1st of the month 
 If only the month and year are specified and the month and year of first dose for direct 
enrollers or first visit for rollover subjects is the same as the month and year of onset, then 
use the date of first dose for direct enrollers or first visit for rollover subjects 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is not the same as the year of onset, then use January 1 of the year of onset 
 If only the year is specified, and the year of first dose for direct enrollers or first visit for 
rollover subjects is the same as the year of onset, then use the date of first dose direct 
enrollers or first visit for rollover subjects 
 If the AE onset date is completely unknown, then use the date of first dose for direct enrollers 
or first visit for rollover subjects 
Section 5.1 Subject disposition, new 5th paragraph was added: 
To assess what happens with subjects during the first 94 weeks of the study, the number and 
percentage of subjects who completed this time period, completed the study before 94 weeks and 
discontinued during this time period will be presented for the SS and FAS by age at baseline in 
SP0982 as well as all subjects including number and percentages for each reason for 
discontinuation during this time period. 
Section 6.2.2 Analysis of other Baseline characteristics, paragraph 3: 
The following Baseline characteristics will be presented: 
 Time since first diagnosis at date of consent  – Time since first diagnosis calculated for all 
EP0012 subjects; this data is stored in SP0982 
 Age at diagnosis of the disease – age at diagnosis calculated for all EP0012 subjects; this data 
is stored in SP0982ILAE Seizure classification history  – see below 
 Classification of epileptic syndrome  – see below 
 Lifetime AEDs and Benzodiazepines (SP0982) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of randomized SP0982 subjects in EP0012; this data is stored 
in SP0982 
 Lifetime AEDs and Benzodiazepines (EP0012) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of all EP0012 subjects 
 Combined Baseline PGTCS frequency per 28 days (as continuous data) – baseline PGTCS 
seizure frequency from CRF of all EP0012 subjects; SP0982 IRT data is not used in EP0012. 
 Combined Baseline PGTCS frequency categories (≤2, >2 per 28 days)  – baseline PGTCS 
seizure frequency categorized from CRF of all EP0012 subjects 
 Concomitant AEDs at SP0982 entry (0, 1, 2, 3, 4) – categorical representation of concomitant 
AEDs of randomized SP0982 subjects in EP0012; this data is stored in SP0982 
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 Concomitant AEDs at EP0012 entry (0, 1, 2, 3, 4) – categorical representation of 
concomitant AEDs of all EP0012 subjects 
 Concomitant benzodiazepine use at SP0982 entry (yes, no, missing) – Yes/No to concomitant 
Benzo use of randomized SP0982 subjects in EP0012; this data is stored in SP0982  
 Concomitant benzodiazepine use at EP0012 entry (yes, no) – Yes/No to concomitant Benzo 
use of all EP0012 subjects 
 LCM study drug status  - continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982 or other) 
 SP0982 exit status  - Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation. 
ILAE Seizure Classification History (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information. 
Classification of Epileptic Syndromes (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information. 
Was revised to: 
The following Baseline characteristics will be presented: 
 Time since first diagnosis at date of consent  – Time since first diagnosis calculated for all 
EP0012 subjects; this data is stored in SP0982 
 Age at diagnosis of the disease – age at diagnosis calculated for all EP0012 subjects; this data 
is stored in SP0982ILAE Seizure classification history  – see below 
 Classification of epileptic syndrome  – see below 
 Lifetime AEDs and Benzodiazepines (EP0012) (0, 1-3, 4-6, 7+) – categorical representation 
of lifetime AEDs and Benzos of all EP0012 subjects 
 Combined Baseline PGTCS frequency per 28 days (as continuous data) – baseline PGTCS 
seizure frequency from CRF of all EP0012 subjects; SP0982 IRT data is not used in EP0012. 
 Combined Baseline PGTCS frequency categories (≤2, >2 per 28 days)  – baseline PGTCS 
seizure frequency categorized from CRF of all EP0012 subjects 
 Concomitant AEDs at EP0012 entry (0, 1, 2, 3, 4) – categorical representation of 
concomitant AEDs of all EP0012 subjects 
 Concomitant benzodiazepine use at EP0012 entry (yes, no) – Yes/No to concomitant Benzo 
use of all EP0012 subjects 
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 LCM study drug status  - continuing LCM treatment (randomized to LCM in SP0982), new 
LCM treatment (randomized to PBO or baseline failure from SP0982 or other) 
 SP0982 exit status  - Baseline failure, 24-week completer, met exit criteria, incomplete 
screener, SP0982 safety follow-up, SP0982 early discontinuation 
 EP0012 entry status – Direct enroller, rollover. 
ILAE Seizure Classification History (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized if it contains the same information as reported in 
SP0982; EP0012 and SP0982 information will be summarized if additional information is 
presented in either study. SP0982 information will be summarized if EP0012 contains no 
updated information. 
Classification of Epileptic Syndromes (SP0982 + EP0012): On a subject level, information 
reported in EP0012 will be summarized. SP0982 information will be summarized if EP0012 
contains no updated information. 
Section 6.3 Subgroups: 
All subgroups detailed in Section 4.8 will be summarized in a table for the SS and FAS.  
Subgroup information will also be listed. 
Was revised to: 
All subgroups detailed in Section 4.8 will be summarized in a table for the SS and FAS.  Other 
subgroups that will be summarized using SP0982 baseline information are: 
 Baseline age in SP0982 (4 to <12 years, 12 to < 18 years, 18 to < 65 years, ≥65 years) 
 Age for PedsQL (4 years, 5 to 7 years, 8 to 12 years, 13 to <18 years) 
 Age for Achenbach CBCL (4 to 5 years, 6 to 18 years) 
 Age for BRIEF-P/BRIEF (4 years, 5 to 18 years). 
Section 6.5 Prior and concomitant medications, 1st paragraph: 
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. 
Was revised to: 
Medications with a start date before the first dose of study medication for direct enrollers 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 taken by rollover subjects 
which are ongoing and concomitant in SP0982 will be considered concomitant in EP0012.  
Section 6.5, Prior and concomitant medications, 8th paragraph: 
The number of subjects withdrawing to Monotherapy during the Treatment Period will be 
identified.  Withdrawing to monotherapy means the subject has documentation that all 
background AEDs [except LCM] were discontinued during Treatment Period. A record for the 
discontinued background AEDs must be present in the concomitant AED data and study 
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medication must be taken continuously (>3 day gaps are not allowed). For the subjects who 
withdrew to monotherapy, the following results will be listed: 
 Treatment Duration 
 Monotherapy Start Date 
 Monotherapy End Date 
 Duration (days) of monotherapy 
 AEDs that were discontinued 
Was revised to: 
The number of subjects entering EP0012 on or withdrawing to Monotherapy during the 
Treatment Period will be identified.  Entering EP0012 on Monotherapy means the subject has no 
documented AEDs that are ongoing at first dose. Withdrawing to monotherapy means the subject 
has documentation that all background AEDs [except LCM] were discontinued during Treatment 
Period. A record for the discontinued background AEDs must be present in the concomitant 
AED data and study medication must be taken continuously (>3 day gaps are not allowed). For 
the subjects who withdrew to monotherapy, the following results will be listed: 
 Exposure 
 Monotherapy Start Date 
 Monotherapy End Date 
 Duration (days) of monotherapy 
 Concomitant AEDs that were discontinued 
Section 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. 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. 
Was revised to: 
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. If a subject has a baseline calculated for 
the 2-4 year old PedsQL, due to the difference in questionnaires, this baseline should not be used 
for calculating change from baseline for the older aged questionnaires. For the 5-7 year old, 8-12 
year old and 13-18 year old questionnaires, if the baseline was calculated from an younger aged 
questionnaire (except the 2-4 year old questionnaire) as the subject ages from 8 through 18 years 
old, change from baseline can use the younger aged baseline.   
Section 10.1.1 Derivation of exposure variables 
Study medication treatment duration (days) will be calculated as follows: 
(last study medication dose – first study medication dose) + 1 day.  
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Gaps in treatment or days with unknown dosing will not be subtracted from the duration of 
exposure. 
Subject-years of exposure is the total treatment duration in days divided by 365.25. 
Was modified to: 
Study medication treatment duration (days) will be calculated as follows for direct enrollers: 
(last study medication dose – first study medication dose) + 1 day.  
Study medication treatment duration (days) will be calculated as follows for rollover subjects: 
(last study medication dose – visit 1 date) + 1 day. 
Gaps in treatment or days with unknown dosing will not be subtracted from the duration of 
exposure. 
Subject-years of exposure is the total study medication treatment duration in days divided by 
365.25. 
Section 10.1.1 Derivation of exposure variable, 7th paragraph: 
For pediatric subjects who take both LCM formulations, their tablet dosing in mg/day will be 
converted to mg/kg/day by dividing the total daily dose in mg/day by the most recently available 
(relative to the dosing date) body weight in kg. Should a subject receive both oral solution and an 
oral tablet on the same day, then the individual tablet dose in mg is converted to mg/kg by 
dividing by the most recently available (relative to the dosing date) body weight, and then the 
individual dose of oral solution in mg/kg is added to the tablet dose in mg/kg to obtain a total 
daily dose in mg/kg/day. 
Was revised to: 
Because some pediatric subjects take both LCM formulations, dosing will be presented for all 
subjects within the formulation taken; this will be presented as raw dosing and some pediatric 
subjects will be summarized in both formulations. For pediatric subjects who take both LCM 
formulations, their tablet dosing in mg/day will be converted to mg/kg/day by dividing the total 
daily dose in mg/day by the most recently available (relative to the dosing date) body weight in 
kg; this will be presented as converted dosing and the summaries of subject data by formulation 
will be mutually exclusive. Should a subject receive both oral solution and an oral tablet on the 
same day, then the individual tablet dose in mg is converted to mg/kg by dividing by the most 
recently available (relative to the dosing date) body weight, and then the individual dose of oral 
solution in mg/kg is added to the tablet dose in mg/kg to obtain a total daily dose in mg/kg/day. 
Section 10.2 Adverse events, 2nd paragraph: 
Adverse events will be considered treatment-emergent if the event had onset on or after the date 
of the first study medication dose in EP0012 and within 30 days following the last study 
medication dose or 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. 
Was revised to: 
Adverse events will be considered treatment-emergent if the event had onset on or after the date 
of the first study medication dose in EP0012 and within 30 days following the last study 
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medication dose or 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. Adverse 
events which were ongoing and treatment-emergent in SP0982 will remain treatment-emergent 
in EP0012 for rollover subjects. 
Section 10.2 Adverse events, 8th paragraph: 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2. Adverse events of unknown dosing are those with no known dose or known 
dosing and partial AE start or stop dates. 
Was revised to: 
The dose at onset TEAE summaries will be presented by the LCM dosing categories presented in 
Section 10.1.2. Adverse events of unknown dosing are those with no known dose or known 
dosing and partial AE start or stop dates. TEAEs which were ongoing from SP0982 will be 
presented for the dose the subject was taking on the date of first dose in EP0012. 
Section 10.3 Clinical laboratory evaluations, 5th paragraph: 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
criteria during the Treatment Period will also be presented. 
Was revised to: 
A table summarizing the number of subjects meeting the potential drug induced liver injury 
(PDILI) criteria during the Treatment Period will also be presented. The categories for PDILI 
that will be presented are: 
 ≥3xULN in ALT Or AST and ≥2xULN total bilirubin and ≥2xULN of alkaline phosphatase 
 ≥3xULN in ALT Or AST and ≥2xULN total bilirubin 
 ≥5xULN in ALT or AST 
 ≥8xULN in ALT or AST 
 ≥3xULN in ALT or AST and the presence of symptoms 
 ≥3-<5xULN and baseline ≥2xULN in ALT or AST and <2xULN total bilirubin and no 
presence of symptoms 
 ≥5xULN and baseline ≥2xULN in ALT Or AST and <2xULN total bilirubin. 
Section 10.4.1 Vital signs, 2nd paragraph: 
The number and percentage of subjects with at least 1 TEMA value will be presented at each 
post-Baseline visit, Last Visit, Early Termination Visit and minimum and maximum post-
Baseline values obtained during the Treatment Period. Percentages will be relative to the number 
of subjects with a value at each time point. 
Was revised to: 
Treatment emergent abnormalities of vital signs, the criteria that do not involve a comparison to 
baseline, are those that were observed during the Treatment Period at scheduled visits and not 
reporting the abnormality during the Baseline Period. The number and percentage of subjects 
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with at least 1 TEMA value will be presented at each post-Baseline visit, Last Visit, Early 
Termination Visit and minimum and maximum post-Baseline values obtained during the 
Treatment Period. Percentages will be relative to the number of subjects with a value at each 
time point.  
Section 10.4.6 Assessment of suicidality, 2nd paragraph: 
Subject data listings of the data for the C-SSRS where questions 4 or 5 was answered ‘Yes’ will 
be provided. No summaries of the C-SSRS data are planned. 
Was revised to: 
Subject data listings of the data for the C-SSRS where questions 4 or 5 was answered ‘Yes’ will 
be provided since this is a study withdrawal criteria. No summaries of the C-SSRS data are 
planned. 
Section 10.4.7.2 Analysis of Achenbach variables, 2nd paragraph: 
Raw scores 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. 
Was revised to: 
Raw scores 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. If a subject has a baseline calculated for the CBCL/1 ½ -5 syndrome, that baseline 
should not be used for calculating change from baseline for the CBCL/6-18 syndrome. 
Section 10.4.8.2 BRIEF scores, 5th paragraph: 
T-score values and change from Baseline for the two indexed scores (BRI and MI), the GEC and 
the 8 individual component scores for the BRIEF questionnaire will be summarized at each visit, 
and Last Visit. 
Was revised to: 
T-score values and change from Baseline for the two indexed scores (BRI and MI), the GEC and 
the 8 individual component scores for the BRIEF questionnaire will be summarized at each visit, 
and Last Visit. If a subject has a baseline calculated for the BRIEF-P, that baseline should not be 
used for calculating change from baseline for the BRIEF. 
 
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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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